Dataset Information

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

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.

SUBMITTER: Wang Z

PROVIDER: S-EPMC4240198 | biostudies-literature | 2014 Dec

REPOSITORIES: biostudies-literature

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

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

Human molecular genetics 20140715 24

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 ...[more]

PMID: 25027329

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Project description:The objective of the present study was to analyze the relationship between genetic polymorphisms of the rs2736098 locus of the telomerase reverse transcriptase (TERT) gene and the rs401681 locus of the cleft lip and palate transmembrane protein 1 (CLPTM1L) gene and the risk of developing lung cancer in males in Jinzhou. A total of 214 lung cancer patients who were admitted in Jinzhou Medical University were analyzed, and 216 healthy males were selected as controls. Venous blood from all subjects and data on relevant risk factors were collected. DNA was extracted from peripheral blood by the phenol-chloroform method. Real-time fluorescent quantitative PCR (TaqMan real-time PCR) was used for DNA amplification. The genotyping results of the genetic polymorphisms of the TERT rs2736098 and CLPTM1L rs401681 loci were detected. The risk of developing lung cancer in the population with the TERT rs2736098 locus carrying the T allele was 1.614 times that with the TERT rs2736098 locus carrying the C allele after adjustment of the age factor. The risk of developing lung cancer in the population carrying the TT mutant genotype and the CT genotype increased significantly compared with that carrying the CC wild genotype [odds ratio (OR)=1.815, 95% CI=1.132-2.957; OR=2.417, 95% CI=1.158-4.943]. Based on a comparison between the combination of the two mutant genotypes (CT+TT) and the wild homozygous genotype (CC), the mutant genotype increased the risk of developing lung cancer (OR=1.955, 95% CI=1.213-3.157). The risk of developing lung cancer in the population with the CLPTM1L rs401681 locus carrying the T allele was 1.399 times that carrying the C allele (OR=1.343, 95% CI=1.035-1.978). The population with the TERT rs2736098 locus carrying the mutant genotype (CT+TT) was associated with the number of tumors (OR=0.553, 95% CI=0.236-0.928). In conclusion, in males, the TERT rs2736098 and CLPTM1L rs401681 T alleles are the susceptibility factors for developing lung cancer. Individuals, including the smoking population, who carry both the TERT rs2736098 and CLPTM1L rs401681 T alleles are more likely to develop lung cancer.

Dataset Information

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

Publications

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

Similar Datasets

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