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Germline mutation in BRCA1 or BRCA2 and ten-year survival for women diagnosed with epithelial ovarian cancer.
Clin. Cancer Res.
PUBLISHED: 11-16-2014
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Purpose:To analyse the effect of germline mutations in BRCA1 and BRCA2 on mortality in ovarian cancer patients up to ten years after diagnosis. Experimental Design:We used unpublished survival time data for 2,242 patients from two case-control studies and extended survival-time data for 4,314 patients from previously reported studies. All participants had been screened for deleterious germline mutations in BRCA1 and BRCA2. Survival time was analysed for the combined data using Cox proportional hazard models with BRCA1 and BRCA2 as time-varying covariates. Competing risks were analysed using Fine and Gray model. Results: The combined 10-year overall survival was 30% (95% CI, 28%-31%) for non-carriers, 25% (95% CI, 22%-28%) for BRCA1 carriers, and 35% (95% CI, 30%-41%) for BRCA2 carriers. The hazard ratio for BRCA1 was 0.53 at time zero and increased over time becoming greater than one at 4.8 years. For BRCA2, the hazard ratio was 0.42 at time zero and increased over time (predicted to become greater than one at 10.5 years). The results were similar when restricted to 3,202 patients with high-grade serous tumors, and to ovarian cancer specific mortality. Conclusions: BRCA1/2 mutations are associated with better short-term survival, but this advantage decreases over time and, in BRCA1 carriers is eventually reversed. This may have important implications for therapy of both primary and relapsed disease and for analysis of long-term survival in clinical trials of new agents, particularly those that are effective in BRCA1/2 mutation carriers.
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Fine-mapping of the HNF1B multicancer locus identifies candidate variants that mediate endometrial cancer risk.
Jodie N Painter, Tracy A O'Mara, Jyotsna Batra, Timothy Cheng, Felicity A Lose, Joe Dennis, Kyriaki Michailidou, Jonathan P Tyrer, Shahana Ahmed, Kaltin Ferguson, Catherine S Healey, Susanne Kaufmann, Kristine M Hillman, Carina Walpole, Leire Moya, Pamela Pollock, Angela Jones, Kimberley Howarth, Lynn Martin, Maggie Gorman, Shirley Hodgson, , Ma Magdalena Echeverry de Polanco, Monica Sans, Angel Carracedo, Sergi Castellvi-Bel, Augusto Rojas-Martinez, Erika Santos, Manuel R Teixeira, Luis Carvajal-Carmona, Xiao-Ou Shu, Jirong Long, Wei Zheng, Yong-Bing Xiang, Grant W Montgomery, Penelope M Webb, Rodney J Scott, Mark McEvoy, John Attia, Elizabeth Holliday, Nicholas G Martin, Dale R Nyholt, Anjali K Henders, Peter A Fasching, Alexander Hein, Matthias W Beckmann, Stefan P Renner, Thilo Dörk, Peter Hillemanns, Matthias Dürst, Ingo Runnebaum, Diether Lambrechts, Lieve Coenegrachts, Stefanie Schrauwen, Frédéric Amant, Boris Winterhoff, Sean C Dowdy, Ellen L Goode, Attila Teoman, Helga B Salvesen, Jone Trovik, Tormund S Njolstad, Henrica M J Werner, Katie Ashton, Tony Proietto, Geoffrey Otton, Gerasimos Tzortzatos, Miriam Mints, Emma Tham, Per Hall, Kamila Czene, Jianjun Liu, Jingmei Li, John L Hopper, Melissa C Southey, Arif B Ekici, Matthias Ruebner, Nicola Johnson, Julian Peto, Barbara Burwinkel, Frederik Marme, Hermann Brenner, Aida K Dieffenbach, Alfons Meindl, Hiltrud Brauch, Annika Lindblom, Jeroen Depreeuw, Matthieu Moisse, Jenny Chang-Claude, Anja Rudolph, Fergus J Couch, Janet E Olson, Graham G Giles, Fiona Bruinsma, Julie M Cunningham, Brooke L Fridley, Anne-Lise Børresen-Dale, Vessela N Kristensen, Angela Cox, Anthony J Swerdlow, Nicholas Orr, Manjeet K Bolla, Qin Wang, Rachel Palmieri Weber, Zhihua Chen, Mitul Shah, Juliet D French, Paul D P Pharoah, Alison M Dunning, Ian Tomlinson, Douglas F Easton, Stacey L Edwards, Deborah J Thompson, Amanda B Spurdle.
Hum. Mol. Genet.
PUBLISHED: 11-08-2014
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Common variants in the hepatocyte nuclear factor 1 homeobox B (HNF1B) gene are associated with the risk of type II diabetes and multiple cancers. Evidence to date indicates that cancer risk may be mediated via genetic or epigenetic effects on HNF1B gene expression. We previously found single nucleotide polymorphisms (SNPs) at the HNF1B locus to be associated with endometrial cancer, and now report extensive fine-mapping and in silico and laboratory analyses of this locus. Analysis of 1,184 genotyped and imputed SNPs in 6,608 Caucasian cases and 37,925 controls, and 895 Asian cases and 1,968 controls, revealed the best signal of association for SNP rs11263763 (P=8.4×10(-14), OR=0.86, 95% CI=0.82-0.89), located within HNF1B intron 1. Haplotype analysis and conditional analyses provide no evidence of further independent endometrial cancer risk variants at this locus. SNP rs11263763 genotype was associated with HNF1B mRNA expression but not with HNF1B methylation in endometrial tumour samples from The Cancer Genome Atlas. Genetic analyses prioritized rs11263763 and four other SNPs in high to moderate LD as the most likely causal SNPs. Three of these SNPs map to the extended HNF1B promoter based on chromatin marks extending from the minimal promoter region. Reporter assays demonstrated that this extended region reduces activity in combination with the minimal HNF1B promoter, and that the minor alleles of rs11263763 or rs8064454 are associated with decreased HNF1B promoter activity. Our findings provide evidence for a single signal associated with endometrial cancer risk at the HNF1B locus, and that risk is likely mediated via altered HNF1B gene expression.
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Genetic variation in platinating agent and taxane pathway genes as predictors of outcome and toxicity in advanced non-small-cell lung cancer.
Pharmacogenomics
PUBLISHED: 10-24-2014
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Lung carcinoma is the most common malignancy and the leading cause of cancer deaths worldwide. Although clinical factors including age, performance status and stage influence the likelihood of benefit from and tolerability of chemotherapy, the genetic profile of individual patients may be an independent predictor of response and toxicity. The present study aimed to identify pharmacogenetic markers associated with clinical response and toxicity in patients with advanced non-small cell lung cancer (NSCLC) treated primarily with carboplatin and paclitaxel.
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Integrative clustering methods for high-dimensional molecular data.
Transl Cancer Res
PUBLISHED: 09-23-2014
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High-throughput 'omic' data, such as gene expression, DNA methylation, DNA copy number, has played an instrumental role in furthering our understanding of the molecular basis in states of human health and disease. As cells with similar morphological characteristics can exhibit entirely different molecular profiles and because of the potential that these discrepancies might further our understanding of patient-level variability in clinical outcomes, there is significant interest in the use of high-throughput 'omic' data for the identification of novel molecular subtypes of a disease. While numerous clustering methods have been proposed for identifying of molecular subtypes, most were developed for single "omic' data types and may not be appropriate when more than one 'omic' data type are collected on study subjects. Given that complex diseases, such as cancer, arise as a result of genomic, epigenomic, transcriptomic, and proteomic alterations, integrative clustering methods for the simultaneous clustering of multiple 'omic' data types have great potential to aid in molecular subtype discovery. Traditionally, ad hoc manual data integration has been performed using the results obtained from the clustering of individual 'omic' data types on the same set of patient samples. However, such methods often result in inconsistent assignment of subjects to the molecular cancer subtypes. Recently, several methods have been proposed in the literature that offers a rigorous framework for the simultaneous integration of multiple 'omic' data types in a single comprehensive analysis. In this paper, we present a systematic review of existing integrative clustering methods.
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Imputation and subset-based association analysis across different cancer types identifies multiple independent risk loci in the TERT-CLPTM1L region on chromosome 5p15.33.
Zhaoming Wang, Bin Zhu, Mingfeng Zhang, Hemang Parikh, Jinping Jia, Charles C Chung, Joshua N Sampson, Jason W Hoskins, Amy Hutchinson, Laurie Burdette, Abdisamad Ibrahim, Christopher Hautman, Preethi S Raj, Christian C Abnet, Andrew A Adjei, Anders Ahlbom, Demetrius Albanes, Naomi E Allen, Christine B Ambrosone, Melinda Aldrich, Pilar Amiano, Christopher Amos, Ulrika Andersson, Gerald Andriole, Irene L Andrulis, Cecilia Arici, Alan A Arslan, Melissa A Austin, Dalsu Baris, Donald A Barkauskas, Bryan A Bassig, Laura E Beane Freeman, Christine D Berg, Sonja I Berndt, Pier Alberto Bertazzi, Richard B Biritwum, Amanda Black, William Blot, Heiner Boeing, Paolo Boffetta, Kelly Bolton, Marie-Christine Boutron-Ruault, Paige M Bracci, Paul Brennan, Louise A Brinton, Michelle Brotzman, H Bas Bueno-de-Mesquita, Julie E Buring, Mary Ann Butler, Qiuyin Cai, Géraldine Cancel-Tassin, Federico Canzian, Guangwen Cao, Neil E Caporaso, Alfredo Carrato, Tania Carreon, Angela Carta, Gee-Chen Chang, I-Shou Chang, Jenny Chang-Claude, Xu Che, Chien-Jen Chen, Chih-Yi Chen, Chung-Hsing Chen, Constance Chen, Kuan-Yu Chen, Yuh-Min Chen, Anand P Chokkalingam, Lisa W Chu, Francoise Clavel-Chapelon, Graham A Colditz, Joanne S Colt, David Conti, Michael B Cook, Victoria K Cortessis, E David Crawford, Olivier Cussenot, Faith G Davis, Immaculata De Vivo, Xiang Deng, Ti Ding, Colin P Dinney, Anna Luisa Di Stefano, W Ryan Diver, Eric J Duell, Joanne W Elena, Jin-Hu Fan, Heather Spencer Feigelson, Maria Feychting, Jonine D Figueroa, Adrienne M Flanagan, Joseph F Fraumeni, Neal D Freedman, Brooke L Fridley, Charles S Fuchs, Manuela Gago-Dominguez, Steven Gallinger, Yu-Tang Gao, Susan M Gapstur, Montserrat Garcia-Closas, Reina Garcia-Closas, Julie M Gastier-Foster, J Michael Gaziano, Daniela S Gerhard, Carol A Giffen, Graham G Giles, Elizabeth M Gillanders, Edward L Giovannucci, Michael Goggins, Nalan Gokgoz, Alisa M Goldstein, Carlos González, Richard Gorlick, Mark H Greene, Myron Gross, H Barton Grossman, Robert Grubb, Jian Gu, Peng Guan, Christopher A Haiman, Göran Hallmans, Susan E Hankinson, Curtis C Harris, Patricia Hartge, Claudia Hattinger, Richard B Hayes, Qincheng He, Lee Helman, Brian E Henderson, Roger Henriksson, Judith Hoffman-Bolton, Chancellor Hohensee, Elizabeth A Holly, Yun-Chul Hong, Robert N Hoover, H Dean Hosgood, Chin-Fu Hsiao, Ann W Hsing, Chao Agnes Hsiung, Nan Hu, Wei Hu, Zhibin Hu, Ming-Shyan Huang, David J Hunter, Peter D Inskip, Hidemi Ito, Eric J Jacobs, Kevin B Jacobs, Mazda Jenab, Bu-Tian Ji, Christoffer Johansen, Mattias Johansson, Alison Johnson, Rudolf Kaaks, Ashish M Kamat, Aruna Kamineni, Margaret Karagas, Chand Khanna, Kay-Tee Khaw, Christopher Kim, In-Sam Kim, Jin Hee Kim, Yeul Hong Kim, Young-Chul Kim, Young Tae Kim, Chang Hyun Kang, Yoo Jin Jung, Cari M Kitahara, Alison P Klein, Robert Klein, Manolis Kogevinas, Woon-Puay Koh, Takashi Kohno, Laurence N Kolonel, Charles Kooperberg, Christian P Kratz, Vittorio Krogh, Hideo Kunitoh, Robert C Kurtz, Nilgun Kurucu, Qing Lan, Mark Lathrop, Ching C Lau, Fernando Lecanda, Kyoung-Mu Lee, Maxwell P Lee, Loic Le Marchand, Seth P Lerner, Donghui Li, Linda M Liao, Wei-Yen Lim, Dongxin Lin, Jie Lin, Sara Lindstrom, Martha S Linet, Jolanta Lissowska, Jianjun Liu, Börje Ljungberg, Josep Lloreta, Daru Lu, Jing Ma, Nuria Malats, Satu Mannisto, Neyssa Marina, Giuseppe Mastrangelo, Keitaro Matsuo, Katherine A McGlynn, Roberta Mckean-Cowdin, Lorna H McNeill, Robert R McWilliams, Beatrice S Melin, Paul S Meltzer, James E Mensah, Xiaoping Miao, Dominique S Michaud, Alison M Mondul, Lee E Moore, Kenneth Muir, Shelley Niwa, Sara H Olson, Nick Orr, Salvatore Panico, Jae Yong Park, Alpa V Patel, Ana Patiño-García, Sofia Pavanello, Petra H M Peeters, Beata Peplonska, Ulrike Peters, Gloria M Petersen, Piero Picci, Malcolm C Pike, Stefano Porru, Jennifer Prescott, Xia Pu, Mark P Purdue, You-Lin Qiao, Preetha Rajaraman, Elio Riboli, Harvey A Risch, Rebecca J Rodabough, Nathaniel Rothman, Avima M Ruder, Jeong-Seon Ryu, Marc Sanson, Alan Schned, Fredrick R Schumacher, Ann G Schwartz, Kendra L Schwartz, Molly Schwenn, Katia Scotlandi, Adeline Seow, Consol Serra, Massimo Serra, Howard D Sesso, Gianluca Severi, Hongbing Shen, Min Shen, Sanjay Shete, Kouya Shiraishi, Xiao-Ou Shu, Afshan Siddiq, Luis Sierrasesúmaga, Sabina Sierri, Alan Dart Loon Sihoe, Debra T Silverman, Matthias Simon, Melissa C Southey, Logan Spector, Margaret Spitz, Meir Stampfer, Pär Stattin, Mariana C Stern, Victoria L Stevens, Rachael Z Stolzenberg-Solomon, Daniel O Stram, Sara S Strom, Wu-Chou Su, Malin Sund, Sook Whan Sung, Anthony Swerdlow, Wen Tan, Hideo Tanaka, Wei Tang, Ze-Zhang Tang, Adonina Tardón, Evelyn Tay, Philip R Taylor, Yao Tettey, David M Thomas, Roberto Tirabosco, Anne Tjonneland, Geoffrey S Tobias, Jorge R Toro, Ruth C Travis, Dimitrios Trichopoulos, Rebecca Troisi, Ann Truelove, Ying-Huang Tsai, Margaret A Tucker, Rosario Tumino, David Van Den Berg, Stephen K Van Den Eeden, Roel Vermeulen, Paolo Vineis, Kala Visvanathan, Ulla Vogel, Chaoyu Wang, Chengfeng Wang, Junwen Wang, Sophia S Wang, Elisabete Weiderpass, Stephanie J Weinstein, Nicolas Wentzensen, William Wheeler, Emily White, John K Wiencke, Alicja Wolk, Brian M Wolpin, Maria Pik Wong, Margaret Wrensch, Chen Wu, Tangchun Wu, Xifeng Wu, Yi-Long Wu, Jay S Wunder, Yong-Bing Xiang, Jun Xu, Hannah P Yang, Pan-Chyr Yang, Yasushi Yatabe, Yuanqing Ye, Edward D Yeboah, Zhihua Yin, Chen Ying, Chong-Jen Yu, Kai Yu, Jian-Min Yuan, Krista A Zanetti, Anne Zeleniuch-Jacquotte, Wei Zheng, Baosen Zhou, Lisa Mirabello, Sharon A Savage, Peter Kraft, Stephen J Chanock, Meredith Yeager, Maria Terese Landi, Jianxin Shi, Nilanjan Chatterjee, Laufey T Amundadottir.
Hum. Mol. Genet.
PUBLISHED: 07-15-2014
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Genome-wide association studies (GWAS) have mapped risk alleles for at least 10 distinct cancers to a small region of 63 000 bp on chromosome 5p15.33. This region harbors the TERT and CLPTM1L genes; the former encodes the catalytic subunit of telomerase reverse transcriptase and the latter may play a role in apoptosis. To investigate further the genetic architecture of common susceptibility alleles in this region, we conducted an agnostic subset-based meta-analysis (association analysis based on subsets) across six distinct cancers in 34 248 cases and 45 036 controls. Based on sequential conditional analysis, we identified as many as six independent risk loci marked by common single-nucleotide polymorphisms: five in the TERT gene (Region 1: rs7726159, P = 2.10 × 10(-39); Region 3: rs2853677, P = 3.30 × 10(-36) and PConditional = 2.36 × 10(-8); Region 4: rs2736098, P = 3.87 × 10(-12) and PConditional = 5.19 × 10(-6), Region 5: rs13172201, P = 0.041 and PConditional = 2.04 × 10(-6); and Region 6: rs10069690, P = 7.49 × 10(-15) and PConditional = 5.35 × 10(-7)) and one in the neighboring CLPTM1L gene (Region 2: rs451360; P = 1.90 × 10(-18) and PConditional = 7.06 × 10(-16)). Between three and five cancers mapped to each independent locus with both risk-enhancing and protective effects. Allele-specific effects on DNA methylation were seen for a subset of risk loci, indicating that methylation and subsequent effects on gene expression may contribute to the biology of risk variants on 5p15.33. Our results provide strong support for extensive pleiotropy across this region of 5p15.33, to an extent not previously observed in other cancer susceptibility loci.
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Genome-wide investigation of regional blood-based DNA methylation adjusted for complete blood counts implicates BNC2 in ovarian cancer.
Genet. Epidemiol.
PUBLISHED: 04-21-2014
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Due to its potential as a biomarker for early cancer detection, blood-based DNA methylation (DNAm) is of interest in cancer research. Specifically, highly predictive mechanisms for early detection of epithelial ovarian cancer (EOC) are desired, so previous studies have compared DNAm between EOC cases and controls. However, case-control studies are confounded by the distribution of white blood cell types through an immune response induced by the cancer. Rather than determining the distribution of the cell types manually or investigating isolated cell types, an alternative approach involves the use of complete blood count (CBC), which is routinely collected. In the analysis of an EOC case-control study of DNAm, we incorporate CBC measures to adjust for this confounding and compare DNAm between 242 EOC cases and 181 age-matched controls (assayed on the Illumina Infinium HumanMethylation27 or HumanMethylation450 Beadchips), at both the individual CpG and CpG island levels. We found that adjustment for leukocyte distribution using CBC measurements dramatically reduced confounding, with 62 single CpG sites found to be associated with EOC status after adjustment (P < 5E-8). Additionally, regional DNAm was assessed by applying principal components analysis to CpG islands. The top associated CpG island (P = 7E-6) was located in the promoter/transcription start site of the human basonuclin 2 gene (BNC2), a known susceptibility gene for EOC risk identified through GWAS. Follow-up studies are necessary to establish the role of BNC2 in blood-based DNA and EOC, including prospective studies to validate this region as a potential biomarker and predictor of EOC susceptibility.
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Methylation of leukocyte DNA and ovarian cancer: relationships with disease status and outcome.
BMC Med Genomics
PUBLISHED: 04-16-2014
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Genome-wide interrogation of DNA methylation (DNAm) in blood-derived leukocytes has become feasible with the advent of CpG genotyping arrays. In epithelial ovarian cancer (EOC), one report found substantial DNAm differences between cases and controls; however, many of these disease-associated CpGs were attributed to differences in white blood cell type distributions.
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Variation in NF-?B signaling pathways and survival in invasive epithelial ovarian cancer.
Matthew S Block, Bridget Charbonneau, Robert A Vierkant, Zachary Fogarty, William R Bamlet, Paul D P Pharoah, , Mary Anne Rossing, Daniel Cramer, Celeste Leigh Pearce, Joellen Schildkraut, Usha Menon, Susanne K Kjaer, Douglas A Levine, Jacek Gronwald, Hoda Anton Culver, Alice S Whittemore, Beth Y Karlan, Diether Lambrechts, Nicolas Wentzensen, Jolanta Kupryjanczyk, Jenny Chang-Claude, Elisa V Bandera, Estrid Hogdall, Florian Heitz, Stanley B Kaye, Peter A Fasching, Ian Campbell, Marc T Goodman, Tanja Pejovic, Yukie T Bean, Laura E Hays, Galina Lurie, Diana Eccles, Alexander Hein, Matthias W Beckmann, Arif B Ekici, James Paul, Robert Brown, James M Flanagan, Philipp Harter, Andreas du Bois, Ira Schwaab, Claus K Hogdall, Lene Lundvall, Sara H Olson, Irene Orlow, Lisa E Paddock, Anja Rudolph, Ursula Eilber, Agnieszka Dansonka-Mieszkowska, Iwona K Rzepecka, Izabela Ziolkowska-Seta, Louise A Brinton, Hannah Yang, Montserrat Garcia-Closas, Evelyn Despierre, Sandrina Lambrechts, Ignace Vergote, Christine S Walsh, Jenny Lester, Weiva Sieh, Valerie McGuire, Joseph H Rothstein, Argyrios Ziogas, Jan Lubiński, Cezary Cybulski, Janusz Menkiszak, Allan Jensen, Simon A Gayther, Susan J Ramus, Aleksandra Gentry-Maharaj, Andrew Berchuck, Anna H Wu, Malcolm C Pike, David Van Den Berg, Kathryn L Terry, Allison F Vitonis, Starr M Ramirez, David N Rider, Keith L Knutson, Thomas A Sellers, Catherine M Phelan, Jennifer A Doherty, Sharon E Johnatty, Anna deFazio, Honglin Song, Jonathan Tyrer, Kimberly R Kalli, Brooke L Fridley, Julie M Cunningham, Ellen L Goode.
Cancer Epidemiol. Biomarkers Prev.
PUBLISHED: 04-16-2014
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Survival in epithelial ovarian cancer (EOC) is influenced by the host immune response, yet the key genetic determinants of inflammation and immunity that affect prognosis are not known. The nuclear factor-?B (NF-?B) transcription factor family plays an important role in many immune and inflammatory responses, including the response to cancer. We studied common inherited variation in 210 genes in the NF-?B family in 10,084 patients with invasive EOC (5,248 high-grade serous, 1,452 endometrioid, 795 clear cell, and 661 mucinous) from the Ovarian Cancer Association Consortium. Associations between genotype and overall survival were assessed using Cox regression for all patients and by major histology, adjusting for known prognostic factors and correcting for multiple testing (threshold for statistical significance, P < 2.5 × 10(-5)). Results were statistically significant when assessed for patients of a single histology. Key associations were with caspase recruitment domain family, member 11 (CARD11) rs41324349 in patients with mucinous EOC [HR, 1.82; 95% confidence interval (CI), 1.41-2.35; P = 4.13 × 10(-6)] and tumor necrosis factor receptor superfamily, member 13B (TNFRSF13B) rs7501462 in patients with endometrioid EOC (HR, 0.68; 95% CI, 0.56-0.82; P = 2.33 × 10(-5)). Other associations of note included TNF receptor-associated factor 2 (TRAF2) rs17250239 in patients with high-grade serous EOC (HR, 0.84; 95% CI, 0.77-0.92; P = 6.49 × 10(-5)) and phospholipase C, gamma 1 (PLCG1) rs11696662 in patients with clear cell EOC (HR, 0.43; 95% CI, 0.26-0.73; P = 4.56 × 10(-4)). These associations highlight the potential importance of genes associated with host inflammation and immunity in modulating clinical outcomes in distinct EOC histologies.
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The contribution of deleterious germline mutations in BRCA1, BRCA2 and the mismatch repair genes to ovarian cancer in the population.
Hum. Mol. Genet.
PUBLISHED: 04-12-2014
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The aim of this study was to estimate the contribution of deleterious mutations in BRCA1, BRCA2, MLH1, MSH2, MSH6 and PMS2 to invasive epithelial ovarian cancer (EOC) in the population. The coding sequence and splice site boundaries of all six genes were amplified in germline DNA from 2240 invasive EOC cases and 1535 controls. Barcoded fragment libraries were sequenced using the Illumina GAII or HiSeq and sequence data for each subject de-multiplexed prior to interpretation. GATK and Annovar were used for variant detection and annotation. After quality control 2222 cases (99.2%) and 1528 controls (99.5%) were included in the final analysis. We identified 193 EOC cases (8.7%) carrying a deleterious mutation in at least one gene compared with 10 controls (0.65%). Mutations were most frequent in BRCA1 and BRCA2, with 84 EOC cases (3.8%) carrying a BRCA1 mutation and 94 EOC cases (4.2%) carrying a BRCA2 mutation. The combined BRCA1 and BRCA2 mutation prevalence was 11% in high-grade serous disease. Seventeen EOC cases carried a mutation in a mismatch repair gene, including 10 MSH6 mutation carriers (0.45%) and 4 MSH2 mutation carriers (0.18%). At least 1 in 10 women with high-grade serous EOC has a BRCA1 or BRCA2 mutation. The development of next generation sequencing technologies enables rapid mutation screening for multiple susceptibility genes at once, suggesting that routine clinical testing of all incidence cases should be considered.
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Tumor hypomethylation at 6p21.3 associates with longer time to recurrence of high-grade serous epithelial ovarian cancer.
Cancer Res.
PUBLISHED: 04-11-2014
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To reveal biologic mechanisms underlying clinical outcome of high-grade serous (HGS) epithelial ovarian carcinomas (EOC), we evaluated the association between tumor epigenetic changes and time to recurrence (TTR). We assessed methylation at approximately 450,000 genome-wide CpGs in tumors of 337 Mayo Clinic (Rochester, MN) patients. Semi-supervised clustering of discovery (n=168) and validation (n=169) sets was used to determine clinically relevant methylation classes. Clustering identified two methylation classes based on 60 informative CpGs, which differed in TTR in the validation set [R vs. L class, P=2.9×10(-3), HR=0.52; 95% confidence interval (CI), 0.34-0.80]. Follow-up analyses considered genome-wide tumor mRNA expression (n=104) and CD8 T-cell infiltration (n=89) in patient subsets. Hypomethylation of CpGs located in 6p21.3 in the R class associated with cis upregulation of genes enriched in immune response processes (TAP1, PSMB8, PSMB9, HLA-DQB1, HLA-DQB2, HLA-DMA, and HLA-DOA), increased CD8 T-cell tumor infiltration (P=7.6×10(-5)), and trans-regulation of genes in immune-related pathways (P=1.6×10(-32)). This is the most comprehensive assessment of clinical outcomes with regard to epithelial ovarian carcinoma tumor methylation to date. Collectively, these results suggest that an epigenetically mediated immune response is a predictor of recurrence and, possibly, treatment response for HGS EOC.
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Thiopurine pharmacogenomics: association of SNPs with clinical response and functional validation of candidate genes.
Pharmacogenomics
PUBLISHED: 03-15-2014
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We investigated candidate genes associated with thiopurine metabolism and clinical response in childhood acute lymphoblastic leukemia.
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Consortium analysis of gene and gene-folate interactions in purine and pyrimidine metabolism pathways with ovarian carcinoma risk.
Linda E Kelemen, Kathryn L Terry, Marc T Goodman, Penelope M Webb, Elisa V Bandera, Valerie McGuire, Mary Anne Rossing, Qinggang Wang, Ed Dicks, Jonathan P Tyrer, Honglin Song, Jolanta Kupryjanczyk, Agnieszka Dansonka-Mieszkowska, Joanna Plisiecka-Halasa, Agnieszka Timorek, Usha Menon, Aleksandra Gentry-Maharaj, Simon A Gayther, Susan J Ramus, Steven A Narod, Harvey A Risch, John R McLaughlin, Nadeem Siddiqui, Rosalind Glasspool, James Paul, Karen Carty, Jacek Gronwald, Jan Lubiński, Anna Jakubowska, Cezary Cybulski, Lambertus A Kiemeney, Leon F A G Massuger, Anne M Van Altena, Katja K H Aben, Sara H Olson, Irene Orlow, Daniel W Cramer, Douglas A Levine, Maria Bisogna, Graham G Giles, Melissa C Southey, Fiona Bruinsma, Susanne K Kjaer, Estrid Høgdall, Allan Jensen, Claus K Høgdall, Lene Lundvall, Svend-Aage Engelholm, Florian Heitz, Andreas du Bois, Philipp Harter, Ira Schwaab, Ralf Bützow, Heli Nevanlinna, Liisa M Pelttari, Arto Leminen, Pamela J Thompson, Galina Lurie, Lynne R Wilkens, Diether Lambrechts, Els Van Nieuwenhuysen, Sandrina Lambrechts, Ignace Vergote, Jonathan Beesley, , Peter A Fasching, Matthias W Beckmann, Alexander Hein, Arif B Ekici, Jennifer A Doherty, Anna H Wu, Celeste L Pearce, Malcolm C Pike, Daniel Stram, Jenny Chang-Claude, Anja Rudolph, Thilo Dörk, Matthias Dürst, Peter Hillemanns, Ingo B Runnebaum, Natalia Bogdanova, Natalia Antonenkova, Kunle Odunsi, Robert P Edwards, Joseph L Kelley, Francesmary Modugno, Roberta B Ness, Beth Y Karlan, Christine Walsh, Jenny Lester, Sandra Orsulic, Brooke L Fridley, Robert A Vierkant, Julie M Cunningham, Xifeng Wu, Karen Lu, Dong Liang, Michelle A T Hildebrandt, Rachel Palmieri Weber, Edwin S Iversen, Shelley S Tworoger, Elizabeth M Poole, Helga B Salvesen, Camilla Krakstad, Line Bjorge, Ingvild L Tangen, Tanja Pejovic, Yukie Bean, Melissa Kellar, Nicolas Wentzensen, Louise A Brinton, Jolanta Lissowska, Montserrat Garcia-Closas, Ian G Campbell, Diana Eccles, Alice S Whittemore, Weiva Sieh, Joseph H Rothstein, Hoda Anton-Culver, Argyrios Ziogas, Catherine M Phelan, Kirsten B Moysich, Ellen L Goode, Joellen M Schildkraut, Andrew Berchuck, Paul D P Pharoah, Thomas A Sellers, Angela Brooks-Wilson, Linda S Cook, Nhu D Le.
Mol Nutr Food Res
PUBLISHED: 02-01-2014
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We reevaluated previously reported associations between variants in pathways of one-carbon (1-C) (folate) transfer genes and ovarian carcinoma (OC) risk, and in related pathways of purine and pyrimidine metabolism, and assessed interactions with folate intake.
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Large-scale evaluation of common variation in regulatory T cell-related genes and ovarian cancer outcome.
Bridget Charbonneau, Kirsten B Moysich, Kimberly R Kalli, Ann L Oberg, Robert A Vierkant, Zachary C Fogarty, Matthew S Block, Matthew J Maurer, Krista M Goergen, Brooke L Fridley, Julie M Cunningham, David N Rider, Claudia Preston, Lynn C Hartmann, Kate Lawrenson, Chen Wang, Jonathan Tyrer, Honglin Song, Anna deFazio, Sharon E Johnatty, Jennifer A Doherty, Catherine M Phelan, Thomas A Sellers, Starr M Ramirez, Allison F Vitonis, Kathryn L Terry, David Van Den Berg, Malcolm C Pike, Anna H Wu, Andrew Berchuck, Aleksandra Gentry-Maharaj, Susan J Ramus, Brenda Diergaarde, Howard Shen, Allan Jensen, Janusz Menkiszak, Cezary Cybulski, Jan Lubiłski, Argyrios Ziogas, Joseph H Rothstein, Valerie McGuire, Weiva Sieh, Jenny Lester, Christine Walsh, Ignace Vergote, Sandrina Lambrechts, Evelyn Despierre, Montserrat Garcia-Closas, Hannah Yang, Louise A Brinton, Beata Spiewankiewicz, Iwona K Rzepecka, Agnieszka Dansonka-Mieszkowska, Petra Seibold, Anja Rudolph, Lisa E Paddock, Irene Orlow, Lene Lundvall, Sara H Olson, Claus K Hogdall, Ira Schwaab, Andreas du Bois, Philipp Harter, James M Flanagan, Robert Brown, James Paul, Arif B Ekici, Matthias W Beckmann, Alexander Hein, Diana Eccles, Galina Lurie, Laura E Hays, Yukie T Bean, Tanja Pejovic, Marc T Goodman, Ian Campbell, Peter A Fasching, Gottfried Konecny, Stanley B Kaye, Florian Heitz, Estrid Hogdall, Elisa V Bandera, Jenny Chang-Claude, Jolanta Kupryjanczyk, Nicolas Wentzensen, Diether Lambrechts, Beth Y Karlan, Alice S Whittemore, Hoda Anton Culver, Jacek Gronwald, Douglas A Levine, Susanne K Kjaer, Usha Menon, Joellen M Schildkraut, Celeste Leigh Pearce, Daniel W Cramer, Mary Anne Rossing, Georgia Chenevix-Trench, , Paul D P Pharoah, Simon A Gayther, Roberta B Ness, Kunle Odunsi, Lara E Sucheston, Keith L Knutson, Ellen L Goode.
Cancer Immunol Res
PUBLISHED: 01-27-2014
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The presence of regulatory T cells (Treg) in solid tumors is known to play a role in patient survival in ovarian cancer and other malignancies. We assessed inherited genetic variations via 749 tag single-nucleotide polymorphisms (SNP) in 25 Treg-associated genes (CD28, CTLA4, FOXP3, IDO1, IL10, IL10RA, IL15, 1L17RA, IL23A, IL23R, IL2RA, IL6, IL6R, IL8, LGALS1, LGALS9, MAP3K8, STAT5A, STAT5B, TGFB1, TGFB2, TGFB3, TGFBR1, TGRBR2, and TGFBR3) in relation to ovarian cancer survival. We analyzed genotype and overall survival in 10,084 women with invasive epithelial ovarian cancer, including 5,248 high-grade serous, 1,452 endometrioid, 795 clear cell, and 661 mucinous carcinoma cases of European descent across 28 studies from the Ovarian Cancer Association Consortium (OCAC). The strongest associations were found for endometrioid carcinoma and IL2RA SNPs rs11256497 [HR, 1.42; 95% confidence interval (CI), 1.22-1.64; P = 5.7 × 10(-6)], rs791587 (HR, 1.36; 95% CI, 1.17-1.57; P = 6.2 × 10(-5)), rs2476491 (HR, = 1.40; 95% CI, 1.19-1.64; P = 5.6 × 10(-5)), and rs10795763 (HR, 1.35; 95% CI, 1.17-1.57; P = 7.9 × 10(-5)), and for clear cell carcinoma and CTLA4 SNP rs231775 (HR, 0.67; 95% CI, 0.54-0.82; P = 9.3 × 10(-5)) after adjustment for age, study site, population stratification, stage, grade, and oral contraceptive use. The rs231775 allele associated with improved survival in our study also results in an amino acid change in CTLA4 and previously has been reported to be associated with autoimmune conditions. Thus, we found evidence that SNPs in genes related to Tregs seem to play a role in ovarian cancer survival, particularly in patients with clear cell and endometrioid epithelial ovarian cancer.
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Integrative genomic analysis identifies epigenetic marks that mediate genetic risk for epithelial ovarian cancer.
BMC Med Genomics
PUBLISHED: 01-22-2014
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Both genetic and epigenetic factors influence the development and progression of epithelial ovarian cancer (EOC). However, there is an incomplete understanding of the interrelationship between these factors and the extent to which they interact to impact disease risk. In the present study, we aimed to gain insight into this relationship by identifying DNA methylation marks that are candidate mediators of ovarian cancer genetic risk.
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Discovery of genetic biomarkers contributing to variation in drug response of cytidine analogues using human lymphoblastoid cell lines.
BMC Genomics
PUBLISHED: 01-10-2014
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Two cytidine analogues, gemcitabine and cytosine arabinoside (AraC), are widely used in the treatment of a variety of cancers with a large individual variation in response. To identify potential genetic biomarkers associated with response to these two drugs, we used a human lymphoblastoid cell line (LCL) model system with extensive genomic data, including 1.3 million SNPs and 54,000 basal expression probesets to perform genome-wide association studies (GWAS) with gemcitabine and AraC IC50 values.
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Acquired chromosomal anomalies in chronic lymphocytic leukemia patients compared with more than 50,000 quasi-normal participants.
Cancer Genet
PUBLISHED: 01-03-2014
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Pretherapy patients with chronic lymphocytic leukemia (CLL) from US Intergroup trial E2997 were analyzed with single nucleotide polymorphism microarrays to detect acquired chromosomal anomalies. The four CLL-typical anomalies (11q-, +12, 13q-, and 17p-) were found at expected frequencies. Acquired anomalies in other regions account for 70% of the total detected anomalies, and their number per participant has a significant effect on progression-free survival after adjusting for the effects of 17p- (and other covariates). These results were compared with those from a previous study of more than 50,000 participants from the GENEVA consortium of genome-wide association studies, which analyzed individuals with a variety of medical conditions and healthy controls. The percentage of individuals with acquired anomalies is vastly different between the two studies (GENEVA 0.8%; E2997 80%). The composition of the anomalies also differs, with GENEVA having a higher percentage of acquired uniparental disomies and a lower percentage of deletions. The four common CLL anomalies are among the most frequent in GENEVA participants, some of whom may have CLL-precursor conditions or early stages of CLL. However, the patients from E2997 (and other studies of symptomatic CLL) have recurrent acquired anomalies that were not found in GENEVA participants, thus identifying genomic changes that may be unique to symptomatic stages of CLL.
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Risk of Ovarian Cancer and the NF-?B Pathway: Genetic association with IL1A and TNFSF10.
Bridget Charbonneau, Matthew S Block, William R Bamlet, Robert A Vierkant, Kimberly R Kalli, Zachary Fogarty, David N Rider, Thomas A Sellers, Shelley S Tworoger, Elizabeth Poole, Harvey A Risch, Helga B Salvesen, Lambertus A Kiemeney, Laura Baglietto, Graham G Giles, Gianluca Severi, Britton Trabert, Nicolas Wentzensen, Georgia Chenevix-Trench, , Alice S Whittemore, Weiva Sieh, Jenny Chang-Claude, Elisa V Bandera, Irene Orlow, Kathryn Terry, Marc T Goodman, Pamela J Thompson, Linda S Cook, Mary Anne Rossing, Roberta B Ness, Steven A Narod, Jolanta Kupryjanczyk, Karen Lu, Ralf Bützow, Thilo Dörk, Tanja Pejovic, Ian Campbell, Nhu D Le, Clareann H Bunker, Natalia Bogdanova, Ingo B Runnebaum, Diana Eccles, James Paul, Anna H Wu, Simon A Gayther, Estrid Hogdall, Florian Heitz, Stanley B Kaye, Beth Y Karlan, Hoda Anton-Culver, Jacek Gronwald, Claus K Hogdall, Diether Lambrechts, Peter A Fasching, Usha Menon, Joellen Schildkraut, Celeste Leigh Pearce, Douglas A Levine, Susanne Krüger Kjaer, Daniel Cramer, James M Flanagan, Catherine M Phelan, Robert Brown, Leon F A G Massuger, Honglin Song, Jennifer A Doherty, Camilla Krakstad, Dong Liang, Kunle Odunsi, Andrew Berchuck, Allan Jensen, Jan Lubiński, Heli Nevanlinna, Yukie T Bean, Galina Lurie, Argyrios Ziogas, Christine Walsh, Evelyn Despierre, Louise Brinton, Alexander Hein, Anja Rudolph, Agnieszka Dansonka-Mieszkowska, Sara H Olson, Philipp Harter, Jonathan Tyrer, Allison F Vitonis, Angela Brooks-Wilson, Katja K Aben, Malcolm C Pike, Susan J Ramus, Elisabeth Wik, Cezary Cybulski, Jie Lin, Lara Sucheston, Robert Edwards, Valerie McGuire, Jenny Lester, Andreas du Bois, Lene Lundvall, Shan Wang-Gohrke, Lukasz M Szafron, Sandrina Lambrechts, Hannah Yang, Matthias W Beckmann, Liisa M Pelttari, Anne M Van Altena, David Van Den Berg, Mari K Halle, Aleksandra Gentry-Maharaj, Ira Schwaab, Urmila Chandran, Janusz Menkiszak, Arif B Ekici, Lynne R Wilkens, Arto Leminen, Francesmary Modugno, Grace Friel, Joseph H Rothstein, Ignace Vergote, Montserrat Garcia-Closas, Michelle A T Hildebrandt, Piotr Sobiczewski, Linda E Kelemen, Paul D P Pharoah, Kirsten Moysich, Keith L Knutson, Julie M Cunningham, Brooke L Fridley, Ellen L Goode.
Cancer Res.
PUBLISHED: 11-22-2013
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A missense single nucleotide polymorphism in the immune modulatory gene IL1A has been associated with ovarian cancer risk (rs17561), but the functional implications of this polymorphism are undefined. IL-1? is regulated by and activated by NF-?B, a transcription factor family that induces transcription of IL1A along with other pro-inflammatory genes and is an important modifier in carcinogenesis. We therefore tagged SNPs in over 200 genes in the NF-?B pathway for a total of 2,282 SNPs (including rs17561) for genotype analysis of 15,604 cases of ovarian cancer in patients of European descent, including 6,179 of high grade serous (HGS), 2,100 endometrioid, 1,591 mucinous, 1,034 clear cell and 1,016 low grade serous (LGS), including 23,235 control cases spanning 40 studies in the Ovarian Cancer Association Consortium (OCAC). In this large population, we confirmed the association between rs17561 and clear cell ovarian cancer (OR=0.84, 95% CI: 0.76-0.93; p=0.00075), which remained intact even after excluding participants in the prior study (OR=0.85, 95% CI: 0.75-0.95; p=0.006). Considering a multiple-testing-corrected significance threshold of p< 2.5x10-5, only one other variant, the TNFSF10 SNP rs6785617, was associated significantly with a risk of ovarian cancer (low malignant potential (LMP) tumors OR=0.85, 95% CI: 0.79-0.91; p=0.00002). Our results extend the evidence that borderline tumors may have a distinct genetic etiology. Further investigation of how these SNPs might modify ovarian cancer associations with other inflammation related risk factors is warranted.
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Integrative Gene Set Analysis: Application to Platinum Pharmacogenomics.
OMICS
PUBLISHED: 11-07-2013
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Abstract Integrative genomics has the potential to uncover relevant loci, as clinical outcome and response to chemotherapies are most likely not due to a single gene (or data type) but rather a complex relationship involving genetic variation, mRNA, DNA methylation, and copy number variation. In addition to this complexity, many complex phenotypes are thought to be controlled by the interplay of multiple genes within the same molecular pathway or gene set (GS). To address these two challenges, we propose an integrative gene set analysis approach and apply this strategy to a cisplatin (CDDP) pharmacogenomics study involving lymphoblastoid cell lines for which genome-wide SNP and mRNA expression data was collected. Application of the integrative GS analysis implicated the role of the RNA binding and cytoskeletal part GSs. The genes LMNB1 and CENPF, within the cytoskeletal part GS, were functionally validated with siRNA knockdown experiments, where the knockdown of LMNB1 and CENPF resulted in CDDP resistance in multiple cancer cell lines. This study demonstrates the utility of an integrative GS analysis strategy for detecting novel genes associated with response to cancer therapies, moving closer to tailored therapy decisions cancer patients.
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Bayseian genomic models for the incorporation of pathway topology knowledge into association studies.
Stat Appl Genet Mol Biol
PUBLISHED: 08-13-2013
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Pathway topology and relationships between genes have the potential to provide information for modeling effects of mRNA gene expression on complex traits. For example, researchers may wish to incorporate the prior belief that "hub" genes (genes with many neighbors) are more likely to influence the trait. In this paper, we propose and compare six Bayesian pathway-based prior models to incorporate pathway topology information into association analyses. Including prior information regarding the relationships among genes in a pathway was effective in somewhat improving detection rates for genes associated with complex traits. Through an extensive set of simulations, we found that when hub (central) effects are expected, the diagonal degree model is preferred; when spoke (edge) effects are expected, the spatial power model is preferred. When there is no prior knowledge about the location of the effect genes in the pathway (e.g., hub versus spoke model), it is worthwhile to apply multiple models, as the model with the best DIC is not always the one with the best detection rate. We also applied the models to pharmacogenomic studies for the drugs gemcitabine and 6-mercaptopurine and found that the diagonal degree model identified an association between 6-mercaptopurine response and expression of the gene SLC28A3, which was not detectable using the model including no pathway information. These results demonstrate the value of incorporating pathway information into association analyses.
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Biomarker-based ovarian carcinoma typing: a histologic investigation in the ovarian tumor tissue analysis consortium.
Cancer Epidemiol. Biomarkers Prev.
PUBLISHED: 07-23-2013
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Ovarian carcinoma is composed of five major histologic types, which associate with outcome and predict therapeutic response. Our aim was to evaluate histologic type assessments across the centers participating in the Ovarian Tumor Tissue Analysis (OTTA) consortium using an immunohistochemical (IHC) prediction model.
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Genome-wide association study of subtype-specific epithelial ovarian cancer risk alleles using pooled DNA.
Madalene A Earp, Linda E Kelemen, Anthony M Magliocco, Kenneth D Swenerton, Georgia Chenevix-Trench, , Yi Lu, Alexander Hein, Arif B Ekici, Matthias W Beckmann, Peter A Fasching, Diether Lambrechts, Evelyn Despierre, Ignace Vergote, Sandrina Lambrechts, Jennifer A Doherty, Mary Anne Rossing, Jenny Chang-Claude, Anja Rudolph, Grace Friel, Kirsten B Moysich, Kunle Odunsi, Lara Sucheston-Campbell, Galina Lurie, Marc T Goodman, Michael E Carney, Pamela J Thompson, Ingo B Runnebaum, Matthias Dürst, Peter Hillemanns, Thilo Dörk, Natalia Antonenkova, Natalia Bogdanova, Arto Leminen, Heli Nevanlinna, Liisa M Pelttari, Ralf Bützow, Clareann H Bunker, Francesmary Modugno, Robert P Edwards, Roberta B Ness, Andreas du Bois, Florian Heitz, Ira Schwaab, Philipp Harter, Beth Y Karlan, Christine Walsh, Jenny Lester, Allan Jensen, Susanne K Kjær, Claus K Høgdall, Estrid Høgdall, Lene Lundvall, Thomas A Sellers, Brooke L Fridley, Ellen L Goode, Julie M Cunningham, Robert A Vierkant, Graham G Giles, Laura Baglietto, Gianluca Severi, Melissa C Southey, Dong Liang, Xifeng Wu, Karen Lu, Michelle A T Hildebrandt, Douglas A Levine, Maria Bisogna, Joellen M Schildkraut, Edwin S Iversen, Rachel Palmieri Weber, Andrew Berchuck, Daniel W Cramer, Kathryn L Terry, Elizabeth M Poole, Shelley S Tworoger, Elisa V Bandera, Urmila Chandran, Irene Orlow, Sara H Olson, Elisabeth Wik, Helga B Salvesen, Line Bjorge, Mari K Halle, Anne M Van Altena, Katja K H Aben, Lambertus A Kiemeney, Leon F A G Massuger, Tanja Pejovic, Yukie T Bean, Cezary Cybulski, Jacek Gronwald, Jan Lubiński, Nicolas Wentzensen, Louise A Brinton, Jolanta Lissowska, Montserrat Garcia-Closas, Ed Dicks, Joe Dennis, Douglas F Easton, Honglin Song, Jonathan P Tyrer, Paul D P Pharoah, Diana Eccles, Ian G Campbell, Alice S Whittemore, Valerie McGuire, Weiva Sieh, Joseph H Rothstein, James M Flanagan, James Paul, Robert Brown, Catherine M Phelan, Harvey A Risch, John R McLaughlin, Steven A Narod, Argyrios Ziogas, Hoda Anton-Culver, Aleksandra Gentry-Maharaj, Usha Menon, Simon A Gayther, Susan J Ramus, Anna H Wu, Celeste L Pearce, Malcolm C Pike, Agnieszka Dansonka-Mieszkowska, Iwona K Rzepecka, Lukasz M Szafron, Jolanta Kupryjanczyk, Linda S Cook, Nhu D Le, Angela Brooks-Wilson.
Hum. Genet.
PUBLISHED: 07-17-2013
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Epithelial ovarian cancer (EOC) is a heterogeneous cancer with both genetic and environmental risk factors. Variants influencing the risk of developing the less-common EOC subtypes have not been fully investigated. We performed a genome-wide association study (GWAS) of EOC according to subtype by pooling genomic DNA from 545 cases and 398 controls of European descent, and testing for allelic associations. We evaluated for replication 188 variants from the GWAS [56 variants for mucinous, 55 for endometrioid and clear cell, 53 for low-malignant potential (LMP) serous, and 24 for invasive serous EOC], selected using pre-defined criteria. Genotypes from 13,188 cases and 23,164 controls of European descent were used to perform unconditional logistic regression under the log-additive genetic model; odds ratios (OR) and 95 % confidence intervals are reported. Nine variants tagging six loci were associated with subtype-specific EOC risk at P < 0.05, and had an OR that agreed in direction of effect with the GWAS results. Several of these variants are in or near genes with a biological rationale for conferring EOC risk, including ZFP36L1 and RAD51B for mucinous EOC (rs17106154, OR = 1.17, P = 0.029, n = 1,483 cases), GRB10 for endometrioid and clear cell EOC (rs2190503, P = 0.014, n = 2,903 cases), and C22orf26/BPIL2 for LMP serous EOC (rs9609538, OR = 0.86, P = 0.0043, n = 892 cases). In analyses that included the 75 GWAS samples, the association between rs9609538 (OR = 0.84, P = 0.0007) and LMP serous EOC risk remained statistically significant at P < 0.0012 adjusted for multiple testing. Replication in additional samples will be important to verify these results for the less-common EOC subtypes.
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Hormone-receptor expression and ovarian cancer survival: an Ovarian Tumor Tissue Analysis consortium study.
Lancet Oncol.
PUBLISHED: 07-09-2013
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Few biomarkers of ovarian cancer prognosis have been established, partly because subtype-specific associations might be obscured in studies combining all histopathological subtypes. We examined whether tumour expression of the progesterone receptor (PR) and oestrogen receptor (ER) was associated with subtype-specific survival.
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PurBayes: estimating tumor cellularity and subclonality in next-generation sequencing data.
Bioinformatics
PUBLISHED: 06-06-2013
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We have developed a novel Bayesian method, PurBayes, to estimate tumor purity and detect intratumor heterogeneity based on next-generation sequencing data of paired tumor-normal tissue samples, which uses finite mixture modeling methods. We demonstrate our approach using simulated data and discuss its performance under varying conditions.
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Soft truncation thresholding for gene set analysis of RNA-seq data: application to a vaccine study.
Sci Rep
PUBLISHED: 05-28-2013
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Gene set analysis (GSA) has been used for analysis of microarray data to aid the interpretation and to increase statistical power. With the advent of next-generation sequencing, the use of GSA is even more relevant, as studies are often conducted on a small number of samples. We propose the use of soft truncation thresholding and the Gamma Method (GM) to determine significant gene set (GS), where a generalized linear model is used to assess per-gene significance. The approach was compared to other methods using an extensive simulation study and RNA-seq data from smallpox vaccine study. The GM was found to outperform other proposed methods. Application of the GM to the smallpox vaccine study found the GSs to be moderately associated with response, including focal adhesion (p = 0.04) and extracellular matrix receptor interaction (p = 0.05). The application of GSA to RNA-seq data will provide new insights into the genomic basis of complex traits.
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Identification of novel variants in colorectal cancer families by high-throughput exome sequencing.
Cancer Epidemiol. Biomarkers Prev.
PUBLISHED: 05-01-2013
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Colorectal cancer (CRC) in densely affected families without Lynch Syndrome may be due to mutations in undiscovered genetic loci. Familial linkage analyses have yielded disparate results; the use of exome sequencing in coding regions may identify novel segregating variants.
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Epigenome-wide ovarian cancer analysis identifies a methylation profile differentiating clear-cell histology with epigenetic silencing of the HERG K+ channel.
Hum. Mol. Genet.
PUBLISHED: 04-09-2013
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Ovarian cancer remains the leading cause of death in women with gynecologic malignancies, despite surgical advances and the development of more effective chemotherapeutics. As increasing evidence indicates that clear-cell ovarian cancer may have unique pathogenesis, further understanding of molecular features may enable us to begin to understand the underlying biology and histology-specific information for improved outcomes. To study epigenetics in clear-cell ovarian cancer, fresh frozen tumor DNA (n = 485) was assayed on Illumina Infinium HumanMethylation450 BeadChips. We identified a clear-cell ovarian cancer tumor methylation profile (n = 163) which we validated in two independent replication sets (set 1, n = 163; set 2, n = 159), highlighting 22 CpG loci associated with nine genes (VWA1, FOXP1, FGFRL1, LINC00340, KCNH2, ANK1, ATXN2, NDRG21 and SLC16A11). Nearly all of the differentially methylated CpGs showed a propensity toward hypermethylation among clear-cell cases. Several loci methylation inversely correlated with tumor gene expression, most notably KCNH2 (HERG, a potassium channel) (P = 9.5 × 10(-7)), indicating epigenetic silencing. In addition, a predicted methylation class mainly represented by the clear-cell cases (20 clear cell out of 23 cases) had improved survival time. Although these analyses included only 30 clear-cell carcinomas, results suggest that loss of expression of KCNH2 (HERG) by methylation could be a good prognostic marker, given that overexpression of the potassium (K(+)) channel Eag family members promotes increased proliferation and results in poor prognosis. Validation in a bigger cohort of clear-cell tumors of the ovary is warranted.
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TSPYL5 SNPs: association with plasma estradiol concentrations and aromatase expression.
Mol. Endocrinol.
PUBLISHED: 03-21-2013
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We performed a discovery genome-wide association study to identify genetic factors associated with variation in plasma estradiol (E2) concentrations using DNA from 772 postmenopausal women with estrogen receptor (ER)-positive breast cancer prior to the initiation of aromatase inhibitor therapy. Association analyses showed that the single nucleotide polymorphisms (SNP) (rs1864729) with the lowest P value (P = 3.49E-08), mapped to chromosome 8 near TSPYL5. We also identified 17 imputed SNPs in or near TSPYL5 with P values < 5E-08, one of which, rs2583506, created a functional estrogen response element. We then used a panel of lymphoblastoid cell lines (LCLs) stably transfected with ER? with known genome-wide SNP genotypes to demonstrate that TSPYL5 expression increased after E2 exposure of cells heterozygous for variant TSPYL5 SNP genotypes, but not in those homozygous for wild-type alleles. TSPYL5 knockdown decreased, and overexpression increased aromatase (CYP19A1) expression in MCF-7 cells, LCLs, and adipocytes through the skin/adipose (I.4) promoter. Chromatin immunoprecipitation assay showed that TSPYL5 bound to the CYP19A1 I.4 promoter. A putative TSPYL5 binding motif was identified in 43 genes, and TSPYL5 appeared to function as a transcription factor for most of those genes. In summary, genome-wide significant SNPs in TSPYL5 were associated with elevated plasma E2 in postmenopausal breast cancer patients. SNP rs2583506 created a functional estrogen response element, and LCLs with variant SNP genotypes displayed increased E2-dependent TSPYL5 expression. TSPYL5 induced CYP19A1 expression and that of many other genes. These studies have revealed a novel mechanism for regulating aromatase expression and plasma E2 concentrations in postmenopausal women with ER(+) breast cancer.
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Analysis of over 10,000 Cases finds no association between previously reported candidate polymorphisms and ovarian cancer outcome.
Kristin L White, Robert A Vierkant, Zachary C Fogarty, Bridget Charbonneau, Matthew S Block, Paul D P Pharoah, Georgia Chenevix-Trench, , Mary Anne Rossing, Daniel W Cramer, Celeste Leigh Pearce, Joellen M Schildkraut, Usha Menon, Susanne Krüger Kjaer, Douglas A Levine, Jacek Gronwald, Hoda Anton Culver, Alice S Whittemore, Beth Y Karlan, Diether Lambrechts, Nicolas Wentzensen, Jolanta Kupryjanczyk, Jenny Chang-Claude, Elisa V Bandera, Estrid Hogdall, Florian Heitz, Stanley B Kaye, Peter A Fasching, Ian Campbell, Marc T Goodman, Tanja Pejovic, Yukie Bean, Galina Lurie, Diana Eccles, Alexander Hein, Matthias W Beckmann, Arif B Ekici, James Paul, Robert Brown, James M Flanagan, Philipp Harter, Andreas du Bois, Ira Schwaab, Claus K Hogdall, Lene Lundvall, Sara H Olson, Irene Orlow, Lisa E Paddock, Anja Rudolph, Ursula Eilber, Agnieszka Dansonka-Mieszkowska, Iwona K Rzepecka, Izabela Ziolkowska-Seta, Louise Brinton, Hannah Yang, Montserrat Garcia-Closas, Evelyn Despierre, Sandrina Lambrechts, Ignace Vergote, Christine Walsh, Jenny Lester, Weiva Sieh, Valerie McGuire, Joseph H Rothstein, Argyrios Ziogas, Jan Lubiński, Cezary Cybulski, Janusz Menkiszak, Allan Jensen, Simon A Gayther, Susan J Ramus, Aleksandra Gentry-Maharaj, Andrew Berchuck, Anna H Wu, Malcolm C Pike, David Van Denberg, Kathryn L Terry, Allison F Vitonis, Jennifer A Doherty, Sharon E Johnatty, Anna deFazio, Honglin Song, Jonathan Tyrer, Thomas A Sellers, Catherine M Phelan, Kimberly R Kalli, Julie M Cunningham, Brooke L Fridley, Ellen L Goode.
Cancer Epidemiol. Biomarkers Prev.
PUBLISHED: 03-19-2013
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Ovarian cancer is a leading cause of cancer-related death among women. In an effort to understand contributors to disease outcome, we evaluated single-nucleotide polymorphisms (SNP) previously associated with ovarian cancer recurrence or survival, specifically in angiogenesis, inflammation, mitosis, and drug disposition genes.
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Epigenetic analysis leads to identification of HNF1B as a subtype-specific susceptibility gene for ovarian cancer.
Hui Shen, Brooke L Fridley, Honglin Song, Kate Lawrenson, Julie M Cunningham, Susan J Ramus, Mine S Cicek, Jonathan Tyrer, Douglas Stram, Melissa C Larson, Martin Köbel, , Argyrios Ziogas, Wei Zheng, Hannah P Yang, Anna H Wu, Eva L Wozniak, Yin Ling Woo, Boris Winterhoff, Elisabeth Wik, Alice S Whittemore, Nicolas Wentzensen, Rachel Palmieri Weber, Allison F Vitonis, Daniel Vincent, Robert A Vierkant, Ignace Vergote, David Van Den Berg, Anne M Van Altena, Shelley S Tworoger, Pamela J Thompson, Daniel C Tessier, Kathryn L Terry, Soo-Hwang Teo, Claire Templeman, Daniel O Stram, Melissa C Southey, Weiva Sieh, Nadeem Siddiqui, Yurii B Shvetsov, Xiao-Ou Shu, Viji Shridhar, Shan Wang-Gohrke, Gianluca Severi, Ira Schwaab, Helga B Salvesen, Iwona K Rzepecka, Ingo B Runnebaum, Mary Anne Rossing, Lorna Rodriguez-Rodriguez, Harvey A Risch, Stefan P Renner, Elizabeth M Poole, Malcolm C Pike, Catherine M Phelan, Liisa M Pelttari, Tanja Pejovic, James Paul, Irene Orlow, Siti Zawiah Omar, Sara H Olson, Kunle Odunsi, Stefan Nickels, Heli Nevanlinna, Roberta B Ness, Steven A Narod, Toru Nakanishi, Kirsten B Moysich, Alvaro N A Monteiro, Joanna Moes-Sosnowska, Francesmary Modugno, Usha Menon, John R McLaughlin, Valerie McGuire, Keitaro Matsuo, Noor Azmi Mat Adenan, Leon F A G Massuger, Galina Lurie, Lene Lundvall, Jan Lubiński, Jolanta Lissowska, Douglas A Levine, Arto Leminen, Alice W Lee, Nhu D Le, Sandrina Lambrechts, Diether Lambrechts, Jolanta Kupryjanczyk, Camilla Krakstad, Gottfried E Konecny, Susanne Krüger Kjaer, Lambertus A Kiemeney, Linda E Kelemen, Gary L Keeney, Beth Y Karlan, Rod Karevan, Kimberly R Kalli, Hiroaki Kajiyama, Bu-Tian Ji, Allan Jensen, Anna Jakubowska, Edwin Iversen, Satoyo Hosono, Claus K Høgdall, Estrid Høgdall, Maureen Hoatlin, Peter Hillemanns, Florian Heitz, Rebecca Hein, Philipp Harter, Mari K Halle, Per Hall, Jacek Gronwald, Martin Gore, Marc T Goodman, Graham G Giles, Aleksandra Gentry-Maharaj, Montserrat Garcia-Closas, James M Flanagan, Peter A Fasching, Arif B Ekici, Robert Edwards, Diana Eccles, Douglas F Easton, Matthias Dürst, Andreas du Bois, Thilo Dörk, Jennifer A Doherty, Evelyn Despierre, Agnieszka Dansonka-Mieszkowska, Cezary Cybulski, Daniel W Cramer, Linda S Cook, Xiaoqing Chen, Bridget Charbonneau, Jenny Chang-Claude, Ian Campbell, Ralf Bützow, Clareann H Bunker, Doerthe Brueggmann, Robert Brown, Angela Brooks-Wilson, Louise A Brinton, Natalia Bogdanova, Matthew S Block, Elizabeth Benjamin, Jonathan Beesley, Matthias W Beckmann, Elisa V Bandera, Laura Baglietto, Francois Bacot, Sebastian M Armasu, Natalia Antonenkova, Hoda Anton-Culver, Katja K Aben, Dong Liang, Xifeng Wu, Karen Lu, Michelle A T Hildebrandt, Joellen M Schildkraut, Thomas A Sellers, David Huntsman, Andrew Berchuck, Georgia Chenevix-Trench, Simon A Gayther, Paul D P Pharoah, Peter W Laird, Ellen L Goode, Celeste Leigh Pearce.
Nat Commun
PUBLISHED: 02-21-2013
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HNF1B is overexpressed in clear cell epithelial ovarian cancer, and we observed epigenetic silencing in serous epithelial ovarian cancer, leading us to hypothesize that variation in this gene differentially associates with epithelial ovarian cancer risk according to histological subtype. Here we comprehensively map variation in HNF1B with respect to epithelial ovarian cancer risk and analyse DNA methylation and expression profiles across histological subtypes. Different single-nucleotide polymorphisms associate with invasive serous (rs7405776 odds ratio (OR)=1.13, P=3.1 × 10(-10)) and clear cell (rs11651755 OR=0.77, P=1.6 × 10(-8)) epithelial ovarian cancer. Risk alleles for the serous subtype associate with higher HNF1B-promoter methylation in these tumours. Unmethylated, expressed HNF1B, primarily present in clear cell tumours, coincides with a CpG island methylator phenotype affecting numerous other promoters throughout the genome. Different variants in HNF1B associate with risk of serous and clear cell epithelial ovarian cancer; DNA methylation and expression patterns are also notably distinct between these subtypes. These findings underscore distinct mechanisms driving different epithelial ovarian cancer histological subtypes.
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Identification and molecular characterization of a new ovarian cancer susceptibility locus at 17q21.31.
Jennifer Permuth-Wey, Kate Lawrenson, Howard C Shen, Aneliya Velkova, Jonathan P Tyrer, Zhihua Chen, Hui-Yi Lin, Y Ann Chen, Ya-Yu Tsai, Xiaotao Qu, Susan J Ramus, Rod Karevan, Janet Lee, Nathan Lee, Melissa C Larson, Katja K Aben, Hoda Anton-Culver, Natalia Antonenkova, Antonis C Antoniou, Sebastian M Armasu, , Francois Bacot, Laura Baglietto, Elisa V Bandera, Jill Barnholtz-Sloan, Matthias W Beckmann, Michael J Birrer, Greg Bloom, Natalia Bogdanova, Louise A Brinton, Angela Brooks-Wilson, Robert Brown, Ralf Bützow, Qiuyin Cai, Ian Campbell, Jenny Chang-Claude, Stephen Chanock, Georgia Chenevix-Trench, Jin Q Cheng, Mine S Cicek, Gerhard A Coetzee, Linda S Cook, Fergus J Couch, Daniel W Cramer, Julie M Cunningham, Agnieszka Dansonka-Mieszkowska, Evelyn Despierre, Jennifer A Doherty, Thilo Dörk, Andreas du Bois, Matthias Dürst, Douglas F Easton, Diana Eccles, Robert Edwards, Arif B Ekici, Peter A Fasching, David A Fenstermacher, James M Flanagan, Montserrat Garcia-Closas, Aleksandra Gentry-Maharaj, Graham G Giles, Rosalind M Glasspool, Jesus Gonzalez-Bosquet, Marc T Goodman, Martin Gore, Bohdan Górski, Jacek Gronwald, Per Hall, Mari K Halle, Philipp Harter, Florian Heitz, Peter Hillemanns, Maureen Hoatlin, Claus K Høgdall, Estrid Høgdall, Satoyo Hosono, Anna Jakubowska, Allan Jensen, Heather Jim, Kimberly R Kalli, Beth Y Karlan, Stanley B Kaye, Linda E Kelemen, Lambertus A Kiemeney, Fumitaka Kikkawa, Gottfried E Konecny, Camilla Krakstad, Susanne Krüger Kjaer, Jolanta Kupryjanczyk, Diether Lambrechts, Sandrina Lambrechts, Johnathan M Lancaster, Nhu D Le, Arto Leminen, Douglas A Levine, Dong Liang, Boon Kiong Lim, Jie Lin, Jolanta Lissowska, Karen H Lu, Jan Lubiński, Galina Lurie, Leon F A G Massuger, Keitaro Matsuo, Valerie McGuire, John R McLaughlin, Usha Menon, Francesmary Modugno, Kirsten B Moysich, Toru Nakanishi, Steven A Narod, Lotte Nedergaard, Roberta B Ness, Heli Nevanlinna, Stefan Nickels, Houtan Noushmehr, Kunle Odunsi, Sara H Olson, Irene Orlow, James Paul, Celeste L Pearce, Tanja Pejovic, Liisa M Pelttari, Malcolm C Pike, Elizabeth M Poole, Paola Raska, Stefan P Renner, Harvey A Risch, Lorna Rodriguez-Rodriguez, Mary Anne Rossing, Anja Rudolph, Ingo B Runnebaum, Iwona K Rzepecka, Helga B Salvesen, Ira Schwaab, Gianluca Severi, Viji Shridhar, Xiao-Ou Shu, Yurii B Shvetsov, Weiva Sieh, Honglin Song, Melissa C Southey, Beata Spiewankiewicz, Daniel Stram, Rebecca Sutphen, Soo-Hwang Teo, Kathryn L Terry, Daniel C Tessier, Pamela J Thompson, Shelley S Tworoger, Anne M Van Altena, Ignace Vergote, Robert A Vierkant, Daniel Vincent, Allison F Vitonis, Shan Wang-Gohrke, Rachel Palmieri Weber, Nicolas Wentzensen, Alice S Whittemore, Elisabeth Wik, Lynne R Wilkens, Boris Winterhoff, Yin Ling Woo, Anna H Wu, Yong-Bing Xiang, Hannah P Yang, Wei Zheng, Argyrios Ziogas, Famida Zulkifli, Catherine M Phelan, Edwin Iversen, Joellen M Schildkraut, Andrew Berchuck, Brooke L Fridley, Ellen L Goode, Paul D P Pharoah, Alvaro N A Monteiro, Thomas A Sellers, Simon A Gayther.
Nat Commun
PUBLISHED: 02-18-2013
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Epithelial ovarian cancer (EOC) has a heritable component that remains to be fully characterized. Most identified common susceptibility variants lie in non-protein-coding sequences. We hypothesized that variants in the 3 untranslated region at putative microRNA (miRNA)-binding sites represent functional targets that influence EOC susceptibility. Here, we evaluate the association between 767 miRNA-related single-nucleotide polymorphisms (miRSNPs) and EOC risk in 18,174 EOC cases and 26,134 controls from 43 studies genotyped through the Collaborative Oncological Gene-environment Study. We identify several miRSNPs associated with invasive serous EOC risk (odds ratio=1.12, P=10(-8)) mapping to an inversion polymorphism at 17q21.31. Additional genotyping of non-miRSNPs at 17q21.31 reveals stronger signals outside the inversion (P=10(-10)). Variation at 17q21.31 is associated with neurological diseases, and our collaboration is the first to report an association with EOC susceptibility. An integrated molecular analysis in this region provides evidence for ARHGAP27 and PLEKHM1 as candidate EOC susceptibility genes.
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Cigarette smoking and risk of ovarian cancer: a pooled analysis of 21 case-control studies.
Cancer Causes Control
PUBLISHED: 02-11-2013
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The majority of previous studies have observed an increased risk of mucinous ovarian tumors associated with cigarette smoking, but the association with other histological types is unclear. In a large pooled analysis, we examined the risk of epithelial ovarian cancer associated with multiple measures of cigarette smoking with a focus on characterizing risks according to tumor behavior and histology.
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Multiple independent variants at the TERT locus are associated with telomere length and risks of breast and ovarian cancer.
Stig E Bojesen, Karen A Pooley, Sharon E Johnatty, Jonathan Beesley, Kyriaki Michailidou, Jonathan P Tyrer, Stacey L Edwards, Hilda A Pickett, Howard C Shen, Chanel E Smart, Kristine M Hillman, Phuong L Mai, Kate Lawrenson, Michael D Stutz, Yi Lu, Rod Karevan, Nicholas Woods, Rebecca L Johnston, Juliet D French, Xiaoqing Chen, Maren Weischer, Sune F Nielsen, Melanie J Maranian, Maya Ghoussaini, Shahana Ahmed, Caroline Baynes, Manjeet K Bolla, Qin Wang, Joe Dennis, Lesley McGuffog, Daniel Barrowdale, Andrew Lee, Sue Healey, Michael Lush, Daniel C Tessier, Daniel Vincent, Françis Bacot, , Ignace Vergote, Sandrina Lambrechts, Evelyn Despierre, Harvey A Risch, Anna González-Neira, Mary Anne Rossing, Guillermo Pita, Jennifer A Doherty, Nuria Alvarez, Melissa C Larson, Brooke L Fridley, Nils Schoof, Jenny Chang-Claude, Mine S Cicek, Julian Peto, Kimberly R Kalli, Annegien Broeks, Sebastian M Armasu, Marjanka K Schmidt, Linde M Braaf, Boris Winterhoff, Heli Nevanlinna, Gottfried E Konecny, Diether Lambrechts, Lisa Rogmann, Pascal Guénel, Attila Teoman, Roger L Milne, Joaquín J García, Angela Cox, Vijayalakshmi Shridhar, Barbara Burwinkel, Frederik Marme, Rebecca Hein, Elinor J Sawyer, Christopher A Haiman, Shan Wang-Gohrke, Irene L Andrulis, Kirsten B Moysich, John L Hopper, Kunle Odunsi, Annika Lindblom, Graham G Giles, Hermann Brenner, Jacques Simard, Galina Lurie, Peter A Fasching, Michael E Carney, Paolo Radice, Lynne R Wilkens, Anthony Swerdlow, Marc T Goodman, Hiltrud Brauch, Montserrat Garcia-Closas, Peter Hillemanns, Robert Winqvist, Matthias Dürst, Peter Devilee, Ingo Runnebaum, Anna Jakubowska, Jan Lubiński, Arto Mannermaa, Ralf Bützow, Natalia V Bogdanova, Thilo Dörk, Liisa M Pelttari, Wei Zheng, Arto Leminen, Hoda Anton-Culver, Clareann H Bunker, Vessela Kristensen, Roberta B Ness, Kenneth Muir, Robert Edwards, Alfons Meindl, Florian Heitz, Keitaro Matsuo, Andreas du Bois, Anna H Wu, Philipp Harter, Soo-Hwang Teo, Ira Schwaab, Xiao-Ou Shu, William Blot, Satoyo Hosono, Daehee Kang, Toru Nakanishi, Mikael Hartman, Yasushi Yatabe, Ute Hamann, Beth Y Karlan, Suleeporn Sangrajrang, Susanne Krüger Kjaer, Valerie Gaborieau, Allan Jensen, Diana Eccles, Estrid Høgdall, Chen-Yang Shen, Judith Brown, Yin Ling Woo, Mitul Shah, Mat Adenan Noor Azmi, Robert Luben, Siti Zawiah Omar, Kamila Czene, Robert A Vierkant, Børge G Nordestgaard, Henrik Flyger, Celine Vachon, Janet E Olson, Xianshu Wang, Douglas A Levine, Anja Rudolph, Rachel Palmieri Weber, Dieter Flesch-Janys, Edwin Iversen, Stefan Nickels, Joellen M Schildkraut, Isabel dos Santos Silva, Daniel W Cramer, Lorna Gibson, Kathryn L Terry, Olivia Fletcher, Allison F Vitonis, C Ellen van der Schoot, Elizabeth M Poole, Frans B L Hogervorst, Shelley S Tworoger, Jianjun Liu, Elisa V Bandera, Jingmei Li, Sara H Olson, Keith Humphreys, Irene Orlow, Carl Blomqvist, Lorna Rodriguez-Rodriguez, Kristiina Aittomäki, Helga B Salvesen, Taru A Muranen, Elisabeth Wik, Barbara Brouwers, Camilla Krakstad, Els Wauters, Mari K Halle, Hans Wildiers, Lambertus A Kiemeney, Claire Mulot, Katja K Aben, Pierre Laurent-Puig, Anne Mvan Altena, Thérèse Truong, Leon F A G Massuger, Javier Benitez, Tanja Pejovic, Jose Ignacio Arias Perez, Maureen Hoatlin, M Pilar Zamora, Linda S Cook, Sabapathy P Balasubramanian, Linda E Kelemen, Andreas Schneeweiss, Nhu D Le, Christof Sohn, Angela Brooks-Wilson, Ian Tomlinson, Michael J Kerin, Nicola Miller, Cezary Cybulski, Brian E Henderson, Janusz Menkiszak, Fredrick Schumacher, Nicolas Wentzensen, Loic Le Marchand, Hannah P Yang, Anna Marie Mulligan, Gord Glendon, Svend Aage Engelholm, Julia A Knight, Claus K Høgdall, Carmel Apicella, Martin Gore, Helen Tsimiklis, Honglin Song, Melissa C Southey, Agnes Jager, Ans M Wvan den Ouweland, Robert Brown, John W M Martens, James M Flanagan, Mieke Kriege, James Paul, Sara Margolin, Nadeem Siddiqui, Gianluca Severi, Alice S Whittemore, Laura Baglietto, Valerie McGuire, Christa Stegmaier, Weiva Sieh, Heiko Muller, Volker Arndt, France Labrèche, Yu-Tang Gao, Mark S Goldberg, Gong Yang, Martine Dumont, John R McLaughlin, Arndt Hartmann, Arif B Ekici, Matthias W Beckmann, Catherine M Phelan, Michael P Lux, Jenny Permuth-Wey, Bernard Peissel, Thomas A Sellers, Filomena Ficarazzi, Monica Barile, Argyrios Ziogas, Alan Ashworth, Aleksandra Gentry-Maharaj, Michael Jones, Susan J Ramus, Nick Orr, Usha Menon, Celeste L Pearce, Thomas Brüning, Malcolm C Pike, Yon-Dschun Ko, Jolanta Lissowska, Jonine Figueroa, Jolanta Kupryjanczyk, Stephen J Chanock, Agnieszka Dansonka-Mieszkowska, Arja Jukkola-Vuorinen, Iwona K Rzepecka, Katri Pylkäs, Mariusz Bidzinski, Saila Kauppila, Antoinette Hollestelle, Caroline Seynaeve, Rob A E M Tollenaar, Katarzyna Durda, Katarzyna Jaworska, Jaana M Hartikainen, Veli-Matti Kosma, Vesa Kataja, Natalia N Antonenkova, Jirong Long, Martha Shrubsole, Sandra Deming-Halverson, Artitaya Lophatananon, Pornthep Siriwanarangsan, Sarah Stewart-Brown, Nina Ditsch, Peter Lichtner, Rita K Schmutzler, Hidemi Ito, Hiroji Iwata, Kazuo Tajima, Chiu-Chen Tseng, Daniel O Stram, David Van Den Berg, Cheng Har Yip, M Kamran Ikram, Yew-Ching Teh, Hui Cai, Wei Lu, Lisa B Signorello, Qiuyin Cai, Dong-Young Noh, Keun-Young Yoo, Hui Miao, Philip Tsau-Choong Iau, Yik Ying Teo, James McKay, Charles Shapiro, Foluso Ademuyiwa, George Fountzilas, Chia-Ni Hsiung, Jyh-Cherng Yu, Ming-Feng Hou, Catherine S Healey, Craig Luccarini, Susan Peock, Dominique Stoppa-Lyonnet, Paolo Peterlongo, Timothy R Rebbeck, Marion Piedmonte, Christian F Singer, Eitan Friedman, Mads Thomassen, Kenneth Offit, Thomas V O Hansen, Susan L Neuhausen, Csilla I Szabo, Ignacio Blanco, Judy Garber, Steven A Narod, Jeffrey N Weitzel, Marco Montagna, Edith Olah, Andrew K Godwin, Drakoulis Yannoukakos, David E Goldgar, Trinidad Caldés, Evgeny N Imyanitov, Laima Tihomirova, Banu K Arun, Ian Campbell, Arjen R Mensenkamp, Christi J van Asperen, Kees E P van Roozendaal, Hanne Meijers-Heijboer, J Margriet Collée, Jan C Oosterwijk, Maartje J Hooning, Matti A Rookus, Rob B van der Luijt, Theo A Mvan Os, D Gareth Evans, Debra Frost, Elena Fineberg, Julian Barwell, Lisa Walker, M John Kennedy, Radka Platte, Rosemarie Davidson, Steve D Ellis, Trevor Cole, Brigitte Bressac-de Paillerets, Bruno Buecher, Francesca Damiola, Laurence Faivre, Marc Frénay, Olga M Sinilnikova, Olivier Caron, Sophie Giraud, Sylvie Mazoyer, Valérie Bonadona, Virginie Caux-Moncoutier, Aleksandra Toloczko-Grabarek, Jacek Gronwald, Tomasz Byrski, Amanda B Spurdle, Bernardo Bonanni, Daniela Zaffaroni, Giuseppe Giannini, Loris Bernard, Riccardo Dolcetti, Siranoush Manoukian, Norbert Arnold, Christoph Engel, Helmut Deissler, Kerstin Rhiem, Dieter Niederacher, Hansjoerg Plendl, Christian Sutter, Barbara Wappenschmidt, Ake Borg, Beatrice Melin, Johanna Rantala, Maria Soller, Katherine L Nathanson, Susan M Domchek, Gustavo C Rodriguez, Ritu Salani, Daphne Gschwantler Kaulich, Muy-Kheng Tea, Shani Shimon Paluch, Yael Laitman, Anne-Bine Skytte, Torben A Kruse, Uffe Birk Jensen, Mark Robson, Anne-Marie Gerdes, Bent Ejlertsen, Lenka Foretova, Sharon A Savage, Jenny Lester, Penny Soucy, Karoline B Kuchenbaecker, Curtis Olswold, Julie M Cunningham, Susan Slager, Vernon S Pankratz, Ed Dicks, Sunil R Lakhani, Fergus J Couch, Per Hall, Alvaro N A Monteiro, Simon A Gayther, Paul D P Pharoah, Roger R Reddel, Ellen L Goode, Mark H Greene, Douglas F Easton, Andrew Berchuck, Antonis C Antoniou, Georgia Chenevix-Trench, Alison M Dunning.
Nat. Genet.
PUBLISHED: 01-31-2013
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TERT-locus SNPs and leukocyte telomere measures are reportedly associated with risks of multiple cancers. Using the Illumina custom genotyping array iCOGs, we analyzed ?480 SNPs at the TERT locus in breast (n = 103,991), ovarian (n = 39,774) and BRCA1 mutation carrier (n = 11,705) cancer cases and controls. Leukocyte telomere measurements were also available for 53,724 participants. Most associations cluster into three independent peaks. The minor allele at the peak 1 SNP rs2736108 associates with longer telomeres (P = 5.8 × 10(-7)), lower risks for estrogen receptor (ER)-negative (P = 1.0 × 10(-8)) and BRCA1 mutation carrier (P = 1.1 × 10(-5)) breast cancers and altered promoter assay signal. The minor allele at the peak 2 SNP rs7705526 associates with longer telomeres (P = 2.3 × 10(-14)), higher risk of low-malignant-potential ovarian cancer (P = 1.3 × 10(-15)) and greater promoter activity. The minor alleles at the peak 3 SNPs rs10069690 and rs2242652 increase ER-negative (P = 1.2 × 10(-12)) and BRCA1 mutation carrier (P = 1.6 × 10(-14)) breast and invasive ovarian (P = 1.3 × 10(-11)) cancer risks but not via altered telomere length. The cancer risk alleles of rs2242652 and rs10069690, respectively, increase silencing and generate a truncated TERT splice variant.
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Survival is associated with genetic variation in inflammatory pathway genes among patients with resected and unresected pancreatic cancer.
Ann. Surg.
PUBLISHED: 01-31-2013
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To test whether or not the association between inflammation and pancreatic ductal adenocarcinoma (PC) is facilitated by host susceptibility, specifically by genetic polymorphisms in inflammation-related genes.
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GWAS meta-analysis and replication identifies three new susceptibility loci for ovarian cancer.
Paul D P Pharoah, Ya-Yu Tsai, Susan J Ramus, Catherine M Phelan, Ellen L Goode, Kate Lawrenson, Melissa Buckley, Brooke L Fridley, Jonathan P Tyrer, Howard Shen, Rachel Weber, Rod Karevan, Melissa C Larson, Honglin Song, Daniel C Tessier, Francois Bacot, Daniel Vincent, Julie M Cunningham, Joe Dennis, Ed Dicks, , Katja K Aben, Hoda Anton-Culver, Natalia Antonenkova, Sebastian M Armasu, Laura Baglietto, Elisa V Bandera, Matthias W Beckmann, Michael J Birrer, Greg Bloom, Natalia Bogdanova, James D Brenton, Louise A Brinton, Angela Brooks-Wilson, Robert Brown, Ralf Bützow, Ian Campbell, Michael E Carney, Renato S Carvalho, Jenny Chang-Claude, Y Anne Chen, Zhihua Chen, Wong-Ho Chow, Mine S Cicek, Gerhard Coetzee, Linda S Cook, Daniel W Cramer, Cezary Cybulski, Agnieszka Dansonka-Mieszkowska, Evelyn Despierre, Jennifer A Doherty, Thilo Dörk, Andreas du Bois, Matthias Dürst, Diana Eccles, Robert Edwards, Arif B Ekici, Peter A Fasching, David Fenstermacher, James Flanagan, Yu-Tang Gao, Montserrat Garcia-Closas, Aleksandra Gentry-Maharaj, Graham Giles, Anxhela Gjyshi, Martin Gore, Jacek Gronwald, Qi Guo, Mari K Halle, Philipp Harter, Alexander Hein, Florian Heitz, Peter Hillemanns, Maureen Hoatlin, Estrid Høgdall, Claus K Høgdall, Satoyo Hosono, Anna Jakubowska, Allan Jensen, Kimberly R Kalli, Beth Y Karlan, Linda E Kelemen, Lambertus A Kiemeney, Susanne Krüger Kjaer, Gottfried E Konecny, Camilla Krakstad, Jolanta Kupryjanczyk, Diether Lambrechts, Sandrina Lambrechts, Nhu D Le, Nathan Lee, Janet Lee, Arto Leminen, Boon Kiong Lim, Jolanta Lissowska, Jan Lubiński, Lene Lundvall, Galina Lurie, Leon F A G Massuger, Keitaro Matsuo, Valerie McGuire, John R McLaughlin, Usha Menon, Francesmary Modugno, Kirsten B Moysich, Toru Nakanishi, Steven A Narod, Roberta B Ness, Heli Nevanlinna, Stefan Nickels, Houtan Noushmehr, Kunle Odunsi, Sara Olson, Irene Orlow, James Paul, Tanja Pejovic, Liisa M Pelttari, Jenny Permuth-Wey, Malcolm C Pike, Elizabeth M Poole, Xiaotao Qu, Harvey A Risch, Lorna Rodriguez-Rodriguez, Mary Anne Rossing, Anja Rudolph, Ingo Runnebaum, Iwona K Rzepecka, Helga B Salvesen, Ira Schwaab, Gianluca Severi, Hui Shen, Vijayalakshmi Shridhar, Xiao-Ou Shu, Weiva Sieh, Melissa C Southey, Paul Spellman, Kazuo Tajima, Soo-Hwang Teo, Kathryn L Terry, Pamela J Thompson, Agnieszka Timorek, Shelley S Tworoger, Anne M Van Altena, David Van Den Berg, Ignace Vergote, Robert A Vierkant, Allison F Vitonis, Shan Wang-Gohrke, Nicolas Wentzensen, Alice S Whittemore, Elisabeth Wik, Boris Winterhoff, Yin Ling Woo, Anna H Wu, Hannah P Yang, Wei Zheng, Argyrios Ziogas, Famida Zulkifli, Marc T Goodman, Per Hall, Douglas F Easton, Celeste L Pearce, Andrew Berchuck, Georgia Chenevix-Trench, Edwin Iversen, Alvaro N A Monteiro, Simon A Gayther, Joellen M Schildkraut, Thomas A Sellers.
Nat. Genet.
PUBLISHED: 01-30-2013
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Genome-wide association studies (GWAS) have identified four susceptibility loci for epithelial ovarian cancer (EOC), with another two suggestive loci reaching near genome-wide significance. We pooled data from a GWAS conducted in North America with another GWAS from the UK. We selected the top 24,551 SNPs for inclusion on the iCOGS custom genotyping array. We performed follow-up genotyping in 18,174 individuals with EOC (cases) and 26,134 controls from 43 studies from the Ovarian Cancer Association Consortium. We validated the two loci at 3q25 and 17q21 that were previously found to have associations close to genome-wide significance and identified three loci newly associated with risk: two loci associated with all EOC subtypes at 8q21 (rs11782652, P = 5.5 × 10(-9)) and 10p12 (rs1243180, P = 1.8 × 10(-8)) and another locus specific to the serous subtype at 17q12 (rs757210, P = 8.1 × 10(-10)). An integrated molecular analysis of genes and regulatory regions at these loci provided evidence for functional mechanisms underlying susceptibility and implicated CHMP4C in the pathogenesis of ovarian cancer.
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Inherited variants in regulatory T cell genes and outcome of ovarian cancer.
PLoS ONE
PUBLISHED: 01-30-2013
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Although ovarian cancer is the most lethal of gynecologic malignancies, wide variation in outcome following conventional therapy continues to exist. The presence of tumor-infiltrating regulatory T cells (Tregs) has a role in outcome of this disease, and a growing body of data supports the existence of inherited prognostic factors. However, the role of inherited variants in genes encoding Treg-related immune molecules has not been fully explored. We analyzed expression quantitative trait loci (eQTL) and sequence-based tagging single nucleotide polymorphisms (tagSNPs) for 54 genes associated with Tregs in 3,662 invasive ovarian cancer cases. With adjustment for known prognostic factors, suggestive results were observed among rarer histological subtypes; poorer survival was associated with minor alleles at SNPs in RGS1 (clear cell, rs10921202, p=2.7×10(-5)), LRRC32 and TNFRSF18/TNFRSF4 (mucinous, rs3781699, p=4.5×10(-4), and rs3753348, p=9.0×10(-4), respectively), and CD80 (endometrioid, rs13071247, p=8.0×10(-4)). Fo0r the latter, correlative data support a CD80 rs13071247 genotype association with CD80 tumor RNA expression (p=0.006). An additional eQTL SNP in CD80 was associated with shorter survival (rs7804190, p=8.1×10(-4)) among all cases combined. As the products of these genes are known to affect induction, trafficking, or immunosuppressive function of Tregs, these results suggest the need for follow-up phenotypic studies.
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Inherited variant on chromosome 11q23 increases susceptibility to IDH-mutated but not IDH-normal gliomas regardless of grade or histology.
Neuro-oncology
PUBLISHED: 01-29-2013
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Recent discoveries of inherited glioma risk loci and acquired IDH mutations are providing new insights into glioma etiology. IDH mutations are common in lower grade gliomas and secondary glioblastomas and uncommon in primary glioblastomas. Because the inherited variant in 11q23 has been associated with risk of lower grade glioma and not with glioblastomas, we hypothesized that this variant increases susceptibility to IDH-mutated gliomas, but not to IDH-wild-type gliomas.
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FKBP5 genetic variation: association with selective serotonin reuptake inhibitor treatment outcomes in major depressive disorder.
Pharmacogenet. Genomics
PUBLISHED: 01-18-2013
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FKBP51 (51 kDa immunophilin) acts as a modulator of the glucocorticoid receptor and a negative regulator of the Akt pathway. Genetic variation in FKBP5 plays a role in antidepressant response. The aim of this study was to comprehensively assess the role of genetic variation in FKBP5, identified by both Sanger and Next Generation DNA resequencing, as well as genome-wide single nucleotide polymorphisms (SNPs) associated with FKBP5 expression in the response to the selective serotonin reuptake inhibitor (SSRI) treatment of major depressive disorder.
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Kernel canonical correlation analysis for assessing gene-gene interactions and application to ovarian cancer.
Eur. J. Hum. Genet.
PUBLISHED: 01-11-2013
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Although single-locus approaches have been widely applied to identify disease-associated single-nucleotide polymorphisms (SNPs), complex diseases are thought to be the product of multiple interactions between loci. This has led to the recent development of statistical methods for detecting statistical interactions between two loci. Canonical correlation analysis (CCA) has previously been proposed to detect gene-gene coassociation. However, this approach is limited to detecting linear relations and can only be applied when the number of observations exceeds the number of SNPs in a gene. This limitation is particularly important for next-generation sequencing, which could yield a large number of novel variants on a limited number of subjects. To overcome these limitations, we propose an approach to detect gene-gene interactions on the basis of a kernelized version of CCA (KCCA). Our simulation studies showed that KCCA controls the Type-I error, and is more powerful than leading gene-based approaches under a disease model with negligible marginal effects. To demonstrate the utility of our approach, we also applied KCCA to assess interactions between 200 genes in the NF-?B pathway in relation to ovarian cancer risk in 3869 cases and 3276 controls. We identified 13 significant gene pairs relevant to ovarian cancer risk (local false discovery rate <0.05). Finally, we discuss the advantages of KCCA in gene-gene interaction analysis and its future role in genetic association studies.
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Genome-wide association study for biomarker identification of Rapamycin and Everolimus using a lymphoblastoid cell line system.
Front Genet
PUBLISHED: 01-01-2013
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The mammalian target of rapamycin (mTOR) inhibitors, a set of promising potential anti-cancer agents, has shown response variability among individuals. This study aimed to identify novel biomarkers and mechanisms that might influence the response to Rapamycin and Everolimus. Genome-wide association (GWA) analyses involving single nucleotide polymorphisms (SNPs), mRNA, and microRNAs microarray data were assessed for association with area under the cytotoxicity dose response curve (AUC) of two mTOR inhibitors in 272 human lymphoblastoid cell lines (LCLs). Integrated analysis among SNPs, expression data, microRNA data and AUC values were also performed to help select candidate genes for further functional characterization. Functional validation of candidate genes using siRNA screening in multiple cell lines followed by MTS assays for the two mTOR inhibitors were performed. We found that 16 expression probe sets (genes) that overlapped between the two drugs were associated with AUC values of two mTOR inhibitors. One hundred and twenty seven and one hundred SNPs had P < 10(-4), while 8 and 10 SNPs had P < 10(-5) with Rapamycin and Everolimus AUC, respectively. Functional studies indicated that 13 genes significantly altered cell sensitivity to either one or both drugs in at least one cell line. Additionally, one microRNA, miR-10a, was significantly associated with AUC values for both drugs and was shown to repress expression of genes that were associated with AUC and desensitize cells to both drugs. In summary, this study identified genes and a microRNA that might contribute to response to mTOR inhibitors.
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Contribution of FKBP5 genetic variation to gemcitabine treatment and survival in pancreatic adenocarcinoma.
PLoS ONE
PUBLISHED: 01-01-2013
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FKBP51, (FKBP5), is a negative regulator of Akt. Variability in FKBP5 expression level is a major factor contributing to variation in response to chemotherapeutic agents including gemcitabine, a first line treatment for pancreatic cancer. Genetic variation in FKBP5 could influence its function and, ultimately, treatment response of pancreatic cancer.
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Obesity and risk of ovarian cancer subtypes: evidence from the Ovarian Cancer Association Consortium.
Endocr. Relat. Cancer
PUBLISHED: 01-01-2013
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Whilst previous studies have reported that higher BMI increases a womans risk of developing ovarian cancer, associations for the different histological subtypes have not been well defined. As the prevalence of obesity has increased dramatically, and classification of ovarian histology has improved in the last decade, we sought to examine the association in a pooled analysis of recent studies participating in the Ovarian Cancer Association Consortium. We evaluated the association between BMI (recent, maximum and in young adulthood) and ovarian cancer risk using original data from 15 case-control studies (13?548 cases and 17?913 controls). We combined study-specific adjusted odds ratios (ORs) using a random-effects model. We further examined the associations by histological subtype, menopausal status and post-menopausal hormone use. High BMI (all time-points) was associated with increased risk. This was most pronounced for borderline serous (recent BMI: pooled OR=1.24 per 5?kg/m(2); 95% CI 1.18-1.30), invasive endometrioid (1.17; 1.11-1.23) and invasive mucinous (1.19; 1.06-1.32) tumours. There was no association with serous invasive cancer overall (0.98; 0.94-1.02), but increased risks for low-grade serous invasive tumours (1.13, 1.03-1.25) and in pre-menopausal women (1.11; 1.04-1.18). Among post-menopausal women, the associations did not differ between hormone replacement therapy users and non-users. Whilst obesity appears to increase risk of the less common histological subtypes of ovarian cancer, it does not increase risk of high-grade invasive serous cancers, and reducing BMI is therefore unlikely to prevent the majority of ovarian cancer deaths. Other modifiable factors must be identified to control this disease.
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Use of the gamma method for self-contained gene-set analysis of SNP data.
Eur. J. Hum. Genet.
PUBLISHED: 12-14-2011
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Gene-set analysis (GSA) evaluates the overall evidence of association between a phenotype and all genotyped single nucleotide polymorphisms (SNPs) in a set of genes, as opposed to testing for association between a phenotype and each SNP individually. We propose using the Gamma Method (GM) to combine gene-level P-values for assessing the significance of GS association. We performed simulations to compare the GM with several other self-contained GSA strategies, including both one-step and two-step GSA approaches, in a variety of scenarios. We denote a one-step GSA approach to be one in which all SNPs in a GS are used to derive a test of GS association without consideration of gene-level effects, and a two-step approach to be one in which all genotyped SNPs in a gene are first used to evaluate association of the phenotype with all measured variation in the gene and then the gene-level tests of association are aggregated to assess the GS association with the phenotype. The simulations suggest that, overall, two-step methods provide higher power than one-step approaches and that combining gene-level P-values using the GM with a soft truncation threshold between 0.05 and 0.20 is a powerful approach for conducting GSA, relative to the competing approaches assessed. We also applied all of the considered GSA methods to data from a pharmacogenomic study of cisplatin, and obtained evidence suggesting that the glutathione metabolism GS is associated with cisplatin drug response.
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Association of TNFSF8 polymorphisms with peripheral neutrophil count.
Mayo Clin. Proc.
PUBLISHED: 10-29-2011
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To investigate the association between 347 single-nucleotide polymorphisms within candidate genes of the tumor necrosis factor, interleukin 1 and interleukin 6 families with neutrophil count.
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Gene set analysis of purine and pyrimidine antimetabolites cancer therapies.
Pharmacogenet. Genomics
PUBLISHED: 08-27-2011
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Responses to therapies, either with regard to toxicities or efficacy, are expected to involve complex relationships of gene products within the same molecular pathway or functional gene set. Therefore, pathways or gene sets, as opposed to single genes, may better reflect the true underlying biology and may be more appropriate units for analysis of pharmacogenomic studies. Application of such methods to pharmacogenomic studies may enable the detection of more subtle effects of multiple genes in the same pathway that may be missed by assessing each gene individually.
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Functional polymorphisms in the TERT promoter are associated with risk of serous epithelial ovarian and breast cancers.
PLoS ONE
PUBLISHED: 08-12-2011
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Genetic variation at the TERT-CLPTM1L locus at 5p15.33 is associated with susceptibility to several cancers, including epithelial ovarian cancer (EOC). We have carried out fine-mapping of this region in EOC which implicates an association with a single nucleotide polymorphism (SNP) within the TERT promoter. We demonstrate that the minor alleles at rs2736109, and at an additional TERT promoter SNP, rs2736108, are associated with decreased breast cancer risk, and that the combination of both SNPs substantially reduces TERT promoter activity.
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Genetic variation predicting cisplatin cytotoxicity associated with overall survival in lung cancer patients receiving platinum-based chemotherapy.
Clin. Cancer Res.
PUBLISHED: 07-20-2011
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Inherited variability in the prognosis of lung cancer patients treated with platinum-based chemotherapy has been widely investigated. However, the overall contribution of genetic variation to platinum response is not well established. To identify novel candidate single nucleotide polymorphisms (SNP)/genes, we carried out a genome-wide association study (GWAS) for cisplatin cytotoxicity by using lymphoblastoid cell lines (LCL), followed by an association study of selected SNPs from the GWAS with overall survival (OS) in lung cancer patients.
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Meta-analysis of 8q24 for seven cancers reveals a locus between NOV and ENPP2 associated with cancer development.
BMC Med. Genet.
PUBLISHED: 07-14-2011
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Human chromosomal region 8q24 contains several genes which could be functionally related to cancer, including the proto-oncogene c-MYC. However, the abundance of associations around 128 Mb on chromosome 8 could mask the appearance of a weaker, but important, association elsewhere on 8q24.
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Associations of high-grade glioma with glioma risk alleles and histories of allergy and smoking.
Am. J. Epidemiol.
PUBLISHED: 07-08-2011
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Glioma risk has consistently been inversely associated with allergy history but not with smoking history despite putative biologic plausibility. Data from 855 high-grade glioma cases and 1,160 controls from 4 geographic regions of the United States during 1997-2008 were analyzed for interactions between allergy and smoking histories and inherited variants in 5 established glioma risk regions: 5p15.3 (TERT), 8q24.21 (CCDC26/MLZE), 9p21.3 (CDKN2B), 11q23.3 (PHLDB1/DDX6), and 20q13.3 (RTEL1). The inverse relation between allergy and glioma was stronger among those who did not (odds ratio(allergy-glioma) = 0.40, 95% confidence interval: 0.28, 0.58) versus those who did (odds ratio(allergy-glioma) = 0.76, 95% confidence interval: 0.59, 0.97; P(interaction) = 0.02) carry the 9p21.3 risk allele. However, the inverse association with allergy was stronger among those who carried (odds ratio(allergy-glioma) = 0.44, 95% confidence interval: 0.29, 0.68) versus those who did not carry (odds ratio(allergy-glioma) = 0.68, 95% confidence interval: 0.54, 0.86) the 20q13.3 glioma risk allele, but this interaction was not statistically significant (P = 0.14). No relation was observed between glioma risk and smoking (odds ratio = 0.92, 95% confidence interval: 0.77, 1.10; P = 0.37), and there were no interactions for glioma risk of smoking history with any of the risk alleles. The authors observations are consistent with a recent report that the inherited glioma risk variants in chromosome regions 9p21.3 and 20q13.3 may modify the inverse association of allergy and glioma.
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Gene set analysis of SNP data: benefits, challenges, and future directions.
Eur. J. Hum. Genet.
PUBLISHED: 04-13-2011
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The last decade of human genetic research witnessed the completion of hundreds of genome-wide association studies (GWASs). However, the genetic variants discovered through these efforts account for only a small proportion of the heritability of complex traits. One explanation for the missing heritability is that the common analysis approach, assessing the effect of each single-nucleotide polymorphism (SNP) individually, is not well suited to the detection of small effects of multiple SNPs. Gene set analysis (GSA) is one of several approaches that may contribute to the discovery of additional genetic risk factors for complex traits. Complex phenotypes are thought to be controlled by networks of interacting biochemical and physiological pathways influenced by the products of sets of genes. By assessing the overall evidence of association of a phenotype with all measured variation in a set of genes, GSA may identify functionally relevant sets of genes corresponding to relevant biomolecular pathways, which will enable more focused studies of genetic risk factors. This approach may thus contribute to the discovery of genetic variants responsible for some of the missing heritability. With the increased use of these approaches for the secondary analysis of data from GWAS, it is important to understand the different GSA methods and their strengths and weaknesses, and consider challenges inherent in these types of analyses. This paper provides an overview of GSA, highlighting the key challenges, potential solutions, and directions for ongoing research.
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Polymorphisms in stromal genes and susceptibility to serous epithelial ovarian cancer: a report from the Ovarian Cancer Association Consortium.
PLoS ONE
PUBLISHED: 04-12-2011
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Alterations in stromal tissue components can inhibit or promote epithelial tumorigenesis. Decorin (DCN) and lumican (LUM) show reduced stromal expression in serous epithelial ovarian cancer (sEOC). We hypothesized that common variants in these genes associate with risk. Associations with sEOC among Caucasians were estimated with odds ratios (OR) among 397 cases and 920 controls in two U.S.-based studies (discovery set), 436 cases and 1,098 controls in Australia (replication set 1) and a consortium of 15 studies comprising 1,668 cases and 4,249 controls (replication set 2). The discovery set and replication set 1 (833 cases and 2,013 controls) showed statistically homogeneous (P(heterogeneity)?0.48) decreased risks of sEOC at four variants: DCN rs3138165, rs13312816 and rs516115, and LUM rs17018765 (OR?=?0.6 to 0.9; P(trend)?=?0.001 to 0.03). Results from replication set 2 were statistically homogeneous (P(heterogeneity)?0.13) and associated with increased risks at DCN rs3138165 and rs13312816, and LUM rs17018765: all ORs?=?1.2; P(trend)?0.02. The ORs at the four variants were statistically heterogeneous across all 18 studies (P(heterogeneity)?0.03), which precluded combining. In post-hoc analyses, interactions were observed between each variant and recruitment period (P(interaction)?0.003), age at diagnosis (P(interaction)?=?0.04), and year of diagnosis (P(interaction)?=?0.05) in the five studies with available information (1,044 cases, 2,469 controls). We conclude that variants in DCN and LUM are not directly associated with sEOC, and that confirmation of possible effect modification of the variants by non-genetic factors is required.
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LIN28B polymorphisms influence susceptibility to epithelial ovarian cancer.
Cancer Res.
PUBLISHED: 04-11-2011
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Defective microRNA (miRNA) biogenesis contributes to the development and progression of epithelial ovarian cancer (EOC). In this study, we examined the hypothesis that single nucleotide polymorphisms (SNP) in miRNA biogenesis genes may influence EOC risk. In an initial investigation, 318 SNPs in 18 genes were evaluated among 1,815 EOC cases and 1,900 controls, followed up by a replicative joint meta-analysis of data from an additional 2,172 cases and 3,052 controls. Of 23 SNPs from 9 genes associated with risk (empirical P < 0.05) in the initial investigation, the meta-analysis replicated 6 SNPs from the DROSHA, FMR1, LIN28, and LIN28B genes, including rs12194974 (G>A), an SNP in a putative transcription factor binding site in the LIN28B promoter region (summary OR = 0.90, 95% CI: 0.82-0.98; P = 0.015) which has been recently implicated in age of menarche and other phenotypes. Consistent with reports that LIN28B overexpression in EOC contributes to tumorigenesis by repressing tumor suppressor let-7 expression, we provide data from luciferase reporter assays and quantitative RT-PCR to suggest that the inverse association among rs12194974 A allele carriers may be because of reduced LIN28B expression. Our findings suggest that variants in LIN28B and possibly other miRNA biogenesis genes may influence EOC susceptibility.
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Inflammation-related gene variants as risk factors for pancreatic cancer.
Cancer Epidemiol. Biomarkers Prev.
PUBLISHED: 04-05-2011
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Recent reports support an association between chronic inflammation and progression to pancreatic cancer (PC).
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Inherited variants in mitochondrial biogenesis genes may influence epithelial ovarian cancer risk.
Cancer Epidemiol. Biomarkers Prev.
PUBLISHED: 03-29-2011
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Mitochondria contribute to oxidative stress, a phenomenon implicated in ovarian carcinogenesis. We hypothesized that inherited variants in mitochondrial-related genes influence epithelial ovarian cancer (EOC) susceptibility.
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Polymorphisms in ABCB1 and ERCC2 associated with ovarian cancer outcome.
Int J Mol Epidemiol Genet
PUBLISHED: 03-11-2011
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Using the most comprehensive approach to selecting polymorphisms to date, we sought to examine whether time to recurrence in ovarian cancer was associated with common inherited variation in eight genes involved in drug metabolism, multi-drug resistance, or DNA repair, namely ABCB1, CYP2C8, CYP3A4, ERCC1, ERCC2, GSTM1, XPC, and XRCC1. Invasive epithelial ovarian cancer patients (N=445) seen at the Mayo Clinic from 1999 to 2009 with 275 observed recurrences or deaths were analyzed at 94 SNPs in these candidate genes. Cox regression was used to estimate hazard ratios and 95% confidence intervals for each single nucleotide polymorphism (SNP) and outcome (defined as time to recurrence or death). Analyses were conducted at the gene level and on case subsets defined by histopathology and chemotherapeutic agent. At ABCB1, minor alleles at several SNPs were associated with outcome, with the most significant being the intronic SNP rs12334183 (HR=0.65, 95% Cl 0.51-0.83; p=0.0005). Overall variation in ABCB1 was predictive of outcome as well (p=0.003). At ERCC2, minor alleles at several SNPs were associated with outcome among women with high-grade serous disease (e.g., rs238417, HR 0.74, 95% Cl 0.59-0.92; p=0.006). No associations with outcome were observed in GSTM1, CYP2C8, CYP3A4, ERCC1, XPC, or XRCC1. In summary, inherited variation in ABCB1 and ERCC2 was associated with outcome in patients with ovarian cancer seen at the Mayo Clinic. As the associated SNPs have not been studied previously in ovarian cancer, these findings suggest novel sites of variation which may, in part, explain the range of treatment responses seen in this disease.
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The role of KRAS rs61764370 in invasive epithelial ovarian cancer: implications for clinical testing.
Paul D P Pharoah, Rachel T Palmieri, Susan J Ramus, Simon A Gayther, Irene L Andrulis, Hoda Anton-Culver, Natalia Antonenkova, Antonis C Antoniou, David Goldgar, , Mary S Beattie, Matthias W Beckmann, Michael J Birrer, Natalia Bogdanova, Kelly L Bolton, Wendy Brewster, Angela Brooks-Wilson, Robert Brown, Ralf Bützow, Trinidad Caldés, Maria Adelaide Caligo, Ian Campbell, Jenny Chang-Claude, Y Ann Chen, Linda S Cook, Fergus J Couch, Daniel W Cramer, Julie M Cunningham, Evelyn Despierre, Jennifer A Doherty, Thilo Dörk, Matthias Dürst, Diana M Eccles, Arif B Ekici, Douglas Easton, Peter A Fasching, Anna de Fazio, David A Fenstermacher, James M Flanagan, Brooke L Fridley, Eitan Friedman, Bo Gao, Olga Sinilnikova, Aleksandra Gentry-Maharaj, Andrew K Godwin, Ellen L Goode, Marc T Goodman, Jenny Gross, Thomas V O Hansen, Paul Harnett, Matti Rookus, Tuomas Heikkinen, Rebecca Hein, Claus Høgdall, Estrid Høgdall, Edwin S Iversen, Anna Jakubowska, Sharon E Johnatty, Beth Y Karlan, Noah D Kauff, Stanley B Kaye, Georgia Chenevix-Trench, Linda E Kelemen, Lambertus A Kiemeney, Susanne Krüger Kjaer, Diether Lambrechts, James P LaPolla, Conxi Lazaro, Nhu D Le, Arto Leminen, Karin Leunen, Douglas A Levine, Yi Lu, Lene Lundvall, Stuart MacGregor, Tamara Marees, Leon F Massuger, John R McLaughlin, Usha Menon, Marco Montagna, Kirsten B Moysich, Steven A Narod, Katherine L Nathanson, Lotte Nedergaard, Roberta B Ness, Heli Nevanlinna, Stefan Nickels, Ana Osorio, Jim Paul, Celeste Leigh Pearce, Catherine M Phelan, Malcolm C Pike, Paolo Radice, Mary Anne Rossing, Joellen M Schildkraut, Thomas A Sellers, Christian F Singer, Honglin Song, Daniel O Stram, Rebecca Sutphen, Annika Lindblom, Kathryn L Terry, Ya-Yu Tsai, Anne M Van Altena, Ignace Vergote, Robert A Vierkant, Allison F Vitonis, Christine Walsh, Shan Wang-Gohrke, Barbara Wappenschmidt, Anna H Wu, Argyrios Ziogas, Andrew Berchuck, Harvey A Risch.
Clin. Cancer Res.
PUBLISHED: 03-08-2011
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An assay for the single-nucleotide polymorphism (SNP), rs61764370, has recently been commercially marketed as a clinical test to aid ovarian cancer risk evaluation in women with family histories of the disease. rs67164370 is in a 3-UTR miRNA binding site of the KRAS oncogene and is a candidate for epithelial ovarian cancer (EOC) susceptibility. However, only one published article, analyzing fewer than 1,000 subjects in total, has examined this association.
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Distinct germ line polymorphisms underlie glioma morphologic heterogeneity.
Cancer Genet
PUBLISHED: 03-02-2011
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Two recent genome-wide association studies reported that single nucleotide polymorphisms (SNPs) in (or near) TERT (5p15), CCDC26 (8q24), CDKN2A/B (9p21), PHLDB1 (11q23), and RTEL1 (20q13) are associated with infiltrating glioma. From these reports, it was not clear whether the single nucleotide polymorphism associations predispose to glioma in general or whether they are specific to certain glioma grades or morphologic subtypes. To identify hypothesized associations between susceptibility loci and tumor subtype, we genotyped two case-control groups composed of the spectrum of infiltrating glioma subtypes and stratified the analyses by type. We report that specific germ line polymorphisms are associated with different glioma subtypes. CCDC26 (8q24) region polymorphisms are strongly associated with oligodendroglial tumor risk (rs4295627, odds ratio [OR] = 2.05, P = 8.3 × 10(-11)) but not glioblastoma risk. The opposite is true of RTEL (20q13) region polymorphisms, which are significantly associated with glioblastoma (rs2297440, OR = 0.56, P = 4.6 × 10(-10)) but not oligodendroglial tumor. The SNPs in or near CCDC26 (8q24) are associated with oligodendroglial tumors regardless of combined 1p and 19q deletion status; however, the association is greatest for those with combined deletion (rs4295627, OR = 2.77, P = 2.6 × 10(-9)). These observations generate hypotheses concerning the possible mechanisms by which specific SNPs (or alterations in linkage disequilibrium with such SNPs) are associated with glioma development.
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A latent model for prioritization of SNPs for functional studies.
PLoS ONE
PUBLISHED: 02-07-2011
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One difficult question facing researchers is how to prioritize SNPs detected from genetic association studies for functional studies. Often a list of the top M SNPs is determined based on solely the p-value from an association analysis, where M is determined by financial/time constraints. For many studies of complex diseases, multiple analyses have been completed and integrating these multiple sets of results may be difficult. One may also wish to incorporate biological knowledge, such as whether the SNP is in the exon of a gene or a regulatory region, into the selection of markers to follow-up. In this manuscript, we propose a Bayesian latent variable model (BLVM) for incorporating "features" about a SNP to estimate a latent "quality score", with SNPs prioritized based on the posterior probability distribution of the rankings of these quality scores. We illustrate the method using data from an ovarian cancer genome-wide association study (GWAS). In addition to the application of the BLVM to the ovarian GWAS, we applied the BLVM to simulated data which mimics the setting involving the prioritization of markers across multiple GWAS for related diseases/traits. The top ranked SNP by BLVM for the ovarian GWAS, ranked 2(nd) and 7(th) based on p-values from analyses of all invasive and invasive serous cases. The top SNP based on serous case analysis p-value (which ranked 197(th) for invasive case analysis), was ranked 8(th) based on the posterior probability of being in the top 5 markers (0.13). In summary, the application of the BLVM allows for the systematic integration of multiple SNP "features" for the prioritization of loci for fine-mapping or functional studies, taking into account the uncertainty in ranking.
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Mycophenolic acid response biomarkers: a cell line model system-based genome-wide screen.
Int. Immunopharmacol.
PUBLISHED: 01-11-2011
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Mycophenolic acid (MPA) is commonly used to treat patients with solid organ transplants during maintenance immunosuppressive therapy. Response to MPA varies widely, both for efficacy and drug-induced toxicity. A portion of this variation can be explained by pharmacokinetic and pharmacodynamic factors, including genetic variation in MPA-metabolizing UDP-glucuronyltransferase isoforms and the MPA targets, inosine monophosphate dehydrogenase 1 and 2. However, much of the variation in MPA response presently remains unexplained. We set out to determine whether there might be additional genes that modify response to MPA by performing a genome-wide association study between basal gene mRNA expression profiles and an MPA cytotoxicity phenotype using a 271 human lymphoblastoid cell line model system to identify and functionally validate genes that might contribute to variation in MPA response. Our association study identified 41 gene expression probe sets, corresponding to 35 genes, that were associated with MPA cytotoxicity as a drug response phenotype (p<1×10(-6)). Follow-up siRNA-mediated knockdown-based functional validation identified four of these candidate genes, C17orf108, CYBRD1, NASP, and RRM2, whose knockdown shifted the MPA cytotoxicity curves in the direction predicted by the association analysis. These studies have identified novel candidate genes that may contribute to variation in response to MPA therapy and, as a result, may help make it possible to move toward more highly individualized MPA-based immunosuppressive therapy.
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Acetaminophen-NAPQI hepatotoxicity: a cell line model system genome-wide association study.
Toxicol. Sci.
PUBLISHED: 12-22-2010
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Acetaminophen is the leading cause of acute hepatic failure in many developed nations. Acetaminophen hepatotoxicity is mediated by the reactive metabolite N-acetyl-p-benzoquinonimine (NAPQI). We performed a "discovery" genome-wide association study using a cell line-based model system to study the possible contribution of genomics to NAPQI-induced cytotoxicity. A total of 176 lymphoblastoid cell lines from healthy subjects were treated with increasing concentrations of NAPQI. Inhibiting concentration 50 values were determined and were associated with "glutathione pathway" gene single nucleotide polymorphisms (SNPs) and genome-wide basal messenger RNA expression, as well as with 1.3 million genome-wide SNPs. A group of SNPs in linkage disequilibrium on chromosome 3 was highly associated with NAPQI toxicity. The p value for rs2880961, the SNP with the lowest p value, was 1.88 × 10(-7). This group of SNPs mapped to a "gene desert," but chromatin immunoprecipitation assays demonstrated binding of several transcription factor proteins including heat shock factor 1 (HSF1) and HSF2, at or near rs2880961. These chromosome 3 SNPs were not significantly associated with variation in basal expression for any of the genome-wide genes represented on the Affymetrix U133 Plus 2.0 GeneChip. We have used a cell line-based model system to identify a SNP signal associated with NAPQI cytotoxicity. If these observations are validated in future clinical studies, this SNP signal might represent a potential biomarker for risk of acetaminophen hepatotoxicity. The mechanisms responsible for this association remain unclear.
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Genome-wide association analyses of genetic, phenotypic, and environmental risks in the age-related eye disease study.
Mol. Vis.
PUBLISHED: 12-13-2010
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To present genome-wide association analyses of genotypic and environmental risks on age-related macular degeneration (AMD) using 593 subjects from the age-related eye disease study (AREDS), after adjusting for population stratification and including questionable controls.
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Betaine-homocysteine methyltransferase: human liver genotype-phenotype correlation.
Mol. Genet. Metab.
PUBLISHED: 10-15-2010
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Betaine-homocysteine methyltransferase (BHMT) catalyzes the remethylation of homocysteine. BHMT is highly expressed in the human liver. In the liver, BHMT catalyzes up to 50% of homocysteine metabolism. Understanding the relationship between BHMT genetic polymorphisms and function might increase our understanding of the role of this reaction in homocysteine remethylation and in S-adenosylmethionine-dependent methylation. To help achieve those goals, we measured levels of BHMT enzyme activity and immunoreactive protein in 268 human hepatic surgical biopsy samples from adult subjects as well as 73 fetal hepatic tissue samples obtained at different gestational ages. BHMT protein levels were correlated significantly (p<0.001) with levels of enzyme activity in both fetal and adult tissues, but both were decreased in fetal tissue when compared with levels in the adult hepatic biopsies. To determine possible genotype-phenotype correlations, 12 tag SNPs for BHMT and the closely related BHMT2 gene were selected from SNPs observed during our own gene resequencing studies as well as from HapMap. These SNPs data were used to genotype DNA from the adult hepatic surgical biopsy samples, and genotype-phenotype association analysis was performed. Three SNPs (rs41272270, rs16876512, and rs6875201), located 28kb upstream, in the 5-UTR and in intron 1 of BHMT, respectively, were significantly correlated with both BHMT activity (p=3.41E-8, 2.55E-9 and 2.46E-10, respectively) and protein levels (p=5.78E-5, 1.08E-5 and 6.92E-6, respectively). We also imputed 230 additional SNPs across the BHMT and BHMT2 genes, identifying an additional imputed SNP, rs7700790, that was also highly associated with hepatic BHMT enzyme activity and protein. However, none of the 3 genotyped or one imputed SNPs displayed a "shift" during electrophoretic mobility shift assays. These observations may help us to understand individual variation in the regulation of BHMT in the human liver and its possible relationship to variation in methylation.
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Radiation pharmacogenomics: a genome-wide association approach to identify radiation response biomarkers using human lymphoblastoid cell lines.
Genome Res.
PUBLISHED: 10-05-2010
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Radiation therapy is used to treat half of all cancer patients. Response to radiation therapy varies widely among patients. Therefore, we performed a genome-wide association study (GWAS) to identify biomarkers to help predict radiation response using 277 ethnically defined human lymphoblastoid cell lines (LCLs). Basal gene expression levels and 1.3 million genome-wide single nucleotide polymorphism (SNP) markers from both Affymetrix and Illumina platforms were assayed for all 277 human LCLs. MTS [3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium] assays for radiation cytotoxicity were also performed to obtain area under the curve (AUC) as a radiation response phenotype for use in the association studies. Functional validation of candidate genes, selected from an integrated analysis that used SNP, expression, and AUC data, was performed with multiple cancer cell lines using specific siRNA knockdown, followed by MTS and colony-forming assays. A total of 27 loci, each containing at least two SNPs within 50 kb with P-values less than 10(-4) were associated with radiation AUC. A total of 270 expression probe sets were associated with radiation AUC with P < 10(-3). The integrated analysis identified 50 SNPs in 14 of the 27 loci that were associated with both AUC and the expression of 39 genes, which were also associated with radiation AUC (P < 10(-3)). Functional validation using siRNA knockdown in multiple tumor cell lines showed that C13orf34, MAD2L1, PLK4, TPD52, and DEPDC1B each significantly altered radiation sensitivity in at least two cancer cell lines. Studies performed with LCLs can help to identify novel biomarkers that might contribute to variation in response to radiation therapy and enhance our understanding of mechanisms underlying that variation.
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JoVE Visualize is a tool created to match the last 5 years of PubMed publications to methods in JoVE's video library.

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In developing our video relationships, we compare around 5 million PubMed articles to our library of over 4,500 methods videos. In some cases the language used in the PubMed abstracts makes matching that content to a JoVE video difficult. In other cases, there happens not to be any content in our video library that is relevant to the topic of a given abstract. In these cases, our algorithms are trying their best to display videos with relevant content, which can sometimes result in matched videos with only a slight relation.