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Find video protocols related to scientific articles indexed in Pubmed.
The 19q12 Bladder Cancer GWAS Signal: Association with Cyclin E Function and Aggressive Disease.
Yi-Ping Fu, Indu Kohaar, Lee E Moore, Petra Lenz, Jonine D Figueroa, Wei Tang, Patricia Porter-Gill, Nilanjan Chatterjee, Alexandra Scott-Johnson, Montserrat Garcia-Closas, Brian Muchmore, Dalsu Baris, Ashley Paquin, Kris Ylaya, Molly Schwenn, Andrea B Apolo, Margaret R Karagas, McAnthony Tarway, Alison Johnson, Adam Mumy, Alan Schned, Liliana Guedez, Michael A Jones, Masatoshi Kida, Gm Monawar Hosain, Nuria Malats, Manolis Kogevinas, Adonina Tardón, Consol Serra, Alfredo Carrato, Reina Garcia-Closas, Josep Lloreta, Xifeng Wu, Mark Purdue, Gerald L Andriole, Robert L Grubb, Amanda Black, Maria T Landi, Neil E Caporaso, Paolo Vineis, Afshan Siddiq, H Bas Bueno-de-Mesquita, Dimitrios Trichopoulos, Börje Ljungberg, Gianluca Severi, Elisabete Weiderpass, Vittorio Krogh, Miren Dorronsoro, Ruth C Travis, Anne Tjønneland, Paul Brennan, Jenny Chang-Claude, Elio Riboli, Jennifer Prescott, Constance Chen, Immaculata De Vivo, Edward Govannucci, David Hunter, Peter Kraft, Sara Lindstrom, Susan M Gapstur, Eric J Jacobs, W Ryan Diver, Demetrius Albanes, Stephanie J Weinstein, Jarmo Virtamo, Charles Kooperberg, Chancellor Hohensee, Rebecca J Rodabough, Victoria K Cortessis, David V Conti, Manuela Gago-Dominguez, Mariana C Stern, Malcolm C Pike, David Van Den Berg, Jian-Min Yuan, Christopher A Haiman, Olivier Cussenot, Géraldine Cancel-Tassin, Morgan Rouprêt, Eva Compérat, Stefano Porru, Angela Carta, Sofia Pavanello, Cecilia Arici, Giuseppe Mastrangelo, H Barton Grossman, Zhaoming Wang, Xiang Deng, Charles C Chung, Amy Hutchinson, Laurie Burdette, William Wheeler, Joseph Fraumeni, Stephen J Chanock, Stephen M Hewitt, Debra T Silverman, Nathaniel Rothman, Ludmila Prokunina-Olsson.
Cancer Res.
PUBLISHED: 10-17-2014
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A genome-wide association study (GWAS) of bladder cancer identified a genetic marker rs8102137 within the 19q12 region as a novel susceptibility variant. This marker is located upstream of the CCNE1 gene, which encodes cyclin E, a cell-cycle protein. We performed genetic fine-mapping analysis of the CCNE1 region using data from two bladder cancer GWAS (5,942 cases and 10,857 controls). We found that the original GWAS marker rs8102137 represents a group of 47 linked SNPs (with r(2) ? 0.7) associated with increased bladder cancer risk. From this group, we selected a functional promoter variant rs7257330, which showed strong allele-specific binding of nuclear proteins in several cell lines. In both GWASs, rs7257330 was associated only with aggressive bladder cancer, with a combined per-allele OR = 1.18 [95% confidence interval (CI), 1.09-1.27, P = 4.67 × 10(-5)] versus OR = 1.01 (95% CI, 0.93-1.10, P = 0.79) for nonaggressive disease, with P = 0.0015 for case-only analysis. Cyclin E protein expression analyzed in 265 bladder tumors was increased in aggressive tumors (P = 0.013) and, independently, with each rs7257330-A risk allele (Ptrend = 0.024). Overexpression of recombinant cyclin E in cell lines caused significant acceleration of cell cycle. In conclusion, we defined the 19q12 signal as the first GWAS signal specific for aggressive bladder cancer. Molecular mechanisms of this genetic association may be related to cyclin E overexpression and alteration of cell cycle in carriers of CCNE1 risk variants. In combination with established bladder cancer risk factors and other somatic and germline genetic markers, the CCNE1 variants could be useful for inclusion into bladder cancer risk prediction models. Cancer Res; 74(20); 5808-18. ©2014 AACR.
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Leukocyte telomere length in relation to pancreatic cancer risk: a prospective study.
Cancer Epidemiol. Biomarkers Prev.
PUBLISHED: 08-07-2014
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Several studies have examined leukocyte telomere length (LTL) as a possible predictor for cancer at various organ sites. The hypothesis originally motivating many of these studies was that shorter telomeres would be associated with an increase in cancer risk; the results of epidemiologic studies have been inconsistent, however, and suggested positive, negative, or null associations. Two studies have addressed the association of LTL in relation to pancreatic cancer risk and the results are contrasting.
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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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Common genetic variants highlight the role of insulin resistance and body fat distribution in type 2 diabetes, independent of obesity.
Diabetes
PUBLISHED: 06-19-2014
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We aimed to validate genetic variants as instruments for insulin resistance and secretion, to characterize their association with intermediate phenotypes, and to investigate their role in type 2 diabetes (T2D) risk among normal-weight, overweight, and obese individuals. We investigated the association of genetic scores with euglycemic-hyperinsulinemic clamp- and oral glucose tolerance test-based measures of insulin resistance and secretion and a range of metabolic measures in up to 18,565 individuals. We also studied their association with T2D risk among normal-weight, overweight, and obese individuals in up to 8,124 incident T2D cases. The insulin resistance score was associated with lower insulin sensitivity measured by M/I value (? in SDs per allele [95% CI], -0.03 [-0.04, -0.01]; P = 0.004). This score was associated with lower BMI (-0.01 [-0.01, -0.0]; P = 0.02) and gluteofemoral fat mass (-0.03 [-0.05, -0.02; P = 1.4 × 10(-6)) and with higher alanine transaminase (0.02 [0.01, 0.03]; P = 0.002) and ?-glutamyl transferase (0.02 [0.01, 0.03]; P = 0.001). While the secretion score had a stronger association with T2D in leaner individuals (Pinteraction = 0.001), we saw no difference in the association of the insulin resistance score with T2D among BMI or waist strata (Pinteraction > 0.31). While insulin resistance is often considered secondary to obesity, the association of the insulin resistance score with lower BMI and adiposity and with incident T2D even among individuals of normal weight highlights the role of insulin resistance and ectopic fat distribution in T2D, independently of body size.
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Mitochondrial DNA copy number and future risk of B-cell lymphoma in a nested case-control study in the prospective EPIC cohort.
Blood
PUBLISHED: 06-04-2014
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It has been suggested that mitochondrial dysfunction and DNA damage are involved in lymphomagenesis. Increased copy number of mitochondrial DNA (mtDNA) as a compensatory mechanism of mitochondrial dysfunction previously has been associated with B-cell lymphomas, in particular chronic lymphocytic leukemia (CLL). However, current evidence is limited and based on a relatively small number of cases. Using a nested case-control study, we extended these findings with a focus on subtype-specific analyses. Relative mtDNA copy number was measured in the buffy coat of prospectively collected blood of 469 lymphoma cases and 469 matched controls. The association between mtDNA copy number and the risk of developing lymphoma and histologic subtypes was examined using logistic regression models. We found no overall association between mtDNA and risk of lymphoma. Subtype analyses revealed significant increased risks of CLL (n = 102) with increasing mtDNA copy number (odds ratio = 1.34, 1.44, and 1.80 for quartiles 2-4, respectively; P trend = .001). mtDNA copy number was not associated with follow-up time, suggesting that this observation is not strongly influenced by indolent disease status. This study substantially strengthens the evidence that mtDNA copy number is related to risk of CLL and supports the importance of mitochondrial dysfunction as a possible mechanistic pathway in CLL ontogenesis.
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A meta-analysis of 87,040 individuals identifies 23 new susceptibility loci for prostate cancer.
Ali Amin Al Olama, Zsofia Kote-Jarai, Sonja I Berndt, David V Conti, Fredrick Schumacher, Ying Han, Sara Benlloch, Dennis J Hazelett, Zhaoming Wang, Ed Saunders, Daniel Leongamornlert, Sara Lindstrom, Sara Jugurnauth-Little, Tokhir Dadaev, Malgorzata Tymrakiewicz, Daniel O Stram, Kristin Rand, Peggy Wan, Alex Stram, Xin Sheng, Loreall C Pooler, Karen Park, Lucy Xia, Jonathan Tyrer, Laurence N Kolonel, Loic Le Marchand, Robert N Hoover, Mitchell J Machiela, Merideth Yeager, Laurie Burdette, Charles C Chung, Amy Hutchinson, Kai Yu, Chee Goh, Mahbubl Ahmed, Koveela Govindasami, Michelle Guy, Teuvo L J Tammela, Anssi Auvinen, Tiina Wahlfors, Johanna Schleutker, Tapio Visakorpi, Katri A Leinonen, Jianfeng Xu, Markus Aly, Jenny Donovan, Ruth C Travis, Tim J Key, Afshan Siddiq, Federico Canzian, Kay-Tee Khaw, Atsushi Takahashi, Michiaki Kubo, Paul Pharoah, Nora Pashayan, Maren Weischer, Borge G Nordestgaard, Sune F Nielsen, Peter Klarskov, Martin Andreas Røder, Peter Iversen, Stephen N Thibodeau, Shannon K McDonnell, Daniel J Schaid, Janet L Stanford, Suzanne Kolb, Sarah Holt, Beatrice Knudsen, Antonio Hurtado Coll, Susan M Gapstur, W Ryan Diver, Victoria L Stevens, Christiane Maier, Manuel Luedeke, Kathleen Herkommer, Antje E Rinckleb, Sara S Strom, Curtis Pettaway, Edward D Yeboah, Yao Tettey, Richard B Biritwum, Andrew A Adjei, Evelyn Tay, Ann Truelove, Shelley Niwa, Anand P Chokkalingam, Lisa Cannon-Albright, Cezary Cybulski, Dominika Wokołorczyk, Wojciech Kluźniak, Jong Park, Thomas Sellers, Hui-Yi Lin, William B Isaacs, Alan W Partin, Hermann Brenner, Aida Karina Dieffenbach, Christa Stegmaier, Constance Chen, Edward L Giovannucci, Jing Ma, Meir Stampfer, Kathryn L Penney, Lorelei Mucci, Esther M John, Sue A Ingles, Rick A Kittles, Adam B Murphy, Hardev Pandha, Agnieszka Michael, Andrzej M Kierzek, William Blot, Lisa B Signorello, Wei Zheng, Demetrius Albanes, Jarmo Virtamo, Stephanie Weinstein, Barbara Nemesure, John Carpten, Cristina Leske, Suh-Yuh Wu, Anselm Hennis, Adam S Kibel, Benjamin A Rybicki, Christine Neslund-Dudas, Ann W Hsing, Lisa Chu, Phyllis J Goodman, Eric A Klein, S Lilly Zheng, Jyotsna Batra, Judith Clements, Amanda Spurdle, Manuel R Teixeira, Paula Paulo, Sofia Maia, Chavdar Slavov, Radka Kaneva, Vanio Mitev, John S Witte, Graham Casey, Elizabeth M Gillanders, Daniella Seminara, Elio Riboli, Freddie C Hamdy, Gerhard A Coetzee, Qiyuan Li, Matthew L Freedman, David J Hunter, Kenneth Muir, Henrik Grönberg, David E Neal, Melissa Southey, Graham G Giles, Gianluca Severi, , Michael B Cook, Hidewaki Nakagawa, Fredrik Wiklund, Peter Kraft, Stephen J Chanock, Brian E Henderson, Douglas F Easton, Rosalind A Eeles, Christopher A Haiman.
Nat. Genet.
PUBLISHED: 03-26-2014
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Genome-wide association studies (GWAS) have identified 76 variants associated with prostate cancer risk predominantly in populations of European ancestry. To identify additional susceptibility loci for this common cancer, we conducted a meta-analysis of > 10 million SNPs in 43,303 prostate cancer cases and 43,737 controls from studies in populations of European, African, Japanese and Latino ancestry. Twenty-three new susceptibility loci were identified at association P < 5 × 10(-8); 15 variants were identified among men of European ancestry, 7 were identified in multi-ancestry analyses and 1 was associated with early-onset prostate cancer. These 23 variants, in combination with known prostate cancer risk variants, explain 33% of the familial risk for this disease in European-ancestry populations. These findings provide new regions for investigation into the pathogenesis of prostate cancer and demonstrate the usefulness of combining ancestrally diverse populations to discover risk loci for disease.
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Genome-wide interaction study of smoking and bladder cancer risk.
Carcinogenesis
PUBLISHED: 03-24-2014
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Bladder cancer is a complex disease with known environmental and genetic risk factors. We performed a genome-wide interaction study (GWAS) of smoking and bladder cancer risk based on primary scan data from 3002 cases and 4411 controls from the National Cancer Institute Bladder Cancer GWAS. Alternative methods were used to evaluate both additive and multiplicative interactions between individual single nucleotide polymorphisms (SNPs) and smoking exposure. SNPs with interaction P values < 5 × 10(-) (5) were evaluated further in an independent dataset of 2422 bladder cancer cases and 5751 controls. We identified 10 SNPs that showed association in a consistent manner with the initial dataset and in the combined dataset, providing evidence of interaction with tobacco use. Further, two of these novel SNPs showed strong evidence of association with bladder cancer in tobacco use subgroups that approached genome-wide significance. Specifically, rs1711973 (FOXF2) on 6p25.3 was a susceptibility SNP for never smokers [combined odds ratio (OR) = 1.34, 95% confidence interval (CI) = 1.20-1.50, P value = 5.18 × 10(-) (7)]; and rs12216499 (RSPH3-TAGAP-EZR) on 6q25.3 was a susceptibility SNP for ever smokers (combined OR = 0.75, 95% CI = 0.67-0.84, P value = 6.35 × 10(-) (7)). In our analysis of smoking and bladder cancer, the tests for multiplicative interaction seemed to more commonly identify susceptibility loci with associations in never smokers, whereas the additive interaction analysis identified more loci with associations among smokers-including the known smoking and NAT2 acetylation interaction. Our findings provide additional evidence of gene-environment interactions for tobacco and bladder cancer.
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Prostate cancer (PCa) risk variants and risk of fatal PCa in the National Cancer Institute Breast and Prostate Cancer Cohort Consortium.
Eur. Urol.
PUBLISHED: 01-04-2014
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Screening and diagnosis of prostate cancer (PCa) is hampered by an inability to predict who has the potential to develop fatal disease and who has indolent cancer. Studies have identified multiple genetic risk loci for PCa incidence, but it is unknown whether they could be used as biomarkers for PCa-specific mortality (PCSM).
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A genome-wide "pleiotropy scan" does not identify new susceptibility loci for estrogen receptor negative breast cancer.
PLoS ONE
PUBLISHED: 01-01-2014
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Approximately 15-30% of all breast cancer tumors are estrogen receptor negative (ER-). Compared with ER-positive (ER+) disease they have an earlier age at onset and worse prognosis. Despite the vast number of risk variants identified for numerous cancer types, only seven loci have been unambiguously identified for ER-negative breast cancer. With the aim of identifying new susceptibility SNPs for this disease we performed a pleiotropic genome-wide association study (GWAS). We selected 3079 SNPs associated with a human complex trait or disease at genome-wide significance level (P<5 × 10(-8)) to perform a secondary analysis of an ER-negative GWAS from the National Cancer Institute's Breast and Prostate Cancer Cohort Consortium (BPC3), including 1998 cases and 2305 controls from prospective studies. We then tested the top ten associations (i.e. with the lowest P-values) using three additional populations with a total sample size of 3509 ER+ cases, 2543 ER- cases and 7031 healthy controls. None of the 3079 selected variants in the BPC3 ER-GWAS were significant at the adjusted threshold. 186 variants were associated with ER- breast cancer risk at a conventional threshold of P<0.05, with P-values ranging from 0.049 to 2.3 × 10(-4). None of the variants reached statistical significance in the replication phase. In conclusion, this study did not identify any novel susceptibility loci for ER-breast cancer using a "pleiotropic approach".
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Genome-wide association study identifies multiple loci associated with bladder cancer risk.
Jonine D Figueroa, Yuanqing Ye, Afshan Siddiq, Montserrat Garcia-Closas, Nilanjan Chatterjee, Ludmila Prokunina-Olsson, Victoria K Cortessis, Charles Kooperberg, Olivier Cussenot, Simone Benhamou, Jennifer Prescott, Stefano Porru, Colin P Dinney, Nuria Malats, Dalsu Baris, Mark Purdue, Eric J Jacobs, Demetrius Albanes, Zhaoming Wang, Xiang Deng, Charles C Chung, Wei Tang, H Bas Bueno-de-Mesquita, Dimitrios Trichopoulos, Börje Ljungberg, Francoise Clavel-Chapelon, Elisabete Weiderpass, Vittorio Krogh, Miren Dorronsoro, Ruth Travis, Anne Tjønneland, Paul Brenan, Jenny Chang-Claude, Elio Riboli, David Conti, Manuela Gago-Dominguez, Mariana C Stern, Malcolm C Pike, David Van Den Berg, Jian-Min Yuan, Chancellor Hohensee, Rebecca Rodabough, Géraldine Cancel-Tassin, Morgan Rouprêt, Eva Compérat, Constance Chen, Immaculata De Vivo, Edward Giovannucci, David J Hunter, Peter Kraft, Sara Lindstrom, Angela Carta, Sofia Pavanello, Cecilia Arici, Giuseppe Mastrangelo, Ashish M Kamat, Seth P Lerner, H Barton Grossman, Jie Lin, Jian Gu, Xia Pu, Amy Hutchinson, Laurie Burdette, William Wheeler, Manolis Kogevinas, Adonina Tardón, Consol Serra, Alfredo Carrato, Reina Garcia-Closas, Josep Lloreta, Molly Schwenn, Margaret R Karagas, Alison Johnson, Alan Schned, Karla R Armenti, G M Hosain, Gerald Andriole, Robert Grubb, Amanda Black, W Ryan Diver, Susan M Gapstur, Stephanie J Weinstein, Jarmo Virtamo, Chris A Haiman, Maria T Landi, Neil Caporaso, Joseph F Fraumeni, Paolo Vineis, Xifeng Wu, Debra T Silverman, Stephen Chanock, Nathaniel Rothman.
Hum. Mol. Genet.
PUBLISHED: 10-24-2013
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Candidate gene and genome-wide association studies (GWAS) have identified 11 independent susceptibility loci associated with bladder cancer risk. To discover additional risk variants, we conducted a new GWAS of 2422 bladder cancer cases and 5751 controls, followed by a meta-analysis with two independently published bladder cancer GWAS, resulting in a combined analysis of 6911 cases and 11 814 controls of European descent. TaqMan genotyping of 13 promising single nucleotide polymorphisms with P < 1 × 10(-5) was pursued in a follow-up set of 801 cases and 1307 controls. Two new loci achieved genome-wide statistical significance: rs10936599 on 3q26.2 (P = 4.53 × 10(-9)) and rs907611 on 11p15.5 (P = 4.11 × 10(-8)). Two notable loci were also identified that approached genome-wide statistical significance: rs6104690 on 20p12.2 (P = 7.13 × 10(-7)) and rs4510656 on 6p22.3 (P = 6.98 × 10(-7)); these require further studies for confirmation. In conclusion, our study has identified new susceptibility alleles for bladder cancer risk that require fine-mapping and laboratory investigation, which could further understanding into the biological underpinnings of bladder carcinogenesis.
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Aberrant DNA Methylation at Genes Associated with a Stem Cell-like Phenotype in Cholangiocarcinoma Tumors.
Cancer Prev Res (Phila)
PUBLISHED: 10-02-2013
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Genetic abnormalities of cholangiocarcinoma have been widely studied; however, epigenomic changes related to cholangiocarcinogenesis have been less well characterized. We have profiled the DNA methylomes of 28 primary cholangiocarcinoma and six matched adjacent normal tissues using Infiniums HumanMethylation27 BeadChips with the aim of identifying gene sets aberrantly and epigenetically regulated in this tumor type. Using a linear model for microarray data, we identified 1610 differentially methylated autosomal CpG sites, with 809 hypermethylated (representing 603 genes) and 801 hypomethylated (representing 712 genes) in cholangiocarcinoma versus adjacent normal tissues (false-discovery rate ? 0.05). Gene ontology and gene set enrichment analyses identified gene sets significantly associated with hypermethylation at linked CpG sites in cholangiocarcinoma including homeobox genes and target genes of PRC2, EED, SUZ12, and histone H3 trimethylation at lysine 27. We confirmed frequent hypermethylation at the homeobox genes HOXA9 and HOXD9 by bisulfite pyrosequencing in a larger cohort of cholangiocarcinoma (n = 102). Our findings indicate a key role for hypermethylation of multiple CpG sites at genes associated with a stem cell-like phenotype as a common molecular aberration in cholangiocarcinoma. These data have implications for cholangiocarcinogenesis, as well as possible novel treatment options using histone methyltransferase inhibitors. Cancer Prev Res; 6(12); 1348-55. ©2013 AACR.
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Single-nucleotide polymorphisms of allergy-related genes and risk of adult glioma.
J. Neurooncol.
PUBLISHED: 03-16-2013
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Previous studies have shown an inverse association between allergies and glioma risk; however, results for associations between single nucleotide polymorphisms (SNPs) of allergy-related genes and glioma risk have been inconsistent and restricted to a small number of SNPs. The objective of this study was to examine the association between 166 SNPs of 21 allergy-related genes and glioma risk in a nested case-control study of participants from three large US prospective cohort studies. Blood collection took place between 1982 and 1994 among the 562 included Caucasian participants (143 cases and 419 matched controls) prior to case diagnosis. Custom Illumina assay chips were used for genotyping. Logistic regression analyses, controlling for age and study cohort, were used to determine associations between each SNP and glioma risk. Statistically significant associations were found between rs2494262 and rs2427824 of the FCER1A gene, which encodes the alpha chain of the high affinity immunoglobulin E receptor, and glioma risk (nominal trend p values 0.01 and 0.03, respectively). Significant associations were also found between SNPs in IL10, ADAM33, NOS1 and IL4R and glioma risk. However, our analyses were not corrected for multiple comparisons and need to be interpreted with caution. Our findings with FCER1A SNPs provide further support for the link between allergies and risk of glioma.
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Nociceptinergic system as potential target in Parkinsons disease.
Mini Rev Med Chem
PUBLISHED: 02-28-2013
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Nociceptinergic system has become an important target for drug development since the identification of the "orphan", opioid-like-1 receptor and the isolation of its endogenous agonist nociceptin. Involvement of nociceptinergic system has been verified in a wide range of pathophysiological processes. A large number of nociceptinergic agonists and antagonists with peptide and non-peptide structures were developed. Several non- peptide nociceptinergic antagonists were recently shown effective in different animal models of parkinsonism. Neuropharmacological background for antiparkinsonian effect of nociceptinergic antagonists, experimental models with high predictive value, nociceptinergic antagonists shown to have potential effect in Parkinsons disease are summarized. Medicinal chemistry data (logP and TPSA) of the NOP receptor antagonists found effective in animal models of Parkinsons disease are provided.
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Insulin-like growth factor pathway genes and blood concentrations, dietary protein and risk of prostate cancer in the NCI Breast and Prostate Cancer Cohort Consortium (BPC3).
Int. J. Cancer
PUBLISHED: 02-15-2013
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It has been hypothesized that a high intake of dairy protein may increase prostate cancer risk by increasing the production of insulin-like growth factor 1 (IGF-1). Several single nucleotide polymorphisms (SNPs) have been weakly associated with circulating concentrations of IGF-1 and IGF binding protein 3 (IGFBP-3), but none of these SNPs was associated with risk of prostate cancer. We examined whether an association between 16 SNPs associated with circulating IGF-1 or IGFBP-3 concentrations and prostate cancer exists within subgroups defined by dietary protein intake in 5,253 cases and 4,963 controls of European ancestry within the NCI Breast and Prostate Cancer Cohort Consortium (BPC3). The BPC3 includes nested case-control studies within large North-American and European cohorts. Per-allele odds ratios for prostate cancer for the SNPs were compared across tertiles of protein intake, which was expressed as the percentage of energy derived from total, animal, dairy or plant protein sources, using conditional logistic regression models. Total, animal, dairy and plant protein intakes were significantly positively associated with blood IGF-1 (p??0.10) or with risk of prostate cancer (p?>?0.20). After adjusting for multiple testing, the SNP-prostate cancer associations did not differ by intakes of protein, although two interactions by intake of plant protein were of marginal statistical significance [SSTR5 (somatostatin receptor 5)-rs197056 (uncorrected p for interaction, 0.001); SSTR5-rs197057 (uncorrected p for interaction, 0.002)]. We found no strong evidence that the associations between 16 IGF pathway SNPs and prostate cancer differed by intakes of dietary protein.
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Medicinal chemistry of drugs with active metabolites following conjugation.
Mini Rev Med Chem
PUBLISHED: 01-29-2013
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Authorities of Drug Administration in the United States of America approved about 5000 drugs for use in the therapy or management of several diseases. About two hundred of these drugs have active metabolites and the knowledge of their medicinal chemistry is important both in medical practice and pharmaceutical research. This review gives a detailed description of the medicinal chemistry of drugs with active metabolites generated after conjugation. This review focused on glucuronide-, acetyl-, sulphate- and phosphate-conjugation of drugs, converting the drug into an active metabolite. This conversion essentially changed the lipophilicity of the drug.
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Identification of 23 new prostate cancer susceptibility loci using the iCOGS custom genotyping array.
Rosalind A Eeles, Ali Amin Al Olama, Sara Benlloch, Edward J Saunders, Daniel A Leongamornlert, Malgorzata Tymrakiewicz, Maya Ghoussaini, Craig Luccarini, Joe Dennis, Sarah Jugurnauth-Little, Tokhir Dadaev, David E Neal, Freddie C Hamdy, Jenny L Donovan, Ken Muir, Graham G Giles, Gianluca Severi, Fredrik Wiklund, Henrik Grönberg, Christopher A Haiman, Fredrick Schumacher, Brian E Henderson, Loic Le Marchand, Sara Lindstrom, Peter Kraft, David J Hunter, Susan Gapstur, Stephen J Chanock, Sonja I Berndt, Demetrius Albanes, Gerald Andriole, Johanna Schleutker, Maren Weischer, Federico Canzian, Elio Riboli, Tim J Key, Ruth C Travis, Daniele Campa, Sue A Ingles, Esther M John, Richard B Hayes, Paul D P Pharoah, Nora Pashayan, Kay-Tee Khaw, Janet L Stanford, Elaine A Ostrander, Lisa B Signorello, Stephen N Thibodeau, Dan Schaid, Christiane Maier, Walther Vogel, Adam S Kibel, Cezary Cybulski, Jan Lubiński, Lisa Cannon-Albright, Hermann Brenner, Jong Y Park, Radka Kaneva, Jyotsna Batra, Amanda B Spurdle, Judith A Clements, Manuel R Teixeira, Ed Dicks, Andrew Lee, Alison M Dunning, Caroline Baynes, Don Conroy, Melanie J Maranian, Shahana Ahmed, Koveela Govindasami, Michelle Guy, Rosemary A Wilkinson, Emma J Sawyer, Angela Morgan, David P Dearnaley, Alan Horwich, Robert A Huddart, Vincent S Khoo, Christopher C Parker, Nicholas J Van As, Christopher J Woodhouse, Alan Thompson, Tim Dudderidge, Chris Ogden, Colin S Cooper, Artitaya Lophatananon, Angela Cox, Melissa C Southey, John L Hopper, Dallas R English, Markus Aly, Jan Adolfsson, Jiangfeng Xu, Siqun L Zheng, Meredith Yeager, Rudolf Kaaks, W Ryan Diver, Mia M Gaudet, Mariana C Stern, Román Corral, Amit D Joshi, Ahva Shahabi, Tiina Wahlfors, Teuvo L J Tammela, Anssi Auvinen, Jarmo Virtamo, Peter Klarskov, Børge G Nordestgaard, M Andreas Røder, Sune F Nielsen, Stig E Bojesen, Afshan Siddiq, Liesel M Fitzgerald, Suzanne Kolb, Erika M Kwon, Danielle M Karyadi, William J Blot, Wei Zheng, Qiuyin Cai, Shannon K McDonnell, Antje E Rinckleb, Bettina Drake, Graham Colditz, Dominika Wokolorczyk, Robert A Stephenson, Craig Teerlink, Heiko Muller, Dietrich Rothenbacher, Thomas A Sellers, Hui-Yi Lin, Chavdar Slavov, Vanio Mitev, Felicity Lose, Srilakshmi Srinivasan, Sofia Maia, Paula Paulo, Ethan Lange, Kathleen A Cooney, Antonis C Antoniou, Daniel Vincent, Francois Bacot, Daniel C Tessier, , Zsofia Kote-Jarai, Douglas F Easton.
Nat. Genet.
PUBLISHED: 01-28-2013
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Prostate cancer is the most frequently diagnosed cancer in males in developed countries. To identify common prostate cancer susceptibility alleles, we genotyped 211,155 SNPs on a custom Illumina array (iCOGS) in blood DNA from 25,074 prostate cancer cases and 24,272 controls from the international PRACTICAL Consortium. Twenty-three new prostate cancer susceptibility loci were identified at genome-wide significance (P < 5 × 10(-8)). More than 70 prostate cancer susceptibility loci, explaining ?30% of the familial risk for this disease, have now been identified. On the basis of combined risks conferred by the new and previously known risk loci, the top 1% of the risk distribution has a 4.7-fold higher risk than the average of the population being profiled. These results will facilitate population risk stratification for clinical studies.
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The DNA methylomes of serous borderline tumors reveal subgroups with malignant- or benign-like profiles.
Am. J. Pathol.
PUBLISHED: 01-25-2013
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Serous borderline tumors (SBOTs) are a challenging group of ovarian tumors positioned between benign and malignant disease. We have profiled the DNA methylomes of 12 low-grade serous carcinomas (LGSCs), 19 SBOTs, and 16 benign serous tumors (BSTs) across 27,578 CpG sites to further characterize the epigenomic relationship between these subtypes of ovarian tumors. Unsupervised hierarchical clustering of DNA methylation levels showed that LGSCs differ distinctly from BSTs, but not from SBOTs. Gene ontology analysis of genes showing differential methylation at linked CpG sites between LGSCs and BSTs revealed significant enrichment of gene groups associated with cell adhesion, cell-cell signaling, and the extracellular region, consistent with a more invasive phenotype of LGSCs compared with BSTs. Consensus clustering highlighted differences between SBOT methylomes and returned subgroups with malignant- or benign-like methylation profiles. Furthermore, a two-loci DNA methylation signature can distinguish between these SBOT subgroups with benign- and malignant-like methylation characteristics. Our findings indicate striking similarities between SBOT and LGSC methylomes, supporting a common origin and the view that LGSC may arise from SBOT. A subgroup of SBOTs can be classified into tumors with a benign- or a malignant-like methylation profile that may help in identifying tumors more likely to progress into LGSCs.
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Mannose-binding lectin 2 gene and risk of adult glioma.
PLoS ONE
PUBLISHED: 01-01-2013
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The immune system is likely to play a key role in the etiology of gliomas. Genetic polymorphisms in the mannose-binding lectin gene, a key activator in the lectin complement pathway, have been associated with risk of several cancers.
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Postmenopausal serum sex steroids and risk of hormone receptor-positive and -negative breast cancer: a nested case-control study.
Cancer Prev Res (Phila)
PUBLISHED: 08-02-2011
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Prediagnostic endogenous sex steroid hormone levels have well established associations with overall risk of breast cancer. While evidence toward the existence of distinct subtypes of breast cancer accumulates, few studies have investigated the associations of sex steroid hormone levels with risk of hormone receptor [estrogen receptor (ER) and/or progesterone receptor (PR)] defined breast cancer. In a case-control study nested within the EPIC cohort (European Prospective Investigation into Cancer and Nutrition), estradiol, testosterone, and sex hormone-binding globulin levels were measured in prediagnostic serum samples from postmenopausal women not using hormone replacement therapy at blood donation. A total of 554 women who developed invasive breast cancer with information on receptor status were matched with 821 control subjects. Conditional logistic regression models estimated breast cancer risk with hormone concentrations according to hormone receptor status of the tumor. Sex steroid hormones were associated with risks of not only ER+PR+ breast cancer [estradiol OR for highest vs. lowest tertile = 2.91 (95% CI: 1.62-5.23), P(trend) = 0.002; testosterone OR = 2.27 (95% CI: 1.35-3.81), P(trend) = 0.002] but also of ER-PR- breast cancer [estradiol OR = 2.11 (95% CI: 1.00-4.46), P(trend) = 0.05; testosterone OR = 2.06 (95% CI: 0.95-4.46), P(trend) = 0.03], with associations appearing somewhat stronger in the receptor-positive disease. Serum androgens and estrogens are associated with risks of both hormone receptor-negative as well as receptor-positive breast tumors. Further research is needed to establish through which molecular pathways, and during which evolutionary stages of development, androgens and estrogens can promote the occurrence of both receptor-positive and -negative clinical breast tumors.
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Genome-wide association study identifies new prostate cancer susceptibility loci.
Hum. Mol. Genet.
PUBLISHED: 07-08-2011
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Prostate cancer (PrCa) is the most common non-skin cancer diagnosed among males in developed countries and the second leading cause of cancer mortality, yet little is known regarding its etiology and factors that influence clinical outcome. Genome-wide association studies (GWAS) of PrCa have identified at least 30 distinct loci associated with small differences in risk. We conducted a GWAS in 2782 advanced PrCa cases (Gleason grade ? 8 or tumor stage C/D) and 4458 controls with 571 243 single nucleotide polymorphisms (SNPs). Based on in silico replication of 4679 SNPs (Stage 1, P < 0.02) in two published GWAS with 7358 PrCa cases and 6732 controls, we identified a new susceptibility locus associated with overall PrCa risk at 2q37.3 (rs2292884, P= 4.3 × 10(-8)). We also confirmed a locus suggested by an earlier GWAS at 12q13 (rs902774, P= 8.6 × 10(-9)). The estimated per-allele odds ratios for these loci (1.14 for rs2292884 and 1.17 for rs902774) did not differ between advanced and non-advanced PrCa (case-only test for heterogeneity P= 0.72 and P= 0.61, respectively). Further studies will be needed to assess whether these or other loci are differentially associated with PrCa subtypes.
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Pancreatic cancer susceptibility loci and their role in survival.
PLoS ONE
PUBLISHED: 06-27-2011
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Pancreatic cancer has one of the worst mortality rates of all cancers. Little is known about its etiology, particularly regarding inherited risk. The PanScan project, a genome-wide association study, identified several common polymorphisms affecting pancreatic cancer susceptibility. Single nucleotide polymorphisms (SNPs) in ABO, sonic hedgehog (SHH), telomerase reverse transcriptase (TERT), nuclear receptor subfamily 5, group A, member 2 (NR5A2) were found to be associated with pancreatic cancer risk. Moreover the scan identified loci on chromosomes 13q22.1 and 15q14, to which no known genes or other functional elements are mapped. We sought to replicate these observations in two additional, independent populations (from Germany and the UK), and also evaluate the possible impact of these SNPs on patient survival. We genotyped 15 SNPs in 690 cases of pancreatic ductal adenocarcinoma (PDAC) and in 1277 healthy controls. We replicated several associations between SNPs and PDAC risk. Furthermore we found that SNP rs8028529 was weakly associated with a better overall survival (OS) in both populations. We have also found that NR5A2 rs12029406_T allele was associated with a shorter survival in the German population. In conclusion, we found that rs8028529 could be, if these results are replicated, a promising marker for both risk and prognosis for this lethal disease.
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Large-scale fine mapping of the HNF1B locus and prostate cancer risk.
Hum. Mol. Genet.
PUBLISHED: 05-16-2011
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Previous genome-wide association studies have identified two independent variants in HNF1B as susceptibility loci for prostate cancer risk. To fine-map common genetic variation in this region, we genotyped 79 single nucleotide polymorphisms (SNPs) in the 17q12 region harboring HNF1B in 10 272 prostate cancer cases and 9123 controls of European ancestry from 10 case-control studies as part of the Cancer Genetic Markers of Susceptibility (CGEMS) initiative. Ten SNPs were significantly related to prostate cancer risk at a genome-wide significance level of P < 5 × 10(-8) with the most significant association with rs4430796 (P = 1.62 × 10(-24)). However, risk within this first locus was not entirely explained by rs4430796. Although modestly correlated (r(2)= 0.64), rs7405696 was also associated with risk (P = 9.35 × 10(-23)) even after adjustment for rs4430769 (P = 0.007). As expected, rs11649743 was related to prostate cancer risk (P = 3.54 × 10(-8)); however, the association within this second locus was stronger for rs4794758 (P = 4.95 × 10(-10)), which explained all of the risk observed with rs11649743 when both SNPs were included in the same model (P = 0.32 for rs11649743; P = 0.002 for rs4794758). Sequential conditional analyses indicated that five SNPs (rs4430796, rs7405696, rs4794758, rs1016990 and rs3094509) together comprise the best model for risk in this region. This study demonstrates a complex relationship between variants in the HNF1B region and prostate cancer risk. Further studies are needed to investigate the biological basis of the association of variants in 17q12 with prostate cancer.
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A common variant at the TERT-CLPTM1L locus is associated with estrogen receptor-negative breast cancer.
Christopher A Haiman, Gary K Chen, Celine M Vachon, Federico Canzian, Alison Dunning, Robert C Millikan, Xianshu Wang, Foluso Ademuyiwa, Shahana Ahmed, Christine B Ambrosone, Laura Baglietto, Rosemary Balleine, Elisa V Bandera, Matthias W Beckmann, Christine D Berg, Leslie Bernstein, Carl Blomqvist, William J Blot, Hiltrud Brauch, Julie E Buring, Lisa A Carey, Jane E Carpenter, Jenny Chang-Claude, Stephen J Chanock, Daniel I Chasman, Christine L Clarke, Angela Cox, Simon S Cross, Sandra L Deming, Robert B Diasio, Athanasios M Dimopoulos, W Ryan Driver, Thomas Dünnebier, Lorraine Durcan, Diana Eccles, Christopher K Edlund, Arif B Ekici, Peter A Fasching, Heather S Feigelson, Dieter Flesch-Janys, Florentia Fostira, Asta Försti, George Fountzilas, Susan M Gerty, , Graham G Giles, Andrew K Godwin, Paul Goodfellow, Nikki Graham, Dario Greco, Ute Hamann, Susan E Hankinson, Arndt Hartmann, Rebecca Hein, Judith Heinz, Andrea Holbrook, Robert N Hoover, Jennifer J Hu, David J Hunter, Sue A Ingles, Astrid Irwanto, Jennifer Ivanovich, Esther M John, Nicola Johnson, Arja Jukkola-Vuorinen, Rudolf Kaaks, Yon-Dschun Ko, Laurence N Kolonel, Irene Konstantopoulou, Veli-Matti Kosma, Swati Kulkarni, Diether Lambrechts, Adam M Lee, Loic Le Marchand, Timothy Lesnick, Jianjun Liu, Sara Lindstrom, Arto Mannermaa, Sara Margolin, Nicholas G Martin, Penelope Miron, Grant W Montgomery, Heli Nevanlinna, Stephan Nickels, Sarah Nyante, Curtis Olswold, Julie Palmer, Harsh Pathak, Dimitrios Pectasides, Charles M Perou, Julian Peto, Paul D P Pharoah, Loreall C Pooler, Michael F Press, Katri Pylkäs, Timothy R Rebbeck, Jorge L Rodriguez-Gil, Lynn Rosenberg, Eric Ross, Thomas Rüdiger, Isabel dos Santos Silva, Elinor Sawyer, Marjanka K Schmidt, Rüdiger Schulz-Wendtland, Fredrick Schumacher, Gianluca Severi, Xin Sheng, Lisa B Signorello, Hans-Peter Sinn, Kristen N Stevens, Melissa C Southey, William J Tapper, Ian Tomlinson, Frans B L Hogervorst, Els Wauters, Joellen Weaver, Hans Wildiers, Robert Winqvist, David Van Den Berg, Peggy Wan, Lucy Y Xia, Drakoulis Yannoukakos, Wei Zheng, Regina G Ziegler, Afshan Siddiq, Susan L Slager, Daniel O Stram, Douglas Easton, Peter Kraft, Brian E Henderson, Fergus J Couch.
Nat. Genet.
PUBLISHED: 05-03-2011
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Estrogen receptor (ER)-negative breast cancer shows a higher incidence in women of African ancestry compared to women of European ancestry. In search of common risk alleles for ER-negative breast cancer, we combined genome-wide association study (GWAS) data from women of African ancestry (1,004 ER-negative cases and 2,745 controls) and European ancestry (1,718 ER-negative cases and 3,670 controls), with replication testing conducted in an additional 2,292 ER-negative cases and 16,901 controls of European ancestry. We identified a common risk variant for ER-negative breast cancer at the TERT-CLPTM1L locus on chromosome 5p15 (rs10069690: per-allele odds ratio (OR) = 1.18 per allele, P = 1.0 × 10(-10)). The variant was also significantly associated with triple-negative (ER-negative, progesterone receptor (PR)-negative and human epidermal growth factor-2 (HER2)-negative) breast cancer (OR = 1.25, P = 1.1 × 10(-9)), particularly in younger women (<50 years of age) (OR = 1.48, P = 1.9 × 10(-9)). Our results identify a genetic locus associated with estrogen receptor negative breast cancer subtypes in multiple populations.
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Fine mapping of a region of chromosome 11q13 reveals multiple independent loci associated with risk of prostate cancer.
Hum. Mol. Genet.
PUBLISHED: 04-29-2011
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Genome-wide association studies have identified prostate cancer susceptibility alleles on chromosome 11q13. As part of the Cancer Genetic Markers of Susceptibility (CGEMS) Initiative, the region flanking the most significant marker, rs10896449, was fine mapped in 10 272 cases and 9123 controls of European origin (10 studies) using 120 common single nucleotide polymorphisms (SNPs) selected by a two-staged tagging strategy using HapMap SNPs. Single-locus analysis identified 18 SNPs below genome-wide significance (P< 10(-8)) with rs10896449 the most significant (P= 7.94 × 10(-19)). Multi-locus models that included significant SNPs sequentially identified a second association at rs12793759 [odds ratio (OR) = 1.14, P= 4.76 × 10(-5), adjusted P= 0.004] that is independent of rs10896449 and remained significant after adjustment for multiple testing within the region. rs10896438, a proxy of previously reported rs12418451 (r(2)= 0.96), independent of both rs10896449 and rs12793759 was detected (OR = 1.07, P= 5.92 × 10(-3), adjusted P= 0.054). Our observation of a recombination hotspot that separates rs10896438 from rs10896449 and rs12793759, and low linkage disequilibrium (rs10896449-rs12793759, r(2)= 0.17; rs10896449-rs10896438, r(2)= 0.10; rs12793759-rs10896438, r(2)= 0.12) corroborate our finding of three independent signals. By analysis of tagged SNPs across ?123 kb using next generation sequencing of 63 controls of European origin, 1000 Genome and HapMap data, we observed multiple surrogates for the three independent signals marked by rs10896449 (n= 31), rs10896438 (n= 24) and rs12793759 (n= 8). Our results indicate that a complex architecture underlying the common variants contributing to prostate cancer risk at 11q13. We estimate that at least 63 common variants should be considered in future studies designed to investigate the biological basis of the multiple association signals.
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Genetic variability of the forkhead box O3 and prostate cancer risk in the European Prospective Investigation on Cancer.
Oncol. Rep.
PUBLISHED: 03-14-2011
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Forkhead box O3 (FOXO3) has a wide range of functions: it promotes tumor suppression, cell cycle arrest, repair of damaged DNA, detoxification of reactive oxygen species, apoptosis and plays a pivotal role in promoting longevity. FOXO3 is a key downstream target of the PI3K-Akt pathway in response to cellular stimulation by growth factors or insulin and has been proposed as a bridge between ageing and tumor suppression. Three SNPs in the FOXO3 gene (rs3800231, rs9400239 and rs479744) that have been shown to be strongly and consistently associated with longevity, were examined in relation to PC risk in a case control study of 1571 incident PC cases and 1840 controls nested within the European Prospective Investigation into Cancer and Nutrition (EPIC). There was no statistically significant association between the SNPs and PC risk regardless of the model of inheritance (dominant, codominant and recessive). The associations were not modified by disease aggressiveness, circulating levels of steroid sex hormones, or IGFs or BMI. We conclude that polymorphisms in the FOXO3 gene that are associated with longevity are not major risk factors for PC risk, in this population of Caucasian men.
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Drug development to protozoan diseases.
Open Med Chem J
PUBLISHED: 03-09-2011
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The diseases caused by protozoan parasite are responsible for considerable mortality and morbidity, affecting more than 500 million of people in the world. The epidemiological control of protozoan is unsatisfactory due to difficulties of vector and reservoir control; while the progress in the development of vaccine tends to be slow and arduous. Currently, the chemotherapy remains essential component of both clinical management and disease control programmer in endemic areas. The drugs in use as anti-protozoan agents were discovered over 50 years and a number of factors limit their utility such as: high cost, poor compliance, drug resistance, low efficacy and poor safety. In the recent years, the searches about the development of new drugs against protozoa parasite have been increased. This special issue of The Open Medicinal Chemistry Journal will present some of developments in this field with the aim to shown the significant advances in the discovery of new anti-protozoan drugs.
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Does atorvastatin work more effectively than biguanides in reducing cardiovascular risk factors?
J Pharm Bioallied Sci
PUBLISHED: 02-19-2011
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Increased risk of coronary artery disease in diabetic persons is associated with increased level of lipoproteins. Usually, such risks are reverted with glycemic control by antidiabetic medicines in Type I diabetes millitus. However, in Type II diabetes mellitus lipid values can be improved using antidiabetics but still the risk of coronary artery disease remains. The initial approach for reducing lipid contents in diabetic patients should include glycemic control, diet, weight loss, and exercise. But if it fails then lipid-lowering agents like fibrate and HMG CoA reductase (3-hydroxy-3-methyl-glutaryl-CoA reductase) inhibitors should work effectively. In the present study results of atorvastatin compared with biguanides proved atorvastatin as a more effective lipid-lowering agent along with antidiabetic activity so it can effectively help in reducing the risk of cardiovascular disease (CVD).
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Characterizing associations and SNP-environment interactions for GWAS-identified prostate cancer risk markers--results from BPC3.
PLoS ONE
PUBLISHED: 01-21-2011
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Genome-wide association studies (GWAS) have identified multiple single nucleotide polymorphisms (SNPs) associated with prostate cancer risk. However, whether these associations can be consistently replicated, vary with disease aggressiveness (tumor stage and grade) and/or interact with non-genetic potential risk factors or other SNPs is unknown. We therefore genotyped 39 SNPs from regions identified by several prostate cancer GWAS in 10,501 prostate cancer cases and 10,831 controls from the NCI Breast and Prostate Cancer Cohort Consortium (BPC3). We replicated 36 out of 39 SNPs (P-values ranging from 0.01 to 10?²?). Two SNPs located near KLK3 associated with PSA levels showed differential association with Gleason grade (rs2735839, P?=?0.0001 and rs266849, P?=?0.0004; case-only test), where the alleles associated with decreasing PSA levels were inversely associated with low-grade (as defined by Gleason grade < 8) tumors but positively associated with high-grade tumors. No other SNP showed differential associations according to disease stage or grade. We observed no effect modification by SNP for association with age at diagnosis, family history of prostate cancer, diabetes, BMI, height, smoking or alcohol intake. Moreover, we found no evidence of pair-wise SNP-SNP interactions. While these SNPs represent new independent risk factors for prostate cancer, we saw little evidence for effect modification by other SNPs or by the environmental factors examined.
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Genetic variability of the mTOR pathway and prostate cancer risk in the European Prospective Investigation on Cancer (EPIC).
PLoS ONE
PUBLISHED: 01-01-2011
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The mTOR (mammalian target of rapamycin) signal transduction pathway integrates various signals, regulating ribosome biogenesis and protein synthesis as a function of available energy and amino acids, and assuring an appropriate coupling of cellular proliferation with increases in cell size. In addition, recent evidence has pointed to an interplay between the mTOR and p53 pathways. We investigated the genetic variability of 67 key genes in the mTOR pathway and in genes of the p53 pathway which interact with mTOR. We tested the association of 1,084 tagging SNPs with prostate cancer risk in a study of 815 prostate cancer cases and 1,266 controls nested within the European Prospective Investigation into Cancer and Nutrition (EPIC). We chose the SNPs (n?=?11) with the strongest association with risk (p<0.01) and sought to replicate their association in an additional series of 838 prostate cancer cases and 943 controls from EPIC. In the joint analysis of first and second phase two SNPs of the PRKCI gene showed an association with risk of prostate cancer (OR(allele)?=?0.85, 95% CI 0.78-0.94, p?=?1.3 x 10?³ for rs546950 and OR(allele)?=?0.84, 95% CI 0.76-0.93, p?=?5.6 x 10?? for rs4955720). We confirmed this in a meta-analysis using as replication set the data from the second phase of our study jointly with the first phase of the Cancer Genetic Markers of Susceptibility (CGEMS) project. In conclusion, we found an association with prostate cancer risk for two SNPs belonging to PRKCI, a gene which is frequently overexpressed in various neoplasms, including prostate cancer.
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Variation in genes coding for AMP-activated protein kinase (AMPK) and breast cancer risk in the European Prospective Investigation on Cancer (EPIC).
Breast Cancer Res. Treat.
PUBLISHED: 10-21-2010
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AMP-activated protein kinase (AMPK) is an energy sensing/signalling intracellular protein which is activated by an increase in the cellular AMP:ATP ratio after ATP depletion. Once activated, AMPK inhibits fatty acid synthesis and the Akt-mTOR pathway, and activates the p53-p21 axis. All these molecular mechanisms are thought to play a key role in breast carcinogenesis. We investigated the genetic variability of four genes encoding AMPK (PRKAA1, PRKAA2, PRKAB1 and PRKAB2). Using a tagging approach and selecting SNPs we covered all the common genetic variation of these genes. We tested association of tagging SNPs in our four candidate genes with breast cancer (BC) risk in a study of 1340 BC cases and 2536 controls nested into the European Prospective Investigation into Cancer and Nutrition (EPIC). Given the relevance of AMPK on fatty acid synthesis and the importance of body fatness as a BC risk factor, we tested association of SNPs and body-mass index as well. We observed no statistically significant association between the SNPs in the PRKAs genes and BC risk and BMI after correction for multiple testing.
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A large study of androgen receptor germline variants and their relation to sex hormone levels and prostate cancer risk. Results from the National Cancer Institute Breast and Prostate Cancer Cohort Consortium.
J. Clin. Endocrinol. Metab.
PUBLISHED: 06-09-2010
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Androgens are key regulators of prostate gland maintenance and prostate cancer growth, and androgen deprivation therapy has been the mainstay of treatment for advanced prostate cancer for many years. A long-standing hypothesis has been that inherited variation in the androgen receptor (AR) gene plays a role in prostate cancer initiation. However, studies to date have been inconclusive and often suffered from small sample sizes.
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Genetic variability of the fatty acid synthase pathway is not associated with prostate cancer risk in the European Prospective Investigation on Cancer (EPIC).
Eur. J. Cancer
PUBLISHED: 04-24-2010
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A western lifestyle, characterised by low rates of energy expenditure and a high-energy diet rich in animal protein, saturated fats and refined carbohydrates, is associated with high incidence of prostate cancer in men. A high-energy nutritional status results in insulin/IGF signalling in cells, which in turn stimulates synthesis of fatty acids. We investigated whether the genetic variability of the genes belonging to the fatty acid synthesis pathway is related to prostate cancer risk in 815 prostate cancer cases and 1266 controls from the European Prospective Investigation on Cancer (EPIC). Using a tagging approach and selecting 252 SNPs in 22 genes, we covered all the common genetic variation of this pathway. None of the SNPs reached statistical significance after adjusting for multiple comparisons. Common SNPs in the fatty acid synthase pathway are not major contributors to prostate cancer risk.
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Refining the prostate cancer genetic association within the JAZF1 gene on chromosome 7p15.2.
Cancer Epidemiol. Biomarkers Prev.
PUBLISHED: 04-20-2010
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Genome-wide association studies have identified multiple genetic variants associated with susceptibility to prostate cancer (PrCa). In the two-stage Cancer Genetic Markers of Susceptibility prostate cancer scan, a single-nucleotide polymorphism (SNP), rs10486567, located within intron 2 of JAZF1 gene on chromosome 7p15.2, showed a promising association with PrCa overall (P=2.14x10(-6)), with a suggestion of stronger association with aggressive disease (P=1.2x10(-7)).
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Pooled analysis of phosphatidylinositol 3-kinase pathway variants and risk of prostate cancer.
Cancer Res.
PUBLISHED: 03-02-2010
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The phosphatidylinositol 3-kinase (PI3K) pathway regulates various cellular processes, including cellular proliferation and intracellular trafficking, and may affect prostate carcinogenesis. Thus, we explored the association between single-nucleotide polymorphisms (SNP) in PI3K genes and prostate cancer. Pooled data from the National Cancer Institute Breast and Prostate Cancer Cohort Consortium were examined for associations between 89 SNPs in PI3K genes (PIK3C2B, PIK3AP1, PIK3C2A, PIK3CD, and PIK3R3) and prostate cancer risk in 8,309 cases and 9,286 controls. Odds ratios (OR) and 95% confidence intervals (95% CI) were estimated using logistic regression. SNP rs7556371 in PIK3C2B was significantly associated with prostate cancer risk [OR(per allele), 1.08 (95% CI, 1.03-1.14); P(trend) = 0.0017] after adjustment for multiple testing (P(adj) = 0.024). Simultaneous adjustment of rs7556371 for nearby SNPs strengthened the association [OR(per allele), 1.21 (95% CI, 1.09-1.34); P(trend) = 0.0003]. The adjusted association was stronger for men who were diagnosed before the age of 65 years [OR(per allele), 1.47 (95% CI, 1.20-1.79); P(trend) = 0.0001] or had a family history [OR(per allele) = 1.57 (95% CI, 1.11-2.23); P(trend) = 0.0114], and was strongest in those with both characteristics [OR(per allele) = 2.31 (95% CI, 1.07-5.07), P-interaction = 0.005]. Increased risks were observed among men in the top tertile of circulating insulin-like growth factor-I (IGF-I) levels [OR(per allele) = 1.46 (95% CI, 1.04-2.06); P(trend) = 0.075]. No differences were observed with disease aggressiveness (Gleason grade >or=8 or stage T(3)/T(4) or fatal). In conclusion, we observed a significant association between PIK3C2B and prostate cancer risk, especially for familial, early-onset disease, which may be attributable to IGF-dependent PI3K signaling.
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The INSIG2 rs7566605 polymorphism is not associated with body mass index and breast cancer risk.
BMC Cancer
PUBLISHED: 01-20-2010
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The single nucleotide polymorphism rs7566605, located in the promoter of the INSIG2 gene, has been the subject of a strong scientific effort aimed to elucidate its possible association with body mass index (BMI). The first report showing that rs7566605 could be associated with body fatness was a genome-wide association study (GWAS) which used BMI as the primary phenotype. Many follow-up studies sought to validate the association of rs7566605 with various markers of obesity, with several publications reporting inconsistent findings. BMI is considered to be one of the measures of choice to evaluate body fatness and there is evidence that body fatness is related with an increased risk of breast cancer (BC).
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Identification of a new prostate cancer susceptibility locus on chromosome 8q24.
Nat. Genet.
PUBLISHED: 03-12-2009
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We report a genome-wide association study in 10,286 cases and 9,135 controls of European ancestry in the Cancer Genetic Markers of Susceptibility (CGEMS) initiative. We identify a new association with prostate cancer risk on chromosome 8q24 (rs620861, P = 1.3 x 10(-10), heterozygote OR = 1.17, 95% CI 1.10-1.24; homozygote OR = 1.33, 95% CI 1.21-1.45). This defines a new locus associated with prostate cancer susceptibility on 8q24.
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A meta-analysis of genome-wide association studies to identify prostate cancer susceptibility loci associated with aggressive and non-aggressive disease.
Ali Amin Al Olama, Zsofia Kote-Jarai, Fredrick R Schumacher, Fredrik Wiklund, Sonja I Berndt, Sara Benlloch, Graham G Giles, Gianluca Severi, David E Neal, Freddie C Hamdy, Jenny L Donovan, David J Hunter, Brian E Henderson, Michael J Thun, Michael Gaziano, Edward L Giovannucci, Afshan Siddiq, Ruth C Travis, David G Cox, Federico Canzian, Elio Riboli, Timothy J Key, Gerald Andriole, Demetrius Albanes, Richard B Hayes, Johanna Schleutker, Anssi Auvinen, Teuvo L J Tammela, Maren Weischer, Janet L Stanford, Elaine A Ostrander, Cezary Cybulski, Jan Lubiński, Stephen N Thibodeau, Daniel J Schaid, Karina D Sorensen, Jyotsna Batra, Judith A Clements, Suzanne Chambers, Joanne Aitken, Robert A Gardiner, Christiane Maier, Walther Vogel, Thilo Dörk, Hermann Brenner, Tomonori Habuchi, Sue Ingles, Esther M John, Joanne L Dickinson, Lisa Cannon-Albright, Manuel R Teixeira, Radka Kaneva, Hong-Wei Zhang, Yong-Jie Lu, Jong Y Park, Kathleen A Cooney, Kenneth R Muir, Daniel A Leongamornlert, Edward Saunders, Malgorzata Tymrakiewicz, Nadiya Mahmud, Michelle Guy, Koveela Govindasami, Lynne T O'Brien, Rosemary A Wilkinson, Amanda L Hall, Emma J Sawyer, Tokhir Dadaev, Jonathan Morrison, David P Dearnaley, Alan Horwich, Robert A Huddart, Vincent S Khoo, Christopher C Parker, Nicholas van As, Christopher J Woodhouse, Alan Thompson, Tim Dudderidge, Chris Ogden, Colin S Cooper, Artitaya Lophatonanon, Melissa C Southey, John L Hopper, Dallas English, Jarmo Virtamo, Loic Le Marchand, Daniele Campa, Rudolf Kaaks, Sara Lindstrom, W Ryan Diver, Susan Gapstur, Meredith Yeager, Angela Cox, Mariana C Stern, Román Corral, Markus Aly, William Isaacs, Jan Adolfsson, Jianfeng Xu, S Lilly Zheng, Tiina Wahlfors, Kimmo Taari, Paula Kujala, Peter Klarskov, Børge G Nordestgaard, M Andreas Røder, Ruth Frikke-Schmidt, Stig E Bojesen, Liesel M Fitzgerald, Suzanne Kolb, Erika M Kwon, Danielle M Karyadi, Torben Falck Orntoft, Michael Borre, Antje Rinckleb, Manuel Luedeke, Kathleen Herkommer, Andreas Meyer, Jürgen Serth, James R Marthick, Briony Patterson, Dominika Wokolorczyk, Amanda Spurdle, Felicity Lose, Shannon K McDonnell, Amit D Joshi, Ahva Shahabi, Pedro Pinto, Joana Santos, Ana Ray, Thomas A Sellers, Hui-Yi Lin, Robert A Stephenson, Craig Teerlink, Heiko Muller, Dietrich Rothenbacher, Norihiko Tsuchiya, Shintaro Narita, Guang-Wen Cao, Chavdar Slavov, Vanio Mitev, , Stephen Chanock, Henrik Grönberg, Christopher A Haiman, Peter Kraft, Douglas F Easton, Rosalind A Eeles.
Hum. Mol. Genet.
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Genome-wide association studies (GWAS) have identified multiple common genetic variants associated with an increased risk of prostate cancer (PrCa), but these explain less than one-third of the heritability. To identify further susceptibility alleles, we conducted a meta-analysis of four GWAS including 5953 cases of aggressive PrCa and 11 463 controls (men without PrCa). We computed association tests for approximately 2.6 million SNPs and followed up the most significant SNPs by genotyping 49 121 samples in 29 studies through the international PRACTICAL and BPC3 consortia. We not only confirmed the association of a PrCa susceptibility locus, rs11672691 on chromosome 19, but also showed an association with aggressive PrCa [odds ratio = 1.12 (95% confidence interval 1.03-1.21), P = 1.4 × 10(-8)]. This report describes a genetic variant which is associated with aggressive PrCa, which is a type of PrCa associated with a poorer prognosis.
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A meta-analysis of genome-wide association studies of breast cancer identifies two novel susceptibility loci at 6q14 and 20q11.
Afshan Siddiq, Fergus J Couch, Gary K Chen, Sara Lindstrom, Diana Eccles, Robert C Millikan, Kyriaki Michailidou, Daniel O Stram, Lars Beckmann, Suhn Kyong Rhie, Christine B Ambrosone, Kristiina Aittomäki, Pilar Amiano, Carmel Apicella, , Laura Baglietto, Elisa V Bandera, Matthias W Beckmann, Christine D Berg, Leslie Bernstein, Carl Blomqvist, Hiltrud Brauch, Louise Brinton, Quang M Bui, Julie E Buring, Saundra S Buys, Daniele Campa, Jane E Carpenter, Daniel I Chasman, Jenny Chang-Claude, Constance Chen, Francoise Clavel-Chapelon, Angela Cox, Simon S Cross, Kamila Czene, Sandra L Deming, Robert B Diasio, W Ryan Diver, Alison M Dunning, Lorraine Durcan, Arif B Ekici, Peter A Fasching, Heather Spencer Feigelson, Laura Fejerman, Jonine D Figueroa, Olivia Fletcher, Dieter Flesch-Janys, Mia M Gaudet, Susan M Gerty, Jorge L Rodriguez-Gil, Graham G Giles, Carla H van Gils, Andrew K Godwin, Nikki Graham, Dario Greco, Per Hall, Susan E Hankinson, Arndt Hartmann, Rebecca Hein, Judith Heinz, Robert N Hoover, John L Hopper, Jennifer J Hu, Scott Huntsman, Sue A Ingles, Astrid Irwanto, Claudine Isaacs, Kevin B Jacobs, Esther M John, Christina Justenhoven, Rudolf Kaaks, Laurence N Kolonel, Gerhard A Coetzee, Mark Lathrop, Loic Le Marchand, Adam M Lee, I-Min Lee, Timothy Lesnick, Peter Lichtner, Jianjun Liu, Eiliv Lund, Enes Makalic, Nicholas G Martin, Catriona A McLean, Hanne Meijers-Heijboer, Alfons Meindl, Penelope Miron, Kristine R Monroe, Grant W Montgomery, Bertram Müller-Myhsok, Stefan Nickels, Sarah J Nyante, Curtis Olswold, Kim Overvad, Domenico Palli, Daniel J Park, Julie R Palmer, Harsh Pathak, Julian Peto, Paul Pharoah, Nazneen Rahman, Fernando Rivadeneira, Daniel F Schmidt, Rita K Schmutzler, Susan Slager, Melissa C Southey, Kristen N Stevens, Hans-Peter Sinn, Michael F Press, Eric Ross, Elio Riboli, Paul M Ridker, Fredrick R Schumacher, Gianluca Severi, Isabel Dos Santos Silva, Jennifer Stone, Malin Sund, William J Tapper, Michael J Thun, Ruth C Travis, Clare Turnbull, André G Uitterlinden, Quinten Waisfisz, Xianshu Wang, Zhaoming Wang, Joellen Weaver, Rüdiger Schulz-Wendtland, Lynne R Wilkens, David Van Den Berg, Wei Zheng, Regina G Ziegler, Elad Ziv, Heli Nevanlinna, Douglas F Easton, David J Hunter, Brian E Henderson, Stephen J Chanock, Montserrat Garcia-Closas, Peter Kraft, Christopher A Haiman, Celine M Vachon.
Hum. Mol. Genet.
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Genome-wide association studies (GWAS) of breast cancer defined by hormone receptor status have revealed loci contributing to susceptibility of estrogen receptor (ER)-negative subtypes. To identify additional genetic variants for ER-negative breast cancer, we conducted the largest meta-analysis of ER-negative disease to date, comprising 4754 ER-negative cases and 31 663 controls from three GWAS: NCI Breast and Prostate Cancer Cohort Consortium (BPC3) (2188 ER-negative cases; 25 519 controls of European ancestry), Triple Negative Breast Cancer Consortium (TNBCC) (1562 triple negative cases; 3399 controls of European ancestry) and African American Breast Cancer Consortium (AABC) (1004 ER-negative cases; 2745 controls). We performed in silico replication of 86 SNPs at P ? 1 × 10(-5) in an additional 11 209 breast cancer cases (946 with ER-negative disease) and 16 057 controls of Japanese, Latino and European ancestry. We identified two novel loci for breast cancer at 20q11 and 6q14. SNP rs2284378 at 20q11 was associated with ER-negative breast cancer (combined two-stage OR = 1.16; P = 1.1 × 10(-8)) but showed a weaker association with overall breast cancer (OR = 1.08, P = 1.3 × 10(-6)) based on 17 869 cases and 43 745 controls and no association with ER-positive disease (OR = 1.01, P = 0.67) based on 9965 cases and 22 902 controls. Similarly, rs17530068 at 6q14 was associated with breast cancer (OR = 1.12; P = 1.1 × 10(-9)), and with both ER-positive (OR = 1.09; P = 1.5 × 10(-5)) and ER-negative (OR = 1.16, P = 2.5 × 10(-7)) disease. We also confirmed three known loci associated with ER-negative (19p13) and both ER-negative and ER-positive breast cancer (6q25 and 12p11). Our results highlight the value of large-scale collaborative studies to identify novel breast cancer risk loci.
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Genetic variation in the lactase gene, dairy product intake and risk for prostate cancer in the European prospective investigation into cancer and nutrition.
Int. J. Cancer
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High dairy protein intake has been found to be associated with increased prostate cancer risk in the European Prospective Investigation into Cancer and Nutrition (EPIC). To further examine this possible relationship, we investigated the hypothesis that a genetic polymorphism in the lactase (LCT) gene might be associated with elevated dairy product intake and increased prostate cancer risk in a case-control study nested in EPIC. The C/T-13910 lactase variant (rs4988235) was genotyped in 630 men with prostate cancer and 873 matched control participants. Dairy product consumption was assessed by diet questionnaire. Odds ratios (ORs) for prostate cancer in relation to lactase genotype were estimated by conditional logistic regression. Lactase genotype frequency varied significantly between countries, with frequencies of the T (lactase persistence) allele ranging from 7% in Greece to 79% in Denmark. Intake of milk and total dairy products varied significantly by lactase genotype after adjustment for recruitment center; adjusted mean intakes of milk were 44.4, 69.8 and 82.3 g/day among men with CC, CT and TT genotypes, respectively. The lactase variant was not significantly associated with prostate cancer risk, both in our data (adjusted OR for TT vs. CC homozygotes: 1.10, 95% CI: 0.76-1.59) and in a meta-analysis of all the published data (combined OR for T allele carriers vs. CC homozygotes: 1.12, 0.96-1.32). These findings show that while variation in the lactase gene is associated with milk intake in men, the lactase polymorphism does not have a large effect on prostate cancer risk.
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Sources of pre-analytical variations in yield of DNA extracted from blood samples: analysis of 50,000 DNA samples in EPIC.
PLoS ONE
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The European Prospective Investigation into Cancer and nutrition (EPIC) is a long-term, multi-centric prospective study in Europe investigating the relationships between cancer and nutrition. This study has served as a basis for a number of Genome-Wide Association Studies (GWAS) and other types of genetic analyses. Over a period of 5 years, 52,256 EPIC DNA samples have been extracted using an automated DNA extraction platform. Here we have evaluated the pre-analytical factors affecting DNA yield, including anthropometric, epidemiological and technical factors such as center of subject recruitment, age, gender, body-mass index, disease case or control status, tobacco consumption, number of aliquots of buffy coat used for DNA extraction, extraction machine or procedure, DNA quantification method, degree of haemolysis and variations in the timing of sample processing. We show that the largest significant variations in DNA yield were observed with degree of haemolysis and with center of subject recruitment. Age, gender, body-mass index, cancer case or control status and tobacco consumption also significantly impacted DNA yield. Feedback from laboratories which have analyzed DNA with different SNP genotyping technologies demonstrate that the vast majority of samples (approximately 88%) performed adequately in different types of assays. To our knowledge this study is the largest to date to evaluate the sources of pre-analytical variations in DNA extracted from peripheral leucocytes. The results provide a strong evidence-based rationale for standardized recommendations on blood collection and processing protocols for large-scale genetic studies.
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Prediagnostic concentrations of plasma genistein and prostate cancer risk in 1,605 men with prostate cancer and 1,697 matched control participants in EPIC.
Cancer Causes Control
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Data from prospective epidemiological studies in Asian populations and from experimental studies in animals and cell lines suggest a possible protective association between dietary isoflavones and the development of prostate cancer. We examined the association between circulating concentrations of genistein and prostate cancer risk in a case-control study nested in the European Prospective Investigation into Cancer and Nutrition.
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Interactions between genome-wide significant genetic variants and circulating concentrations of insulin-like growth factor 1, sex hormones, and binding proteins in relation to prostate cancer risk in the National Cancer Institute Breast and Prostate Cance
Am. J. Epidemiol.
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Genome-wide association studies (GWAS) have identified many single nucleotide polymorphisms (SNPs) associated with prostate cancer risk. There is limited information on the mechanistic basis of these associations, particularly about whether they interact with circulating concentrations of growth factors and sex hormones, which may be important in prostate cancer etiology. Using conditional logistic regression, the authors compared per-allele odds ratios for prostate cancer for 39 GWAS-identified SNPs across thirds (tertile groups) of circulating concentrations of insulin-like growth factor 1 (IGF-1), insulin-like growth factor binding protein 3 (IGFBP-3), testosterone, androstenedione, androstanediol glucuronide, estradiol, and sex hormone-binding globulin (SHBG) for 3,043 cases and 3,478 controls in the Breast and Prostate Cancer Cohort Consortium. After allowing for multiple testing, none of the SNPs examined were significantly associated with growth factor or hormone concentrations, and the SNP-prostate cancer associations did not differ by these concentrations, although 4 interactions were marginally significant (MSMB-rs10993994 with androstenedione (uncorrected P = 0.008); CTBP2-rs4962416 with IGFBP-3 (uncorrected P = 0.003); 11q13.2-rs12418451 with IGF-1 (uncorrected P = 0.006); and 11q13.2-rs10896449 with SHBG (uncorrected P = 0.005)). The authors found no strong evidence that associations between GWAS-identified SNPs and prostate cancer are modified by circulating concentrations of IGF-1, sex hormones, or their major binding proteins.
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