Imputation and subset-based association analysis across different cancer types identifies multiple independent risk loci in the TERT-CLPTM1L region on chromosome 5p15.33
Zhou Wang(Frederick National Laboratory for Cancer Research), Bin Zhu(Cancer Genetics (United States)), Mingjie Zhang(Cancer Genetics (United States)), Hemang Parikh(Cancer Genetics (United States)), Jinping Jia(Cancer Genetics (United States)), C. C. Chung(Frederick National Laboratory for Cancer Research), Joshua N. Sampson(Cancer Genetics (United States)), Jason W. Hoskins(Cancer Genetics (United States)), Amy Hutchinson(Frederick National Laboratory for Cancer Research), Laurie Burdette(Frederick National Laboratory for Cancer Research), Abdisamad Ibrahim(Cancer Genetics (United States)), Christopher Hautman(Frederick National Laboratory for Cancer Research), Preethi S. Raj(Cancer Genetics (United States)), Christian C. Abnet(Cancer Genetics (United States)), Andrew A. Adjei(University of Ghana), Anders Ahlbom, Demetrius Albanes(Cancer Genetics (United States)), N. E. Allen(University of Oxford), Christine B. Ambrosone(Roswell Park Comprehensive Cancer Center), Melinda C. Aldrich(Vanderbilt University), Pilar Amiano(Basque Government), Christopher I. Amos(Dartmouth College), Ulrika Andersson‐Hall, Gerald L. Andriole(Washington University in St. Louis), Irene L. Andrulis(Mount Sinai Hospital), Cecilia Arici(University of Brescia), Alan A. Arslan(New York University), Melissa A. Austin(University of Washington), Dalsu Baris(Cancer Genetics (United States)), Don Barkauskas(Keck Graduate Institute), Bryan A. Bassig(Yale Cancer Center), Laura E. Beane Freeman(Cancer Genetics (United States)), Christine D. Berg, S. I. Berndt(Cancer Genetics (United States)), Pier Alberto Bertazzi(University of Milan), Richard Biritwum(University of Ghana), Amanda Black(Cancer Genetics (United States)), William J. Blot(Vanderbilt University), Heiner Boeing(German Institute of Human Nutrition), Paolo Boffetta(Mount Sinai Hospital), Kelly L. Bolton(University of Cambridge), Marie‐Christine Boutron‐Ruault(Inserm), Paige M. Bracci(University of California, San Francisco), Paul Brennan(Centre international de recherche sur le cancer), Louise A. Brinton(Cancer Genetics (United States)), Michelle Brotzman(Westat (United States)), H. Bas Bueno‐de‐Mesquita(University Medical Center Utrecht), Julie E. Buring(Brigham and Women's Hospital), M. A. Butler(Centers for Disease Control and Prevention), Qingping Cai(Vanderbilt University), Géraldine Cancel‐Tassin(Délégation Paris 7), Federico Canzian(German Cancer Research Center), Guangwen Cao(Second Military Medical University), Neil E. Caporaso(Cancer Genetics (United States)), Alfredo Carrato(Hospital Universitario Ramón y Cajal), Tania Carreón(Centers for Disease Control and Prevention), Angela Carta(Mount Sinai Hospital), G.-C. Chang(National Yang Ming Chiao Tung University), I. Chang(Institute of Cancer Research), Jenny Chang‐Claude(German Cancer Research Center), Xu Che, Chiou‐Jong Chen(National Taiwan University), C.-Y. Chen(China Medical University), Chieh‐Hung Chen(China Medical University), C. Chen(China Medical University), K.-Y. Chen(National Taiwan University Hospital), Yaow-Ming Chen(Taipei Medical University Hospital), Anand P. Chokkalingam(University of California, Berkeley), L.W. Chu(Cancer Prevention Institute of California), Françoise Clavel‐Chapelon(Inserm), Graham A. Colditz(Washington University in St. Louis), Joanne S. Colt(Cancer Genetics (United States)), David V. Conti(Keck Graduate Institute), Michael B. Cook(Cancer Genetics (United States)), Victoria K. Cortessis(Keck Graduate Institute), E. David Crawford(University of Colorado Cancer Center), Olivier Cussenot(Sorbonne Université), Faith G. Davis(University of Alberta), Immaculata De Vivo(Brigham and Women's Hospital), X. Deng(Frederick National Laboratory for Cancer Research), Ti Ding(Shanxi Provincial Cancer Hospital), Colin P. Dinney, Anna Luisa Di Stefano(Inserm), W. Ryan Diver(American Cancer Society), Eric J. Duell(Institut d'Investigació Biomédica de Bellvitge), J Elena(National Cancer Institute), Jin‐Hu Fan(Shanghai Cancer Institute), Heather Spencer Feigelson(Kaiser Permanente), Maria Feychting, Jonine D. Figueroa(Cancer Genetics (United States)), Adrienne M. Flanagan(Royal National Orthopaedic Hospital), Joseph F. Fraumeni(Cancer Genetics (United States)), Neal D. Freedman(Cancer Genetics (United States)), Brooke L. Fridley(University of Kansas Medical Center), Charles S. Fuchs(Dana-Farber Cancer Institute), Manuela Gago-Domínguez(Complejo Hospitalario Universitario de Santiago), Steven Gallinger(Lunenfeld-Tanenbaum Research Institute), Yu‐Tang Gao(Renji Hospital), Susan M. Gapstur(American Cancer Society), Montserrat García‐Closas(Institute of Cancer Research), Reina García‐Closas(Hospital Universitario de Canarias), Julie M. Gastier‐Foster(Nationwide Children's Hospital), J. Michael Gaziano(Brigham and Women's Hospital), Daniela S. Gerhard(National Institutes of Health), Carol Giffen(Information Management Services), Graham G. Giles(The University of Melbourne), Elizabeth M. Gillanders, Edward L. Giovannucci(Institute of Molecular Genetics), Michael Goggins(Johns Hopkins University), Nalan Gökgöz(Mount Sinai Hospital), Alisa M. Goldstein(Cancer Genetics (United States)), Carlos A. González(Institut Català d'Oncologia), Richard Görlick(Albert Einstein College of Medicine), Mark H. Greene(Cancer Genetics (United States)), M. Gross(University of Minnesota), H. Barton Grossman, Robert L. Grubb(Washington University in St. Louis), Jian Gu, Peng Guan(China Medical University), Christopher A. Haiman(University of Southern California), G. Hallmans, Susan E. Hankinson, Curtis C. Harris(National Cancer Institute), Patricia Hartge(Cancer Genetics (United States)), Claudia Maria Hattinger(Istituto Ortopedico Rizzoli), Richard B. Hayes(NYU Langone Health), Qiang He(China Medical University), Lee J. Helman(Center for Cancer Research), Brian E. Henderson(University of Southern California), Roger Henriksson, Judith Hoffman–Bolton(Johns Hopkins University), Chancellor Hohensee(Fred Hutch Cancer Center), Elizabeth A. Holly(University of California, San Francisco), Yun‐Chul Hong(Seoul National University), Robert N. Hoover(Cancer Genetics (United States)), H. Dean Hosgood(Albert Einstein College of Medicine), Chin‐Fu Hsiao(National Health Research Institutes), Ann W. Hsing(Cancer Prevention Institute of California), Chao A. Hsiung, Nan Hu(Cancer Genetics (United States)), Wei Hu(Cancer Genetics (United States)), Zhigang Hu(Nanjing Medical University), Ming‐Shyan Huang(National Taiwan University Hospital), David J. Hunter(Broad Institute), Peter D. Inskip(Cancer Genetics (United States)), Hiromu Ito(Aichi Cancer Center), Eric J. Jacobs(American Cancer Society), Kevin B. Jacobs(Frederick National Laboratory for Cancer Research), Mazda Jenab(Centre international de recherche sur le cancer), B.-T. Ji(Cancer Genetics (United States)), Christoffer Johansen(Rigshospitalet), Mattias Johansson(Centre international de recherche sur le cancer), Alison Johnson(Vermont Cancer Support Network), R. Kaaks(German Cancer Research Center), Ashish M. Kamat, Aruna Kamineni(Kaiser Permanente Washington Health Research Institute), Margaret R. Karagas(Dartmouth College), C. Khanna(Center for Cancer Research), Kay‐Tee Khaw(University of Cambridge), C. Kim(Cancer Genetics (United States)), In-Sung Kim(Kyungpook National University), Jin Hee Kim(Seoul National University), Yeul Hong Kim(Seoul National University), Y.-C. Kim(Seoul National University), Young Tae Kim(Seoul National University), Chang Hyun Kang(Seoul National University), Yoo Jin Jung(Seoul National University), Cari M. Kitahara(Cancer Genetics (United States)), Alison P. Klein(Johns Hopkins University), Robert J. Klein, Manolis Kogevinas(Center for Research in Environmental Epidemiology), Woon‐Puay Koh(National University of Singapore), Takashi Kohno, Laurence N. Kolonel(University of Hawaiʻi at Mānoa), Charles Kooperberg(Fred Hutch Cancer Center), Christian P. Kratz(Cancer Genetics (United States)), Vittorio Krogh(Fondazione IRCCS Istituto Nazionale dei Tumori), Hideo Kunitoh(Mitsui Memorial Hospital), Robert C. Kurtz, Nilgün Kurucu(Ministry of Health), Qing Lan(Cancer Genetics (United States)), Mark Lathrop(Commissariat à l'Énergie Atomique et aux Énergies Alternatives), Ching C. Lau(Children's Cancer Center), Fernando Lecanda(Clinica Universidad de Navarra), Kyung‐Mi Lee(Korea National Open University), M. P. Lee(Center for Cancer Research), Loı̈c Le Marchand(University of Hawaiʻi at Mānoa), Seth P. Lerner, D. Li, Linda M. Liao(Cancer Genetics (United States)), Wei Yen Lim(National University of Singapore), Dongxin Lin(Chinese Academy of Medical Sciences & Peking Union Medical College), Jung‐Yaw Lin, Sara Lindström, Martha S. Linet(Cancer Genetics (United States)), Jolanta Lissowska(The Maria Sklodowska-Curie National Research Institute of Oncology), Jianjun Liu(Anhui Medical University), Börje Ljungberg, Josep Lloreta(Centro de Investigación Biomédica en Red de Epidemiología y Salud Pública), Daru Lu(Fudan University), Jiahe Ma(Brigham and Women's Hospital), Núria Malats(Spanish National Cancer Research Centre), Satu Männistö(Finnish Institute for Health and Welfare), Neyssa Marina(Lucile Packard Children's Hospital), Giuseppe Mastrangelo(University of Padua), Keitaro Matsuo(Kyushu University), Katherine A. McGlynn(Cancer Genetics (United States)), Roberta McKean‐Cowdin, Lorna H. McNeill, Robert R. McWilliams(Mayo Clinic in Florida), Beatrice S. Melin, Paul S. Meltzer(Center for Cancer Research), James E. Mensah(University of Ghana), Xiaoping Miao(Huazhong University of Science and Technology), Dominique S. Michaud(Brown University), Alison M. Mondul(Cancer Genetics (United States)), Lee E. Moore(Cancer Genetics (United States)), Kenneth Muir(University of Warwick), Shelley Niwa(Westat (United States)), Sara H. Olson(Memorial Sloan Kettering Cancer Center), Nick Orr, Salvatore Panico(Federico II University Hospital), J. Y. Park(Kyungpook National University), Alpa V. Patel(American Cancer Society), A. Patino-Garcia(Clinica Universidad de Navarra), Sofia Pavanello(University of Padua), P. H. M. Peeters(University Medical Center Utrecht), Beata Pepłońska(Nofer Institute of Occupational Medicine), Ulrike Peters(Fred Hutch Cancer Center), Gloria M. Petersen(Mayo Clinic in Florida), Piero Picci(Istituto Ortopedico Rizzoli), Malcolm C. Pike(University of Southern California), Stefano Porru(University of Brescia), Jennifer Prescott(Brigham and Women's Hospital), Pu Xia, Mark P. Purdue(Cancer Genetics (United States)), You‐Lin Qiao(Chinese Academy of Medical Sciences & Peking Union Medical College), Preetha Rajaraman(Cancer Genetics (United States)), Elio Ríboli(Imperial College London), H. A. Risch(Yale University), Rebecca J. Rodabough(Fred Hutch Cancer Center), Nathanial Rothman(Cancer Genetics (United States)), Avima M. Ruder(Centers for Disease Control and Prevention), Jeong‐Seon Ryu(Inha University), Marc Sanson(Inserm), Alan R. Schned(Dartmouth College), Fredrick R. Schumacher(University of Southern California), Ann G. Schwartz(The Barbara Ann Karmanos Cancer Institute), Kendra Schwartz(Wayne State University), Molly Schwenn, Katia Scotlandi(Istituto Ortopedico Rizzoli), Adeline Seow(National University of Singapore), Cònsol Serra(Universitat Pompeu Fabra), Massimo Serra(Istituto Ortopedico Rizzoli), Howard D. Sesso(Brigham and Women's Hospital), Gianluca Severi(The University of Melbourne), Hongbing Shen(Nanjing Medical University), Minxue Shen(Cancer Genetics (United States)), Sanjay Shete(The University of Texas MD Anderson Cancer Center), Kouya Shiraishi, Xiao‐Ou Shu(Vanderbilt University), Afshan Siddiq(Genomics (United Kingdom)), Luis Sierrasesúmaga(Clinica Universidad de Navarra), Sabina Sierri(Fondazione IRCCS Istituto Nazionale dei Tumori), Alan Sihoe(Queen Mary Hospital), Debra T. Silverman(Cancer Genetics (United States)), Matthias Simon(University of Bonn), Melissa C. Southey(The University of Melbourne), Logan G. Spector(University of Minnesota), M R Spitz(Baylor College of Medicine), M.J. Stampfer(Brigham and Women's Hospital), P Stattin, Mariana C. Stern(University of Southern California), Victoria L. Stevens(American Cancer Society), Rachael Z. Stolzenberg‐Solomon(Cancer Genetics (United States)), Daniel O. Stram(University of Southern California), Sara S. Strom(The University of Texas MD Anderson Cancer Center), Wu‐Chou Su(National Cheng Kung University Hospital), Malin Sund(Umeå University), Sook Whan Sung(The Catholic University of Korea Seoul St. Mary's Hospital), Anthony J. Swerdlow(Institute of Cancer Research), Wen Tan(Chinese Academy of Medical Sciences & Peking Union Medical College), Hideo Tanaka(Aichi Cancer Center), Wei Tang(Cancer Genetics (United States)), Zheng-Zheng Tang(Shanxi Provincial Cancer Hospital), Adonina Tardón(Universidad de Oviedo), Beng Kang Tay(University of Ghana), Philip R. Taylor(Cancer Genetics (United States)), Yao Tettey(University of Ghana), David M. Thomas(The University of Melbourne), Roberto Tirabosco(Royal National Orthopaedic Hospital), Anne Tjønneland(Danish Cancer Society), Geoffrey S. Tobias(Cancer Genetics (United States)), Jorge R. Toro(Cancer Genetics (United States)), Ruth C. Travis(University of Oxford), Dimitrios Trichopoulos(Harvard University), Rebecca Troisi(Cancer Genetics (United States)), Ann Truelove(Westat (United States)), Ying Tsai(Chiayi Chang Gung Memorial Hospital), Margaret A. Tucker(Cancer Genetics (United States)), Rosario Tumino(University of Ragusa), David Van Den Berg(University of Southern California), Stephen K. Van Den Eeden(Kaiser Permanente), Roel Vermeulen(Utrecht University), Paolo Vineis(Italian institute for Genomic Medicine), Kala Visvanathan(Johns Hopkins University), Ulla Vogel(National Research Centre for the Working Environment), Carol A. Wang(Cancer Genetics (United States)), Carol A. Wang(Cancer Genetics (United States)), Junwen Wang(Frederick National Laboratory for Cancer Research), Sophia Wang(City of Hope), Elisabete Weiderpass(Cancer Registry of Norway), Stephanie J. Weinstein(Cancer Genetics (United States)), Nicolas Wentzensen(Cancer Genetics (United States)), William Wheeler(Information Management Services), Emily White(Fred Hutch Cancer Center), John K. Wiencke(University of California, San Francisco), Alicja Wolk(Karolinska Institutet), Brian M. Wolpin(Dana-Farber Cancer Institute), Maria Pik Wong, Margaret Wrensch(University of California, San Francisco), Chen Wu(Chinese Academy of Medical Sciences & Peking Union Medical College), Tao Wu(University of Padua), Xifeng Wu, Yi‐Long Wu(Guangdong General Hospital), Jay S. Wunder(Washington University in St. Louis), Yong‐Bing Xiang(Renji Hospital), Jianfeng Xu(University of Hong Kong), Hannah Yang(Cancer Genetics (United States)), Pan‐Chyr Yang(National Taiwan University Hospital), Yasushi Yatabe(Aichi Cancer Center), Y. Ye, Edward D. Yeboah(University of Ghana), Zhihua Yin(China Medical University), C. Ying(National University of Singapore), Chong‐Jen Yu(National Cheng Kung University Hospital), Kai Yu(Cancer Genetics (United States)), Jian‐Min Yuan(UPMC Hillman Cancer Center), Krista A. Zanetti(National Cancer Institute), Anne Zeleniuch‐Jacquotte(New York University), Wei Zheng(Vanderbilt University), Baosen Zhou(China Medical University), L. Mirabello(Cancer Genetics (United States)), Sharon A. Savage(Cancer Genetics (United States)), Peter Kraft(Harvard University), Stephen J. Chanock(Frederick National Laboratory for Cancer Research), Meredith Yeager(Frederick National Laboratory for Cancer Research), Maria Teresa Landi(Cancer Genetics (United States)), Jianxin Shi(Cancer Genetics (United States)), Nilanjan Chatterjee(Cancer Genetics (United States)), Laufey T. Ámundadóttir(Cancer Genetics (United States))
Cited by 107Open Access
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 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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