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 AldrichPilar Amiano, Christopher Amos, Ulrika Andersson, G. A. 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, Geraldine 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 Gonzalez, Richard Gorlick, Mark H. Greene, Myron Gross, H. Barton Grossman, Robert Grubb, Jian Gu, Peng Guan, Christopher A. Haiman, Goran 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. McNeil, 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 Patino-Garcia, 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 Sierrasesumaga, Sabina Sierri, Alan Dart Loon Sihoe, Debra T. Silverman, Matthias Simon, Melissa C. Southey, Logan Spector, Margaret Spitz, Meir Stampfer, Par 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 Tardon, 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

Research output: Contribution to journalArticle

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 = 2.10×10-39; 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 CLPTM1Lgene(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.

Original languageEnglish
Pages (from-to)6616-6633
Number of pages18
JournalHuman Molecular Genetics
Volume23
Issue number24
DOIs
Publication statusPublished - Nov 15 2014

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ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)
  • Molecular Biology

Cite this

Wang, Z., Zhu, B., Zhang, M., Parikh, H., Jia, J., Chung, C. C., Sampson, J. N., Hoskins, J. W., Hutchinson, A., Burdette, L., Ibrahim, A., Hautman, C., Raj, P. S., Abnet, C. C., Adjei, A. A., Ahlbom, A., Albanes, D., Allen, N. E., Ambrosone, C. B., ... Amundadottir, L. T. (2014). Imputation and subset-based association analysis across different cancer types identifies multiple independent risk loci in the TERT-CLPTM1L region on chromosome 5p15.33. Human Molecular Genetics, 23(24), 6616-6633. https://doi.org/10.1093/hmg/ddu363