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

Authors:
Dr. Jonine Figueroa, PhD
Dr. Jonine Figueroa, PhD
Usher Institute of Population Health Sciences and Informatics
Chancellor's Fellow
Molecular epidemiology
Edinburgh, Scotland | United Kingdom
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 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 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 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

Hum Mol Genet 2014 Dec 15;23(24):6616-33. Epub 2014 Jul 15.

Division of Cancer Epidemiology and Genetics,

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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December 2014
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References

(Supplied by CrossRef)

Rothman et al.
Nature genetics 2010

Haiman et al.
Nature genetics 2011

Shete et al.
Nature genetics 2009

Wang et al.
Nature genetics 2008

McKay et al.
Nature genetics 2008

Cancer Research 2009

Landi et al.
American journal of human genetics 2009

Beesley et al.
2011

Rafnar et al.
Nature genetics 2009

Stacey et al.
Nature genetics 2009

Archives for dermatological research. Archiv f  r dermatologische Forschung 2013

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