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Hum Mol Genet DOI:10.1093/hmg/ddu363

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

Publication TypeJournal Article
Year of Publication2014
AuthorsWang, Z, Zhu, B, Zhang, M, Parikh, H, Jia, J, Chung, CC, Sampson, JN, Hoskins, JW, Hutchinson, A, Burdette, L, Ibrahim, A, Hautman, C, Raj, PS, Abnet, CC, Adjei, AA, Ahlbom, A, Albanes, D, Allen, NE, Ambrosone, CB, Aldrich, M, Amiano, P, Amos, C, Andersson, U, Andriole, G, Andrulis, IL, Arici, C, Arslan, AA, Austin, MA, Baris, D, Barkauskas, DA, Bassig, BA, Freeman, LEBeane, Berg, CD, Berndt, SI, Bertazzi, PAlberto, Biritwum, RB, Black, A, Blot, W, Boeing, H, Boffetta, P, Bolton, K, Boutron-Ruault, M-C, Bracci, PM, Brennan, P, Brinton, LA, Brotzman, M, H Bueno-de-Mesquita, B, Buring, JE, Butler, MAnn, Cai, Q, Cancel-Tassin, G, Canzian, F, Cao, G, Caporaso, NE, Carrato, A, Carreon, T, Carta, A, Chang, G-C, Chang, I-S, Chang-Claude, J, Che, X, Chen, C-J, Chen, C-Y, Chen, C-H, Chen, C, Chen, K-Y, Chen, Y-M, Chokkalingam, AP, Chu, LW, Clavel-Chapelon, F, Colditz, GA, Colt, JS, Conti, D, Cook, MB, Cortessis, VK, E Crawford, D, Cussenot, O, Davis, FG, De Vivo, I, Deng, X, Ding, T, Dinney, CP, Di Stefano, ALuisa, W Diver, R, Duell, EJ, Elena, JW, Fan, J-H, Feigelson, HSpencer, Feychting, M, Figueroa, JD, Flanagan, AM, Fraumeni, JF, Freedman, ND, Fridley, BL, Fuchs, CS, Gago-Dominguez, M, Gallinger, S, Gao, Y-T, Gapstur, SM, García-Closas, M, Garcia-Closas, R, Gastier-Foster, JM, J Gaziano, M, Gerhard, DS, Giffen, CA, Giles, GG, Gillanders, EM, Giovannucci, EL, Goggins, M, Gokgoz, N, Goldstein, AM, Gonzalez, C, Gorlick, R, Greene, MH, Gross, M, H Grossman, B, Grubb, R, Gu, J, Guan, P, Haiman, CA, Hallmans, G, Hankinson, SE, Harris, CC, Hartge, P, Hattinger, C, Hayes, RB, He, Q, Helman, L, Henderson, BE, Henriksson, R, Hoffman-Bolton, J, Hohensee, C, Holly, EA, Hong, Y-C, Hoover, RN, H Hosgood, D, Hsiao, C-F, Hsing, AW, Hsiung, CAgnes, Hu, N, Hu, W, Hu, Z, Huang, M-S, Hunter, DJ, Inskip, PD, Ito, H, Jacobs, EJ, Jacobs, KB, Jenab, M, Ji, B-T, Johansen, C, Johansson, M, Johnson, A, Kaaks, R, Kamat, AM, Kamineni, A, Karagas, M, Khanna, C, Khaw, K-T, Kim, C, Kim, I-S, Kim, JHee, Kim, YHong, Kim, Y-C, Kim, YTae, Kang, CHyun, Jung, YJin, Kitahara, CM, Klein, AP, Klein, R, Kogevinas, M, Koh, W-P, Kohno, T, Kolonel, LN, Kooperberg, C, Kratz, CP, Krogh, V, Kunitoh, H, Kurtz, RC, Kurucu, N, Lan, Q, Lathrop, M, Lau, CC, Lecanda, F, Lee, K-M, Lee, MP, Le Marchand, L, Lerner, SP, Li, D, Liao, LM, Lim, W-Y, Lin, D, Lin, J, Lindström, S, Linet, MS, Lissowska, J, Liu, J, Ljungberg, B, Lloreta, J, Lu, D, Ma, J, Malats, N, Männistö, S, Marina, N, Mastrangelo, G, Matsuo, K, McGlynn, KA, McKean-Cowdin, R, McNeill, LH, McWilliams, RR, Melin, BS, Meltzer, PS, Mensah, JE, Miao, X, Michaud, DS, Mondul, AM, Moore, LE, Muir, K, Niwa, S, Olson, SH, Orr, N, Panico, S, Park, JYong, Patel, AV, Patino-Garcia, A, Pavanello, S, Peeters, PHM, Peplonska, B, Peters, U, Petersen, GM, Picci, P, Pike, MC, Porru, S, Prescott, J, Pu, X, Purdue, MP, Qiao, Y-L, Rajaraman, P, Riboli, E, Risch, HA, Rodabough, RJ, Rothman, N, Ruder, AM, Ryu, J-S, Sanson, M, Schned, A, Schumacher, FR, Schwartz, AG, Schwartz, KL, Schwenn, M, Scotlandi, K, Seow, A, Serra, C, Serra, M, Sesso, HD, Severi, G, Shen, H, Shen, M, Shete, S, Shiraishi, K, Shu, X-O, Siddiq, A, Sierrasesumaga, L, Sierri, S, Sihoe, ADart Loon, Silverman, DT, Simon, M, Southey, MC, Spector, L, Spitz, M, Stampfer, M, Stattin, P, Stern, MC, Stevens, VL, Stolzenberg-Solomon, RZ, Stram, DO, Strom, SS, Su, W-C, Sund, M, Sung, SWhan, Swerdlow, A, Tan, W, Tanaka, H, Tang, W, Tang, Z-Z, Tardon, A, Tay, E, Taylor, PR, Tettey, Y, Thomas, DM, Tirabosco, R, Tjonneland, A, Tobias, GS, Toro, JR, Travis, RC, Trichopoulos, D, Troisi, R, Truelove, A, Tsai, Y-H, Tucker, MA, Tumino, R, Van Den Berg, D, Van Den Eeden, SK, Vermeulen, R, Vineis, P, Visvanathan, K, Vogel, U, Wang, C, Wang, C, Wang, J, Wang, SS, Weiderpass, E, Weinstein, SJ, Wentzensen, N, Wheeler, W, White, E, Wiencke, JK, Wolk, A, Wolpin, BM, Wong, MPik, Wrensch, M, Wu, C, Wu, T, Wu, X, Wu, Y-L, Wunder, JS, Xiang, Y-B, Xu, J, Yang, HP, Yang, P-C, Yatabe, Y, Ye, Y, Yeboah, ED, Yin, Z, Ying, C, Yu, C-J, Yu, K, Yuan, J-M, Zanetti, KA, Zeleniuch-Jacquotte, A, Zheng, W, Zhou, B, Mirabello, L, Savage, SA, Kraft, P, Chanock, SJ, Yeager, M, Landi, MTerese, Shi, J, Chatterjee, N, Amundadottir, LT
JournalHum Mol Genet
Volume23
Issue24
Pages6616-33
Date Published2014 Dec 15
ISSN1460-2083
KeywordsAlleles, Chromosomes, Human, Pair 5, Computational Biology, DNA Methylation, Epigenesis, Genetic, Female, Gene Expression Regulation, Neoplastic, Gene Frequency, Genetic Loci, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Male, Membrane Proteins, Neoplasm Proteins, Neoplasms, Odds Ratio, Polymorphism, Single Nucleotide, Risk, Telomerase
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.

URLhttp://hmg.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=25027329
DOI10.1093/hmg/ddu363
Pubmed

http://www.ncbi.nlm.nih.gov/pubmed/25027329?dopt=Abstract

Alternate JournalHum. Mol. Genet.
PubMed ID25027329
PubMed Central IDPMC4240198
Grant ListP50 CA091846 / CA / NCI NIH HHS / United States
P30 CA016672 / CA / NCI NIH HHS / United States
P30 CA015704 / CA / NCI NIH HHS / United States
P50 CA062924 / CA / NCI NIH HHS / United States
R01 CA092447 / CA / NCI NIH HHS / United States
G1000143 / / Medical Research Council / United Kingdom
UM1 CA173640 / CA / NCI NIH HHS / United States
K07 CA172294 / CA / NCI NIH HHS / United States
14136 / / Cancer Research UK / United Kingdom
P50 CA097257 / CA / NCI NIH HHS / United States
G0401527 / / Medical Research Council / United Kingdom
P30 CA015083 / CA / NCI NIH HHS / United States
R01 CA154823 / CA / NCI NIH HHS / United States
U10 CA180899 / CA / NCI NIH HHS / United States
UM1 CA182910 / CA / NCI NIH HHS / United States
HHSN261200800001E / CA / NCI NIH HHS / United States
R01 CA052689 / CA / NCI NIH HHS / United States
UM1 CA182876 / CA / NCI NIH HHS / United States