Imputation and subset-based association analysis across different cancer types identifies multiple independent risk loci in the TERT-CLPTM1L region on chromosome 5p15.33.
نویسندگان
- 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
چکیده
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.
منابع مشابه
Role of 5p15.33 (TERT-CLPTM1L), 6p21.33 and 15q25.1 (CHRNA5-CHRNA3) variation and lung cancer risk in never-smokers.
Genome-wide association studies have provided evidence that common variation at 5p15.33 (TERT-CLPTM1L), 6p21.33 and 15q25.1 (CHRNA5-CHRNA3) influences lung cancer risk. To examine if variation at any of these loci influences the risk of lung cancer in never-smokers, we compared 5p15.33-TERT (rs2736100), 5p15.33-CLPTM1L (rs4975616), 6p21.33-BAT3 (rs3117582), 15q25.1-CHRNA3 (rs8042374) and 15q25....
متن کاملThe identification of two regulatory ESCC susceptibility genetic variants in the TERT-CLPTM1L loci
The chromosome 5p15.33 TERT-CLPTM1L region has been identified by genome-wide association studies as a susceptibility locus of multiple malignancies. However, the involvement of this locus in esophageal squamous cell carcinoma (ESCC) development is still largely unclear. We fine-mapped the TERT-CLPTM1L region through genotyping 15 haplotype-tagging single nucleotide polymorphisms (htSNPs) using...
متن کاملCharacterization of population-based variation and putative functional elements for the multiple-cancer susceptibility loci at 5p15.33 [version 1; referees: 2 approved]
Background: encodes the telomerase reverse transcriptase, which is responsible for TERT maintaining telomere ends by addition of (TTAGGG) nucleotide repeats at the telomere. Recent genome-wide association studies have found common genetic variants at the locus (5p15.33) associated with an TERT-CLPTM1L increased risk of several cancers. Results: Data were acquired for 1627 variants in 1092 unrel...
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Chromosome 5p15.33 has been identified by genome-wide association studies as one of the regions that associate with lung cancer risk. A few single-nucleotide polymorphisms (SNPs) in the telomerase reverse transcriptase (TERT) and cleft lip and palate transmembrane 1-like (CLPTM1L) genes located in this region have shown consistent associations. We performed dense genotyping of SNPs in this regi...
متن کاملCharacterization of population-based variation and putative functional elements for the multiple-cancer susceptibility loci at 5p15.33
BACKGROUND TERT encodes the telomerase reverse transcriptase, which is responsible for maintaining telomere ends by addition of (TTAGGG) n nucleotide repeats at the telomere. Recent genome-wide association studies have found common genetic variants at the TERT-CLPTM1L locus (5p15.33) associated with an increased risk of several cancers. RESULTS Data were acquired for 1627 variants in 1092 u...
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ورودعنوان ژورنال:
- Human molecular genetics
دوره 23 24 شماره
صفحات -
تاریخ انتشار 2014