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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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Joint analysis of three genome-wide association studies of esophageal squamous cell carcinoma in Chinese populations.
Chen Wu, Zhaoming Wang, Xin Song, Xiao-Shan Feng, Christian C Abnet, Jie He, Nan Hu, Xian-Bo Zuo, Wen Tan, Qimin Zhan, Zhibin Hu, Zhonghu He, Weihua Jia, Yifeng Zhou, Kai Yu, Xiao-Ou Shu, Jian-Min Yuan, Wei Zheng, Xue-Ke Zhao, She-Gan Gao, Zhi-Qing Yuan, Fu-You Zhou, Zong-Min Fan, Ji-Li Cui, Hong-Li Lin, Xue-Na Han, Bei Li, Xi Chen, Sanford M Dawsey, Linda Liao, Maxwell P Lee, Ti Ding, You-Lin Qiao, Zhihua Liu, Yu Liu, Dianke Yu, Jiang Chang, Lixuan Wei, Yu-Tang Gao, Woon-Puay Koh, Yong-Bing Xiang, Ze-Zhong Tang, Jin-Hu Fan, Jing-jing Han, Sheng-Li Zhou, Peng Zhang, Dong-Yun Zhang, Yuan Yuan, Ying Huang, Chunling Liu, Kan Zhai, Yan Qiao, Guangfu Jin, Chuanhai Guo, Jianhua Fu, Xiaoping Miao, Changdong Lu, Haijun Yang, Chaoyu Wang, William A Wheeler, Mitchell Gail, Meredith Yeager, Jeff Yuenger, Er-Tao Guo, Ai-li Li, Wei Zhang, Xue-Min Li, Liang-Dan Sun, Bao-Gen Ma, Yan Li, Sa Tang, Xiu-Qing Peng, Jing Liu, Amy Hutchinson, Kevin Jacobs, Carol Giffen, Laurie Burdette, Joseph F Fraumeni, Hongbing Shen, Yang Ke, Yixin Zeng, Tangchun Wu, Peter Kraft, Charles C Chung, Margaret A Tucker, Zhi-Chao Hou, Ya-Li Liu, Yan-Long Hu, Li Wang, Guo Yuan, Li-Sha Chen, Xiao Liu, Teng Ma, Hui Meng, Li Sun, Xin-Min Li, Xiu-Min Li, Jian-Wei Ku, Ying-Fa Zhou, Liu-Qin Yang, Zhou Wang, Yin Li, Qirenwang Qige, Wen-jun Yang, Guang-Yan Lei, Long-qi Chen, En-Min Li, Ling Yuan, Wen-Bin Yue, Ran Wang, Lu-Wen Wang, Xue-Ping Fan, Fang-Heng Zhu, Wei-Xing Zhao, Yi-min Mao, Mei Zhang, Guo-Lan Xing, Ji-Lin Li, Min Han, Jing-Li Ren, Bin Liu, Shu-Wei Ren, Qing-Peng Kong, Feng Li, Ilyar Sheyhidin, Wu Wei, Yan-Rui Zhang, Chang-Wei Feng, Jin Wang, Yu-Hua Yang, Hong-Zhang Hao, Qi-De Bao, Bao-Chi Liu, Ai-Qun Wu, Dong Xie, Wan-Cai Yang, Liang Wang, Xiao-Hang Zhao, Shu-Qing Chen, Jun-Yan Hong, Xue-Jun Zhang, Neal D Freedman, Alisa M Goldstein, Dongxin Lin, Philip R Taylor, Li-dong Wang, Stephen J Chanock.
Nat. Genet.
PUBLISHED: 08-17-2014
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We conducted a joint (pooled) analysis of three genome-wide association studies (GWAS) of esophageal squamous cell carcinoma (ESCC) in individuals of Chinese ancestry (5,337 ESCC cases and 5,787 controls) with 9,654 ESCC cases and 10,058 controls for follow-up. In a logistic regression model adjusted for age, sex, study and two eigenvectors, two new loci achieved genome-wide significance, marked by rs7447927 at 5q31.2 (per-allele odds ratio (OR) = 0.85, 95% confidence interval (CI) = 0.82-0.88; P = 7.72 × 10(-20)) and rs1642764 at 17p13.1 (per-allele OR = 0.88, 95% CI = 0.85-0.91; P = 3.10 × 10(-13)). rs7447927 is a synonymous SNP in TMEM173, and rs1642764 is an intronic SNP in ATP1B2, near TP53. Furthermore, a locus in the HLA class II region at 6p21.32 (rs35597309) achieved genome-wide significance in the two populations at highest risk for ESSC (OR = 1.33, 95% CI = 1.22-1.46; P = 1.99 × 10(-10)). Our joint analysis identifies new ESCC susceptibility loci overall as well as a new locus unique to the population in the Taihang Mountain region at high risk of ESCC.
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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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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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Genome-wide association study identifies multiple susceptibility loci for pancreatic cancer.
Brian M Wolpin, Cosmeri Rizzato, Peter Kraft, Charles Kooperberg, Gloria M Petersen, Zhaoming Wang, Alan A Arslan, Laura Beane-Freeman, Paige M Bracci, Julie Buring, Federico Canzian, Eric J Duell, Steven Gallinger, Graham G Giles, Gary E Goodman, Phyllis J Goodman, Eric J Jacobs, Aruna Kamineni, Alison P Klein, Laurence N Kolonel, Matthew H Kulke, Donghui Li, Nuria Malats, Sara H Olson, Harvey A Risch, Howard D Sesso, Kala Visvanathan, Emily White, Wei Zheng, Christian C Abnet, Demetrius Albanes, Gabriella Andreotti, Melissa A Austin, Richard Barfield, Daniela Basso, Sonja I Berndt, Marie-Christine Boutron-Ruault, Michelle Brotzman, Markus W Büchler, H Bas Bueno-de-Mesquita, Peter Bugert, Laurie Burdette, Daniele Campa, Neil E Caporaso, Gabriele Capurso, Charles Chung, Michelle Cotterchio, Eithne Costello, Joanne Elena, Niccola Funel, J Michael Gaziano, Nathalia A Giese, Edward L Giovannucci, Michael Goggins, Megan J Gorman, Myron Gross, Christopher A Haiman, Manal Hassan, Kathy J Helzlsouer, Brian E Henderson, Elizabeth A Holly, Nan Hu, David J Hunter, Federico Innocenti, Mazda Jenab, Rudolf Kaaks, Timothy J Key, Kay-Tee Khaw, Eric A Klein, Manolis Kogevinas, Vittorio Krogh, Juozas Kupcinskas, Robert C Kurtz, Andrea LaCroix, Maria T Landi, Stefano Landi, Loic Le Marchand, Andrea Mambrini, Satu Mannisto, Roger L Milne, Yusuke Nakamura, Ann L Oberg, Kouros Owzar, Alpa V Patel, Petra H M Peeters, Ulrike Peters, Raffaele Pezzilli, Ada Piepoli, Miquel Porta, Francisco X Real, Elio Riboli, Nathaniel Rothman, Aldo Scarpa, Xiao-Ou Shu, Debra T Silverman, Pavel Soucek, Malin Sund, Renata Talar-Wojnarowska, Philip R Taylor, George E Theodoropoulos, Mark Thornquist, Anne Tjønneland, Geoffrey S Tobias, Dimitrios Trichopoulos, Pavel Vodicka, Jean Wactawski-Wende, Nicolas Wentzensen, Chen Wu, Herbert Yu, Kai Yu, Anne Zeleniuch-Jacquotte, Robert Hoover, Patricia Hartge, Charles Fuchs, Stephen J Chanock, Rachael S Stolzenberg-Solomon, Laufey T Amundadottir.
Nat. Genet.
PUBLISHED: 02-26-2014
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We performed a multistage genome-wide association study including 7,683 individuals with pancreatic cancer and 14,397 controls of European descent. Four new loci reached genome-wide significance: rs6971499 at 7q32.3 (LINC-PINT, per-allele odds ratio (OR) = 0.79, 95% confidence interval (CI) 0.74-0.84, P = 3.0 × 10(-12)), rs7190458 at 16q23.1 (BCAR1/CTRB1/CTRB2, OR = 1.46, 95% CI 1.30-1.65, P = 1.1 × 10(-10)), rs9581943 at 13q12.2 (PDX1, OR = 1.15, 95% CI 1.10-1.20, P = 2.4 × 10(-9)) and rs16986825 at 22q12.1 (ZNRF3, OR = 1.18, 95% CI 1.12-1.25, P = 1.2 × 10(-8)). We identified an independent signal in exon 2 of TERT at the established region 5p15.33 (rs2736098, OR = 0.80, 95% CI 0.76-0.85, P = 9.8 × 10(-14)). We also identified a locus at 8q24.21 (rs1561927, P = 1.3 × 10(-7)) that approached genome-wide significance located 455 kb telomeric of PVT1. Our study identified multiple new susceptibility alleles for pancreatic cancer that are worthy of follow-up studies.
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Characterization of T gene sequence variants and germline duplications in familial and sporadic chordoma.
Hum. Genet.
PUBLISHED: 02-24-2014
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Chordoma is a rare bone cancer that is believed to originate from notochordal remnants. We previously identified germline T duplication as a major susceptibility mechanism in several chordoma families. Recently, a common genetic variant in T (rs2305089) was significantly associated with the risk of sporadic chordoma. We sequenced all T exons in 24 familial cases and 54 unaffected family members from eight chordoma families (three with T duplications), 103 sporadic cases, and 160 unrelated controls. We also measured T copy number variation in all sporadic cases. We confirmed the association between the previously reported variant rs2305089 and risk of familial [odds ratio (OR) = 2.6, 95% confidence interval (CI) = 0.93, 7.25, P = 0.067] and sporadic chordoma (OR = 2.85, 95% CI = 1.89, 4.29, P < 0.0001). We also identified a second common variant, rs1056048, that was strongly associated with chordoma in families (OR = 4.14, 95% CI = 1.43, 11.92, P = 0.0086). Among sporadic cases, another common variant (rs3816300) was significantly associated with risk when jointly analyzed with rs2305089. The association with rs3816300 was significantly stronger in cases with early age onset. In addition, we identified three rare variants that were only observed among sporadic chordoma cases, all of which have potential functional relevance based on in silico predictions. Finally, we did not observe T duplication in any sporadic chordoma case. Our findings further highlight the importance of the T gene in the pathogenesis of both familial and sporadic chordoma and suggest a complex susceptibility related to T.
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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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Pesticide exposure and inherited variants in vitamin d pathway genes in relation to prostate cancer.
Cancer Epidemiol. Biomarkers Prev.
PUBLISHED: 07-05-2013
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Vitamin D and its metabolites are believed to impede carcinogenesis by stimulating cell differentiation, inhibiting cell proliferation, and inducing apoptosis. Certain pesticides have been shown to deregulate vitamin Ds anticarcinogenic properties. We hypothesize that certain pesticides may be linked to prostate cancer via an interaction with vitamin D genetic variants.
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Genome-wide association study identifies multiple risk loci for chronic lymphocytic leukemia.
Sonja I Berndt, Christine F Skibola, Vijai Joseph, Nicola J Camp, Alexandra Nieters, Zhaoming Wang, Wendy Cozen, Alain Monnereau, Sophia S Wang, Rachel S Kelly, Qing Lan, Lauren R Teras, Nilanjan Chatterjee, Charles C Chung, Meredith Yeager, Angela R Brooks-Wilson, Patricia Hartge, Mark P Purdue, Brenda M Birmann, Bruce K Armstrong, Pierluigi Cocco, Yawei Zhang, Gianluca Severi, Anne Zeleniuch-Jacquotte, Charles Lawrence, Laurie Burdette, Jeffrey Yuenger, Amy Hutchinson, Kevin B Jacobs, Timothy G Call, Tait D Shanafelt, Anne J Novak, Neil E Kay, Mark Liebow, Alice H Wang, Karin E Smedby, Hans-Olov Adami, Mads Melbye, Bengt Glimelius, Ellen T Chang, Martha Glenn, Karen Curtin, Lisa A Cannon-Albright, Brandt Jones, W Ryan Diver, Brian K Link, George J Weiner, Lucia Conde, Paige M Bracci, Jacques Riby, Elizabeth A Holly, Martyn T Smith, Rebecca D Jackson, Lesley F Tinker, Yolanda Benavente, Nikolaus Becker, Paolo Boffetta, Paul Brennan, Lenka Foretova, Marc Maynadié, James McKay, Anthony Staines, Kari G Rabe, Sara J Achenbach, Celine M Vachon, Lynn R Goldin, Sara S Strom, Mark C Lanasa, Logan G Spector, Jose F Leis, Julie M Cunningham, J Brice Weinberg, Vicki A Morrison, Neil E Caporaso, Aaron D Norman, Martha S Linet, Anneclaire J De Roos, Lindsay M Morton, Richard K Severson, Elio Riboli, Paolo Vineis, Rudolph Kaaks, Dimitrios Trichopoulos, Giovanna Masala, Elisabete Weiderpass, Maria-Dolores Chirlaque, Roel C H Vermeulen, Ruth C Travis, Graham G Giles, Demetrius Albanes, Jarmo Virtamo, Stephanie Weinstein, Jacqueline Clavel, Tongzhang Zheng, Theodore R Holford, Kenneth Offit, Andrew Zelenetz, Robert J Klein, John J Spinelli, Kimberly A Bertrand, Francine Laden, Edward Giovannucci, Peter Kraft, Anne Kricker, Jenny Turner, Claire M Vajdic, Maria Grazia Ennas, Giovanni M Ferri, Lucia Miligi, Liming Liang, Joshua Sampson, Simon Crouch, Ju-Hyun Park, Kari E North, Angela Cox, John A Snowden, Josh Wright, Angel Carracedo, Carlos Lopez-Otin, Sílvia Beà, Itziar Salaverria, David Martín-Garcia, Elias Campo, Joseph F Fraumeni, Silvia de Sanjosé, Henrik Hjalgrim, James R Cerhan, Stephen J Chanock, Nathaniel Rothman, Susan L Slager.
Nat. Genet.
PUBLISHED: 05-02-2013
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Genome-wide association studies (GWAS) have previously identified 13 loci associated with risk of chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL). To identify additional CLL susceptibility loci, we conducted the largest meta-analysis for CLL thus far, including four GWAS with a total of 3,100 individuals with CLL (cases) and 7,667 controls. In the meta-analysis, we identified ten independent associated SNPs in nine new loci at 10q23.31 (ACTA2 or FAS (ACTA2/FAS), P=1.22×10(-14)), 18q21.33 (BCL2, P=7.76×10(-11)), 11p15.5 (C11orf21, P=2.15×10(-10)), 4q25 (LEF1, P=4.24×10(-10)), 2q33.1 (CASP10 or CASP8 (CASP10/CASP8), P=2.50×10(-9)), 9p21.3 (CDKN2B-AS1, P=1.27×10(-8)), 18q21.32 (PMAIP1, P=2.51×10(-8)), 15q15.1 (BMF, P=2.71×10(-10)) and 2p22.2 (QPCT, P=1.68×10(-8)), as well as an independent signal at an established locus (2q13, ACOXL, P=2.08×10(-18)). We also found evidence for two additional promising loci below genome-wide significance at 8q22.3 (ODF1, P=5.40×10(-8)) and 5p15.33 (TERT, P=1.92×10(-7)). Although further studies are required, the proximity of several of these loci to genes involved in apoptosis suggests a plausible underlying biological mechanism.
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Association of Genetic Variants in CDK6 and XRCC1 with the Risk of Dysplastic Nevi in Melanoma-Prone Families.
J. Invest. Dermatol.
PUBLISHED: 05-01-2013
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Dysplastic nevi (DN) is a strong risk factor for cutaneous malignant melanoma (CMM), and it frequently occurs in melanoma-prone families. To identify genetic variants for DN, we genotyped 677 tagSNPs in 38 melanoma candidate genes that are involved in pigmentation, DNA repair, cell cycle control, and melanocyte proliferation pathways in a total of 504 individuals (310 with DN, 194 without DN) from 53 melanoma-prone families (23 CDKN2A mutation positive and 30 negative). Conditional logistic regression, conditioning on families, was used to estimate the association between DN and each single-nucleotide polymorphism (SNP) separately, adjusted for age, sex, CMM, and CDKN2A status. P-values for SNPs in the same gene were combined to yield gene-specific P-values. Two genes, CDK6 (cyclin-dependent kinase 6) and XRCC1, were significantly associated with DN after Bonferroni correction for multiple testing (P=0.0001 and 0.00025, respectively), whereas neither gene was significantly associated with CMM. Associations for CDK6 SNPs were stronger in CDKN2A mutation-positive families (rs2079147, Pinteraction=0.0033), whereas XRCC1 SNPs had similar effects in mutation-positive and -negative families. The association for one of the associated SNPs in XRCC1 (rs25487) was replicated in two independent data sets (random-effect meta-analysis: P<0.0001). Our findings suggest that some genetic variants may contribute to DN risk independently of their association with CMM in melanoma-prone families.Journal of Investigative Dermatology advance online publication, 29 August 2013; doi:10.1038/jid.2013.316.
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Germline variation in NCF4, an innate immunity gene, is associated with an increased risk of colorectal cancer.
Int. J. Cancer
PUBLISHED: 03-07-2013
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Chronic inflammation has been implicated in the etiology of colorectal adenoma and cancer; however, few key inflammatory genes mediating this relationship have been identified. In this study, we investigated the association of germline variation in innate immunity genes in relation to the risk of colorectal neoplasia. Our study was based on the analysis of samples collected from the prostate, lung, colorectal and ovarian (PLCO) Cancer Screening Trial. We investigated the association between 196 tag single nucleotide polymorphisms (SNPs) in 20 key innate immunity genes with risk of advanced colorectal adenoma and cancer in 719 adenoma cases, 481 cancer cases and 719 controls. Logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CIs). After Bonferroni correction, the AG/GG genotype of rs5995355, which is upstream of NCF4, was associated with an increased risk of colorectal cancer (OR?=?2.43, 95% CI?=?1.73-3.39; p?
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Telomere length and the risk of cutaneous malignant melanoma in melanoma-prone families with and without CDKN2A mutations.
PLoS ONE
PUBLISHED: 01-01-2013
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Recent evidence suggests a link between constitutional telomere length (TL) and cancer risk. Previous studies have suggested that longer telomeres were associated with an increased risk of melanoma and larger size and number of nevi. The goal of this study was to examine whether TL modified the risk of melanoma in melanoma-prone families with and without CDKN2A germline mutations.
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Genetic variation in nucleotide excision repair pathway genes, pesticide exposure and prostate cancer risk.
Carcinogenesis
PUBLISHED: 11-18-2011
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Previous research demonstrates increased prostate cancer risk for pesticide applicators and pesticide manufacturing workers. Although underlying mechanisms are unknown, human biomonitoring studies indicate increased genetic damage (e.g. chromosomal aberrations) with pesticide exposure. Given that the nucleotide excision repair (NER) pathway repairs a broad range of DNA damage, we evaluated interactions between pesticide exposure and 324 single-nucleotide polymorphisms (SNPs) tagging 27 NER genes among 776 prostate cancer cases and 1444 male controls in a nested case-control study of white Agricultural Health Study pesticide applicators. We determined interaction P values using likelihood ratio tests from logistic regression models and three-level pesticide variables (none/low/high) based on lifetime days of use weighted to an intensity score. We adjusted for multiple comparisons using the false discovery rate (FDR) method. Of the 17 interactions that met FDR <0.2, 3 displayed a monotonic increase in prostate cancer risk with increasing exposure in one genotype group and no significant association in the other group. Men carrying the variant A allele at ERCC1 rs2298881 exhibited increased prostate cancer risk with high versus no fonofos use [odds ratio (OR) 2.98; 95% confidence interval (CI) 1.65-5.39; P(interact) = 3.6 × 10(-4); FDR-adjusted P = 0.11]. Men carrying the homozygous wild-type TT genotype at two correlated CDK7 SNPs, rs11744596 and rs2932778 (r(2) = 1.0), exhibited increased risk with high versus no carbofuran use (OR 2.01; 95% CI 1.31-3.10 for rs11744596; P(interact) = 7.2 × 10(-4); FDR-adjusted P = 0.09). In contrast, we did not observe associations among men with other genotypes at these loci. While requiring replication, our findings suggest a role for NER genetic variation in pesticide-associated prostate cancer risk.
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Xenobiotic-metabolizing gene variants, pesticide use, and the risk of prostate cancer.
Pharmacogenet. Genomics
PUBLISHED: 07-01-2011
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To explore associations with prostate cancer and farming, it is important to investigate the relationship between pesticide use and single nucleotide polymorphisms (SNPs) in xenobiotic metabolic enzyme (XME) genes.
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DNA repair gene polymorphisms and tobacco smoking in the risk for colorectal adenomas.
Carcinogenesis
PUBLISHED: 04-18-2011
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DNA damage is thought to play a critical role in the development of colorectal adenoma. Variation in DNA repair genes may alter their capacity to correct endogenous and exogenous DNA damage. We explored the association between common single-nucleotide polymorphisms (SNPs) in DNA repair genes and adenoma risk with a case-control study nested in the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial. A total of 1338 left sided, advanced colorectal adenoma cases and 1503 matched controls free of left-sided polyps were included in the study. Using DNA extracted from blood, 3144 tag SNPs in 149 DNA repair genes were successfully genotyped. Among Caucasians, 30 SNPs were associated with adenoma risk at P < 0.01, with four SNPs remaining significant after gene-based adjustment for multiple testing. The most significant finding was for a non-synonymous SNP (rs9350) in Exonuclease-1 (EXO1) [odds ratio (OR) = 1.30, 95% confidence interval (CI) = 1.11-1.51, P = 0.001)], which was predicted to be damaging using bioinformatics methods. However, the association was limited to smokers with a strong risk for current smokers (OR = 2.15, 95% CI = 1.27-3.65) and an intermediate risk for former smokers (OR = 1.45, 95% CI = 1.14-1.82) and no association for never smokers (OR = 0.98, 95% CI = 0.76-1.25) (P(interaction) = 0.002). Among the top findings, an SNP (rs17503908) in ataxia telangiectasia mutated (ATM) was inversely related to adenoma risk (OR = 0.75, 95% CI = 0.63-0.91). The association was restricted to never smokers (OR = 0.55, 95% CI = 0.40-0.76) with no increased risk observed among smokers (OR = 0.89, 95% CI = 0.70-1.13) (P(interaction) = 0.006). This large comprehensive study, which evaluated all presently known DNA repair genes, suggests that polymorphisms in EXO1 and ATM may be associated with risk for advanced colorectal adenoma with the associations modified by tobacco-smoking status.
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Genetic variants in DNA repair genes and the risk of cutaneous malignant melanoma in melanoma-prone families with/without CDKN2A mutations.
Int. J. Cancer
PUBLISHED: 03-03-2011
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Cutaneous malignant melanoma (CMM) is an etiologically heterogeneous disease with genetic, environmental (sun exposure) and host (pigmentation/nevi) factors and their interactions contributing to risk. Genetic variants in DNA repair genes may be particularly important since their altered function in response to sun exposure-related DNA damage maybe related to risk for CMM. However, systematic evaluations of genetic variants in DNA repair genes are limited, particularly in high-risk families. We comprehensively analyzed DNA repair gene polymorphisms and CMM risk in melanoma-prone families with/without CDKN2A mutations. A total of 586 individuals (183 CMM) from 53 families (23 CDKN2A (+), 30 CDKN2A (-)) were genotyped for 2964 tagSNPs in 131 DNA repair genes. Conditional logistic regression, conditioning on families, was used to estimate trend p-values, odds ratios and 95% confidence intervals for the association between CMM and each SNP separately, adjusted for age and sex. p-Values for SNPs in the same gene were combined to yield gene specific p-values. Two genes, POLN and PRKDC, were significantly associated with melanoma after Bonferroni correction for multiple testing (p = 0.0003 and 0.00035, respectively). DCLRE1B showed suggestive association (p = 0.0006). 28 ? 56% of genotyped SNPs in these genes had single SNP p < 0.05. The most significant SNPs in POLN and PRKDC had similar effects in CDKN2A (+) and CDKN2A (-) families. Our finding suggests that polymorphisms in DNA repair genes, POLN and PRKDC, were associated with increased melanoma risk in melanoma families with and without CDKN2A mutations.
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Genetic variation in base excision repair pathway genes, pesticide exposure, and prostate cancer risk.
Environ. Health Perspect.
PUBLISHED: 01-18-2011
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Previous research indicates increased prostate cancer risk for pesticide applicators and pesticide manufacturing workers. Although underlying mechanisms are unknown, evidence suggests a role of oxidative DNA damage.
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Selected human leukocyte antigen class II polymorphisms and risk of adult glioma.
J. Neuroimmunol.
PUBLISHED: 08-06-2010
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Few studies have examined the relationship between human leukocyte antigen (HLA) polymorphisms and adult glioma, particularly at class II loci. We evaluated the association between selected HLA class II polymorphisms and adult glioma in a large, hospital-based case-control study, using unconditional logistic regression. DQB1 06 (OR=1.67, 95% CI=1.17-2.39) and DRB1 13 (OR=1.69, 95% CI=1.08-2.64) alleles were associated with an increased risk of glioma, while the DQB1 05 allele showed an inverse association (OR=0.63, 95% CI=0.43-0.93). These results, which were of borderline significance once controlled for the false discovery rate, suggest a potential role for the DQB1 06, DQB1 05, and DRB1 13 alleles in glioma susceptibility.
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Associations of 9p21 variants with cutaneous malignant melanoma, nevi, and pigmentation phenotypes in melanoma-prone families with and without CDKN2A mutations.
Fam. Cancer
PUBLISHED: 06-25-2010
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Chromosome 9p21 has been implicated in the pathogenesis of cutaneous malignant melanoma (CMM). In addition to CDKN2A, the major known high-risk susceptibility gene for CMM, recent studies suggest that other 9p21 genes may be involved in melanoma/nevi development. To identify 9p21 variants that influence susceptibility to CMM and number of nevi in CMM-prone families with and without CDKN2A mutations, we analyzed 562 individuals (183 CMM) from 53 families (23 CDKN2A+, 30 CDKN2A-) for 233 tagging SNPs in 21 genes at 9p21. Single SNP- and gene-based regression analyses were used to assess the risk of CMM, nevi count, skin complexion, and tanning ability associated with these SNPs and genes. We found that SNP rs7023329 in the MTAP gene was associated with number of nevi (P (trend) = 0.003) confirming a recent finding by a genome-wide association study. In addition, three SNPs in the ACO1 gene, rs7855483 (P (trend) = 0.002), rs17288067 (P (trend) = 0.0009), and rs10813813 (P (trend) = 0.005), showed the strongest associations with CMM risk. None of the examined 9p21 SNPs was associated with skin complexion, whereas two SNPs, rs10964862 in IFNW1 (P (trend) = 0.003), and rs13290968 in TUSC1 (P (trend) = 0.0006), were associated with tanning ability. Gene-based analyses suggested that the ACO1 gene was significantly associated with CMM (P = 0.0004); genes IFNW1 (P = 0.002) and ACO1 (P = 0.0002) were significantly associated with tanning ability. Our findings are consistent with recent proposals that additional 9p21 genes may contribute to CMM susceptibility in CMM-prone families. These genetic variants may, at least partially, exert their effects through nevi and tanning ability.
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Genetic admixture and population substructure in Guanacaste Costa Rica.
PLoS ONE
PUBLISHED: 06-24-2010
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The population of Costa Rica (CR) represents an admixture of major continental populations. An investigation of the CR population structure would provide an important foundation for mapping genetic variants underlying common diseases and traits. We conducted an analysis of 1,301 women from the Guanacaste region of CR using 27,904 single nucleotide polymorphisms (SNPs) genotyped on a custom Illumina InfiniumII iSelect chip. The program STRUCTURE was used to compare the CR Guanacaste sample with four continental reference samples, including HapMap Europeans (CEU), East Asians (JPT+CHB), West African Yoruba (YRI), as well as Native Americans (NA) from the Illumina iControl database. Our results show that the CR Guanacaste sample comprises a three-way admixture estimated to be 43% European, 38% Native American and 15% West African. An estimated 4% residual Asian ancestry may be within the error range. Results from principal components analysis reveal a correlation between genetic and geographic distance. The magnitude of linkage disequilibrium (LD) measured by the number of tagging SNPs required to cover the same region in the genome in the CR Guanacaste sample appeared to be weaker than that observed in CEU, JPT+CHB and NA reference samples but stronger than that of the HapMap YRI sample. Based on the clustering pattern observed in both STRUCTURE and principal components analysis, two subpopulations were identified that differ by approximately 20% in LD block size averaged over all LD blocks identified by Haploview. We also show in a simulated association study conducted within the two subpopulations, that the failure to account for population stratification (PS) could lead to a noticeable inflation in the false positive rate. However, we further demonstrate that existing PS adjustment approaches can reduce the inflation to an acceptable level for gene discovery.
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Novel breast cancer risk alleles and interaction with ionizing radiation among U.S. radiologic technologists.
Radiat. Res.
PUBLISHED: 01-26-2010
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As genome-wide association studies of breast cancer are replicating findings and refinement studies are narrowing the signal location, additional efforts are necessary to elucidate the underlying functional relationships. One approach is to evaluate variation in risk by genotype based on known breast carcinogens, such as ionizing radiation. Given the public health concerns associated with recent increases in medical radiation exposure, this approach may also identify potentially susceptible subpopulations. We examined interaction between 27 newly identified breast cancer risk alleles (identified within the NCI Cancer Genetic Markers of Susceptibility and the Breast Cancer Association Consortium genome-wide association studies) and occupational and medical diagnostic radiation exposure among 859 cases and 1083 controls nested within the United States Radiologic Technologists cohort. We did not find significant variation in the radiation-related breast cancer risk for the variant in RAD51L1 (rs10483813) on 14q24.1 as we had hypothesized. In exploratory analyses, we found that the radiation-associated breast cancer risk varied significantly by linked markers in 5p12 (rs930395, rs10941679, rs2067980 and rs4415084) in the mitochondrial ribosomal protein S30 (MRPS30) gene (P(interaction) = 0.04). Chance, however, may explain these findings, and as such, these results need to be confirmed in other populations with low to moderate levels of radiation exposure. Even though a complete understanding of the way(s) in which these variants may increase breast cancer risk remains elusive, this approach may yield clues for further investigation.
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Common genetic variation in the sex hormone metabolic pathway and endometrial cancer risk: pathway-based evaluation of candidate genes.
Carcinogenesis
PUBLISHED: 01-06-2010
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Estrogen plays a major role in endometrial carcinogenesis, suggesting that common variants of genes in the sex hormone metabolic pathway may be related to endometrial cancer risk. In support of this view, variants in CYP19A1 [cytochrome P450 (CYP), family 19, subfamily A, polypeptide 1] have been associated with both circulating estrogen levels and endometrial cancer risk. Associations with variants in other genes have been suggested, but findings have been inconsistent.
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Dietary quercetin, quercetin-gene interaction, metabolic gene expression in lung tissue and lung cancer risk.
Carcinogenesis
PUBLISHED: 01-02-2010
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Epidemiological and mechanistic evidence on the association of quercetin-rich food intake with lung cancer risk and carcinogenesis are inconclusive. We investigated the role of dietary quercetin and the interaction between quercetin and P450 and glutathione S-transferase (GST) polymorphisms on lung cancer risk in 1822 incident lung cancer cases and 1991 frequency-matched controls from the Environment And Genetics in Lung cancer Etiology study. In non-tumor lung tissue from 38 adenocarcinoma patients, we assessed the correlation between quercetin intake and messenger RNA expression of the same P450 and GST metabolic genes. Multivariate odds ratios (ORs) and 95% confidence intervals (CIs) for sex-specific quintiles of intake were calculated using unconditional logistic regression adjusting for putative risk factors. Frequent intake of quercetin-rich foods was inversely associated with lung cancer risk (OR = 0.49; 95% CI: 0.37-0.67; P-trend < 0.001) and did not differ by P450 or GST genotypes, gender or histological subtypes. The association was stronger in subjects who smoked >20 cigarettes per day (OR = 0.35; 95% CI: 0.19-0.66; P-trend = 0.003). Based on a two-sample t-test, we compared gene expression and high versus low consumption of quercetin-rich foods and observed an overall upregulation of GSTM1, GSTM2, GSTT2, and GSTP1 as well as a downregulation of specific P450 genes (P-values < 0.05, adjusted for age and smoking status). In conclusion, we observed an inverse association of quercetin-rich food with lung cancer risk and identified a possible mechanism of quercetin-related changes in the expression of genes involved in the metabolism of tobacco carcinogens in humans. Our findings suggest an interplay between quercetin intake, tobacco smoking, and lung cancer risk. Further research on this relationship is warranted.
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A genome-wide association study of lung cancer identifies a region of chromosome 5p15 associated with risk for adenocarcinoma.
Am. J. Hum. Genet.
PUBLISHED: 07-03-2009
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Three genetic loci for lung cancer risk have been identified by genome-wide association studies (GWAS), but inherited susceptibility to specific histologic types of lung cancer is not well established. We conducted a GWAS of lung cancer and its major histologic types, genotyping 515,922 single-nucleotide polymorphisms (SNPs) in 5739 lung cancer cases and 5848 controls from one population-based case-control study and three cohort studies. Results were combined with summary data from ten additional studies, for a total of 13,300 cases and 19,666 controls of European descent. Four studies also provided histology data for replication, resulting in 3333 adenocarcinomas (AD), 2589 squamous cell carcinomas (SQ), and 1418 small cell carcinomas (SC). In analyses by histology, rs2736100 (TERT), on chromosome 5p15.33, was associated with risk of adenocarcinoma (odds ratio [OR]=1.23, 95% confidence interval [CI]=1.13-1.33, p=3.02x10(-7)), but not with other histologic types (OR=1.01, p=0.84 and OR=1.00, p=0.93 for SQ and SC, respectively). This finding was confirmed in each replication study and overall meta-analysis (OR=1.24, 95% CI=1.17-1.31, p=3.74x10(-14) for AD; OR=0.99, p=0.69 and OR=0.97, p=0.48 for SQ and SC, respectively). Other previously reported association signals on 15q25 and 6p21 were also refined, but no additional loci reached genome-wide significance. In conclusion, a lung cancer GWAS identified a distinct hereditary contribution to adenocarcinoma.
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Phase I metabolic genes and risk of lung cancer: multiple polymorphisms and mRNA expression.
PLoS ONE
PUBLISHED: 02-02-2009
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Polymorphisms in genes coding for enzymes that activate tobacco lung carcinogens may generate inter-individual differences in lung cancer risk. Previous studies had limited sample sizes, poor exposure characterization, and a few single nucleotide polymorphisms (SNPs) tested in candidate genes. We analyzed 25 SNPs (some previously untested) in 2101 primary lung cancer cases and 2120 population controls from the Environment And Genetics in Lung cancer Etiology (EAGLE) study from six phase I metabolic genes, including cytochrome P450s, microsomal epoxide hydrolase, and myeloperoxidase. We evaluated the main genotype effects and genotype-smoking interactions in lung cancer risk overall and in the major histology subtypes. We tested the combined effect of multiple SNPs on lung cancer risk and on gene expression. Findings were prioritized based on significance thresholds and consistency across different analyses, and accounted for multiple testing and prior knowledge. Two haplotypes in EPHX1 were significantly associated with lung cancer risk in the overall population. In addition, CYP1B1 and CYP2A6 polymorphisms were inversely associated with adenocarcinoma and squamous cell carcinoma risk, respectively. Moreover, the association between CYP1A1 rs2606345 genotype and lung cancer was significantly modified by intensity of cigarette smoking, suggesting an underlying dose-response mechanism. Finally, increasing number of variants at CYP1A1/A2 genes revealed significant protection in never smokers and risk in ever smokers. Results were supported by differential gene expression in non-tumor lung tissue samples with down-regulation of CYP1A1 in never smokers and up-regulation in smokers from CYP1A1/A2 SNPs. The significant haplotype associations emphasize that the effect of multiple SNPs may be important despite null single SNP-associations, and warrants consideration in genome-wide association studies (GWAS). Our findings emphasize the necessity of post-GWAS fine mapping and SNP functional assessment to further elucidate cancer risk associations.
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Vitamin D receptor polymorphisms and breast cancer risk: results from the National Cancer Institute Breast and Prostate Cancer Cohort Consortium.
Cancer Epidemiol. Biomarkers Prev.
PUBLISHED: 01-07-2009
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Vitamin D is hypothesized to lower the risk of breast cancer by inhibiting cell proliferation via the nuclear vitamin D receptor (VDR). Two common single nucleotide polymorphisms (SNP) in the VDR gene (VDR), rs1544410 (BsmI), and rs2228570 (FokI), have been inconsistently associated with breast cancer risk. Increased risk has been reported for the FokI ff genotype, which encodes a less transcriptionally active isoform of VDR, and reduced risk has been reported for the BsmI BB genotype, a SNP in strong linkage disequilibrium with a 3-untranslated region, which may influence VDR mRNA stability.
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On the interplay of telomeres, nevi and the risk of melanoma.
PLoS ONE
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The relationship between telomeres, nevi and melanoma is complex. Shorter telomeres have been found to be associated with many cancers and with number of nevi, a known risk factor for melanoma. However, shorter telomeres have also been found to decrease melanoma risk. We performed a systematic analysis of telomere-related genes and tagSNPs within these genes, in relation to the risk of melanoma, dysplastic nevi, and nevus count combining data from four studies conducted in Italy. In addition, we examined whether telomere length measured in peripheral blood leukocytes is related to the risk of melanoma, dysplastic nevi, number of nevi, or telomere-related SNPs. A total of 796 cases and 770 controls were genotyped for 517 SNPs in 39 telomere-related genes genotyped with a custom-made array. Replication of the top SNPs was conducted in two American populations consisting of 488 subjects from 53 melanoma-prone families and 1,086 cases and 1,024 controls from a case-control study. We estimated odds ratios for associations with SNPs and combined SNP P-values to compute gene region-specific, functional group-specific, and overall P-value using an adaptive rank-truncated product algorithm. In the Mediterranean population, we found suggestive evidence that RECQL4, a gene involved in genome stability, RTEL1, a gene regulating telomere elongation, and TERF2, a gene implicated in the protection of telomeres, were associated with melanoma, the presence of dysplastic nevi and number of nevi, respectively. However, these associations were not found in the American samples, suggesting variable melanoma susceptibility for these genes across populations or chance findings in our discovery sample. Larger studies across different populations are necessary to clarify these associations.
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The Interaction between Pesticide Use and Genetic Variants Involved in Lipid Metabolism on Prostate Cancer Risk.
J Cancer Epidemiol
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Background. Lipid metabolism processes have been implicated in prostate carcinogenesis. Since several pesticides are lipophilic or are metabolized via lipid-related mechanisms, they may interact with variants of genes in the lipid metabolism pathway. Methods. In a nested case-control study of 776 cases and 1444 controls from the Agricultural Health Study (AHS), a prospective cohort study of pesticide applicators, we examined the interactions between 39 pesticides (none, low, and high exposure) and 220 single nucleotide polymorphisms (SNPs) in 59 genes. The false discovery rate (FDR) was used to account for multiple comparisons. Results. We found 17 interactions that displayed a significant monotonic increase in prostate cancer risk with pesticide exposure in one genotype and no significant association in the other genotype. The most noteworthy association was for ALOXE3 rs3027208 and terbufos, such that men carrying the T allele who were low users had an OR of 1.86 (95% CI = 1.16-2.99) and high users an OR of 2.00 (95% CI = 1.28-3.15) compared to those with no use of terbufos, while men carrying the CC genotype did not exhibit a significant association. Conclusion. Genetic variation in lipid metabolism genes may modify pesticide associations with prostate cancer; however our results require replication.
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Single nucleotide polymorphisms in the PRDX3 and RPS19 and risk of HPV persistence and cervical precancer/cancer.
PLoS ONE
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Host genetic factors might affect the risk of progression from infection with carcinogenic human papillomavirus (HPV), the etiologic agent for cervical cancer, to persistent HPV infection, and hence to cervical precancer and cancer.
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Associations between genes in the one-carbon metabolism pathway and advanced colorectal adenoma risk in individuals with low folate intake.
Cancer Epidemiol. Biomarkers Prev.
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Folate is essential for one-carbon metabolism, a pathway required by DNA synthesis, methylation, and repair. Low dietary and circulating folate and polymorphic variation in this pathway are associated with increased risk of colorectal adenoma and cancer.
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Large-scale pathway-based analysis of bladder cancer genome-wide association data from five studies of European background.
PLoS ONE
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Pathway analysis of genome-wide association studies (GWAS) offer a unique opportunity to collectively evaluate genetic variants with effects that are too small to be detected individually. We applied a pathway analysis to a bladder cancer GWAS containing data from 3,532 cases and 5,120 controls of European background (n?=?5 studies). Thirteen hundred and ninety-nine pathways were drawn from five publicly available resources (Biocarta, Kegg, NCI-PID, HumanCyc, and Reactome), and we constructed 22 additional candidate pathways previously hypothesized to be related to bladder cancer. In total, 1421 pathways, 5647 genes and ?90,000 SNPs were included in our study. Logistic regression model adjusting for age, sex, study, DNA source, and smoking status was used to assess the marginal trend effect of SNPs on bladder cancer risk. Two complementary pathway-based methods (gene-set enrichment analysis [GSEA], and adapted rank-truncated product [ARTP]) were used to assess the enrichment of association signals within each pathway. Eighteen pathways were detected by either GSEA or ARTP at P?0.01. To minimize false positives, we used the I(2) statistic to identify SNPs displaying heterogeneous effects across the five studies. After removing these SNPs, seven pathways (Aromatic amine metabolism [P(GSEA)?=?0.0100, P(ARTP)?=?0.0020], NAD biosynthesis [P(GSEA)?=?0.0018, P(ARTP)?=?0.0086], NAD salvage [P(ARTP)?=?0.0068], Clathrin derived vesicle budding [P(ARTP)?=?0.0018], Lysosome vesicle biogenesis [P(GSEA)?=?0.0023, P(ARTP)<0.00012], Retrograde neurotrophin signaling [P(GSEA)?=?0.00840], and Mitotic metaphase/anaphase transition [P(GSEA)?=?0.0040]) remained. These pathways seem to belong to three fundamental cellular processes (metabolic detoxification, mitosis, and clathrin-mediated vesicles). Identification of the aromatic amine metabolism pathway provides support for the ability of this approach to identify pathways with established relevance to bladder carcinogenesis.
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What is Visualize?

JoVE Visualize is a tool created to match the last 5 years of PubMed publications to methods in JoVE's video library.

How does it work?

We use abstracts found on PubMed and match them to JoVE videos to create a list of 10 to 30 related methods videos.

Video X seems to be unrelated to Abstract Y...

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.