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4. Imputation and subset-based association analysis across different cancer types identifies multiple independent risk loci in the TERT-CLPTM1L region on chromosome 5p15.33

Author

Wang, Zhaoming Zhu, Bin Zhang, Mingfeng Parikh, Hemang and Jia, Jinping Chung, Charles C. Sampson, Joshua N. Hoskins, Jason W. Hutchinson, Amy Burdette, Laurie Ibrahim, Abdisamad and Hautman, Christopher Raj, Preethi S. Abnet, Christian C. and Adjei, Andrew A. Ahlbom, Anders Albanes, Demetrius Allen, Naomi E. Ambrosone, Christine B. Aldrich, Melinda Amiano, Pilar Amos, Christopher Andersson, Ulrika Andriole, Jr., Gerald Andrulis, Irene L. Arici, Cecilia Arslan, Alan A. and Austin, Melissa A. Baris, Dalsu Barkauskas, Donald A. and Bassig, Bryan A. Freeman, Laura E. Beane Berg, Christine D. and Berndt, Sonja I. Bertazzi, Pier Alberto Biritwum, Richard B. and Black, Amanda Blot, William Boeing, Heiner Boffetta, Paolo and Bolton, Kelly Boutron-Ruault, Marie-Christine Bracci, Paige M. Brennan, Paul Brinton, Louise A. Brotzman, Michelle and Bueno-de-Mesquita, H. Bas Buring, Julie E. Butler, Mary Ann and Cai, Qiuyin Cancel-Tassin, Geraldine Canzian, Federico Cao, Guangwen Caporaso, Neil E. Carrato, Alfredo Carreon, Tania and Carta, Angela Chang, Gee-Chen Chang, I-Shou and Chang-Claude, Jenny Che, Xu Chen, Chien-Jen Chen, Chih-Yi and Chen, Chung-Hsing Chen, Constance Chen, Kuan-Yu Chen, Yuh-Min Chokkalingam, Anand P. Chu, Lisa W. Clavel-Chapelon, Francoise Colditz, Graham A. Colt, Joanne S. Conti, David and Cook, Michael B. Cortessis, Victoria K. Crawford, E. David and Cussenot, Olivier Davis, Faith G. De Vivo, Immaculata and Deng, Xiang Ding, Ti Dinney, Colin P. Di Stefano, Anna Luisa and Diver, W. Ryan Duell, Eric J. Elena, Joanne W. Fan, Jin-Hu Feigelson, Heather Spencer Feychting, Maria Figueroa, Jonine D. Flanagan, Adrienne M. Fraumeni, Jr., Joseph F. and Freedman, Neal D. Fridley, Brooke L. Fuchs, Charles S. and Gago-Dominguez, Manuela Gallinger, Steven Gao, Yu-Tang and Gapstur, Susan M. Garcia-Closas, Montserrat Garcia-Closas, Reina and Gastier-Foster, Julie M. Gaziano, J. Michael Gerhard, Daniela S. Giffen, Carol A. Giles, Graham G. Gillanders, Elizabeth M. Giovannucci, Edward L. Goggins, Michael Gokgoz, Nalan Goldstein, Alisa M. Gonzalez, Carlos Gorlick, Richard and Greene, Mark H. Gross, Myron Grossman, H. Barton Grubb, III, Robert Gu, Jian Guan, Peng Haiman, Christopher A. and Hallmans, Goran Hankinson, Susan E. Harris, Curtis C. and Hartge, Patricia Hattinger, Claudia Hayes, Richard B. He, Qincheng Helman, Lee Henderson, Brian E. Henriksson, Roger and Hoffman-Bolton, Judith Hohensee, Chancellor Holly, Elizabeth A. Hong, Yun-Chul Hoover, Robert N. Hosgood, H. Dean and Hsiao, Chin-Fu Hsing, Ann W. Hsiung, Chao Agnes Hu, Nan and Hu, Wei Hu, Zhibin Huang, Ming-Shyan Hunter, David J. and Inskip, Peter D. Ito, Hidemi Jacobs, Eric J. Jacobs, Kevin B. Jenab, Mazda Ji, Bu-Tian Johansen, Christoffer and Johansson, Mattias Johnson, Alison Kaaks, Rudolf Kamat, Ashish M. Kamineni, Aruna Karagas, Margaret Khanna, Chand and Khaw, Kay-Tee Kim, Christopher Kim, In-Sam Kim, Jin Hee and Kim, Yeul Hong Kim, Young-Chul Kim, Young Tae Kang, Chang Hyun Jung, Yoo Jin Kitahara, Cari M. Klein, Alison P. and Klein, Robert Kogevinas, Manolis Koh, Woon-Puay Kohno, Takashi Kolonel, Laurence N. Kooperberg, Charles Kratz, Christian P. Krogh, Vittorio Kunitoh, Hideo Kurtz, Robert C. and Kurucu, Nilgun Lan, Qing Lathrop, Mark Lau, Ching C. and Lecanda, Fernando Lee, Kyoung-Mu Lee, Maxwell P. Le Marchand, Loic Lerner, Seth P. Li, Donghui Liao, Linda M. and Lim, Wei-Yen Lin, Dongxin Lin, Jie Lindstrom, Sara and Linet, Martha S. Lissowska, Jolanta Liu, Jianjun Ljungberg, Boerje Lloreta, Josep Lu, Daru Ma, Jing Malats, Nuria and Mannisto, Satu Marina, Neyssa Mastrangelo, Giuseppe and Matsuo, Keitaro McGlynn, Katherine A. McKean-Cowdin, Roberta and McNeill, Lorna H. McWilliams, Robert R. Melin, Beatrice S. and Meltzer, Paul S. Mensah, James E. Miao, Xiaoping Michaud, Dominique S. Mondul, Alison M. Moore, Lee E. Muir, Kenneth and Niwa, Shelley Olson, Sara H. Orr, Nick Panico, Salvatore and Park, Jae Yong Patel, Alpa V. Patino-Garcia, Ana and Pavanello, Sofia Peeters, Petra H. M. Peplonska, Beata and Peters, Ulrike Petersen, Gloria M. Picci, Piero Pike, Malcolm C. Porru, Stefano Prescott, Jennifer Pu, Xia and Purdue, Mark P. Qiao, You-Lin Rajaraman, Preetha Riboli, Elio Risch, Harvey A. Rodabough, Rebecca J. Rothman, Nathaniel Ruder, Avima M. Ryu, Jeong-Seon Sanson, Marc and Schned, Alan Schumacher, Fredrick R. Schwartz, Ann G. and Schwartz, Kendra L. Schwenn, Molly Scotlandi, Katia Seow, Adeline Serra, Consol Serra, Massimo Sesso, Howard D. and Severi, Gianluca Shen, Hongbing Shen, Min Shete, Sanjay and Shiraishi, Kouya Shu, Xiao-Ou Siddiq, Afshan Sierrasesumaga, Luis Sierri, Sabina Sihoe, Alan Dart Loon Silverman, Debra T. Simon, Matthias Southey, Melissa C. Spector, Logan and Spitz, Margaret Stampfer, Meir Stattin, Par Stern, Mariana C. Stevens, Victoria L. Stolzenberg-Solomon, Rachael Z. and Stram, Daniel O. Strom, Sara S. Su, Wu-Chou Sund, Malin and Sung, Sook Whan Swerdlow, Anthony Tan, Wen Tanaka, Hideo and Tang, Wei Tang, Ze-Zhang Tardon, Adonina Tay, Evelyn and Taylor, Philip R. Tettey, Yao Thomas, David M. Tirabosco, Roberto Tjonneland, Anne Tobias, Geoffrey S. Toro, Jorge R. and Travis, Ruth C. Trichopoulos, Dimitrios Troisi, Rebecca and Truelove, Ann Tsai, Ying-Huang Tucker, Margaret A. Tumino, Rosario Van Den Berg, David Van Den Eeden, Stephen K. and Vermeulen, Roel Vineis, Paolo Visvanathan, Kala Vogel, Ulla and Wang, Chaoyu Wang, Chengfeng Wang, Junwen Wang, Sophia S. Weiderpass, Elisabete Weinstein, Stephanie J. Wentzensen, Nicolas Wheeler, William White, Emily Wiencke, John K. and Wolk, Alicja Wolpin, Brian M. Wong, Maria Pik Wrensch, Margaret Wu, Chen Wu, Tangchun Wu, Xifeng Wu, Yi-Long and Wunder, Jay S. Xiang, Yong-Bing Xu, Jun Yang, Hannah P. and Yang, Pan-Chyr Yatabe, Yasushi Ye, Yuanqing Yeboah, Edward D. Yin, Zhihua Ying, Chen Yu, Chong-Jen Yu, Kai and Yuan, Jian-Min Zanetti, Krista A. Zeleniuch-Jacquotte, Anne and Zheng, Wei Zhou, Baosen Mirabello, Lisa Savage, Sharon A. Kraft, Peter Chanock, Stephen J. Yeager, Meredith and Landi, Maria Terese Shi, Jianxin Chatterjee, Nilanjan and Amundadottir, Laufey T.

Abstract

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 x 10(-39); Region 3: rs2853677, P = 3.30 x 10(-36) and P-Conditional = 2.36 x 10(-8); Region 4: rs2736098, P = 3.87 x 10(-12) and P-Conditional = 5.19 x 10(-6), Region 5: rs13172201, P = 0.041 and P-Conditional = 2.04 x 10(-6); and Region 6: rs10069690, P = 7.49 x 10 215 and P-Conditional = 5.35 x 10(-7)) and one in the neighboring CLPTM1L gene(Region 2: rs451360; P = 1.90 x 10(-18) and P-Conditional = 7.06 x 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.

Published
2014

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