Hum Mol Genet. 2014 Jul 15. pii: ddu363. [Epub ahead of print]
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 Z1, Zhu B2, Zhang M2, Parikh H2, Jia J2, Chung CC1, Sampson JN2, Hoskins JW2, Hutchinson A1, Burdette L1, Ibrahim A2, Hautman C1, Raj PS2, Abnet CC2, Adjei AA3, Ahlbom A4, Albanes D2, Allen NE5, Ambrosone CB6, Aldrich M7, Amiano P8, Amos C9, Andersson U10, Andriole G Jr11, Andrulis IL12, Arici C13,Arslan AA14, Austin MA15, Baris D2, Barkauskas DA16, Bassig BA17, Beane Freeman LE2, Berg CD18, Berndt SI2, Bertazzi PA19, Biritwum RB3, Black A2, Blot W20, Boeing H21, Boffetta P22, Bolton K23, Boutron-Ruault MC24, Bracci PM25, Brennan P26, Brinton LA2, Brotzman M27, Bueno-de-Mesquita HB28, Buring JE29, Butler MA30, Cai Q7, Cancel-Tassin G31, Canzian F32, Cao G33, Caporaso NE2, Carrato A34, Carreon T30, Carta A12, Chang GC35, Chang IS36, Chang-Claude J32, Che X37, Chen CJ38, Chen CY39, Chen CH36, Chen C40, Chen KY41, Chen YM42, Chokkalingam AP43, Chu LW44, Clavel-Chapelon F45, Colditz GA46, Colt JS2, Conti D16, Cook MB2, Cortessis VK16, Crawford ED47, Cussenot O48, Davis FG49, De Vivo I50, Deng X1, Ding T51, Dinney CP52, Di Stefano AL53, Diver WR54, Duell EJ55, Elena JW56, Fan JH57, Feigelson HS58, Feychting M4, Figueroa JD2, Flanagan AM59, Fraumeni JF Jr2, Freedman ND2, Fridley BL60, Fuchs CS61, Gago-Dominguez M62, Gallinger S63, Gao YT64, Gapstur SM54, Garcia-Closas M65, Garcia-Closas R66, Gastier-Foster JM67, Gaziano JM68, Gerhard DS69, Giffen CA70, Giles GG71, Gillanders EM72, Giovannucci EL73, Goggins M74, Gokgoz N75, Goldstein AM2, Gonzalez C76, Gorlick R77,Greene MH2, Gross M78, Grossman HB52, Grubb R 3rd79, Gu J80, Guan P81, Haiman CA82, Hallmans G83, Hankinson SE84, Harris CC85, Hartge P2,Hattinger C86, Hayes RB87, He Q81, Helman L88, Henderson BE82, Henriksson R10, Hoffman-Bolton J89, Hohensee C90, Holly EA25, Hong YC91, Hoover RN2, Hosgood HD 3rd92, Hsiao CF93, Hsing AW94, Hsiung CA95, Hu N2, Hu W2, Hu Z96, Huang MS97, Hunter DJ98, Inskip PD2, Ito H99, Jacobs EJ54, Jacobs KB100, Jenab M26, Ji BT2, Johansen C101, Johansson M102, Johnson A103, Kaaks R32, Kamat AM52, Kamineni A104, Karagas M9, Khanna C88, Khaw KT105,Kim C2, Kim IS106, Kim YH107, Kim YC108, Kim YT109, Kang CH109, Jung YJ109, Kitahara CM2, Klein AP110, Klein R111, Kogevinas M112, Koh WP113, Kohno T114, Kolonel LN115, Kooperberg C90, Kratz CP116, Krogh V117, Kunitoh H118, Kurtz RC111, Kurucu N119, Lan Q2, Lathrop M120, Lau CC121, Lecanda F122,Lee KM123, Lee MP88, Le Marchand L115, Lerner SP124, Li D125, Liao LM2, Lim WY126, Lin D127, Lin J80, Lindstrom S40, Linet MS2, Lissowska J128, Liu J129,Ljungberg B130, Lloreta J131, Lu D132, Ma J133, Malats N134, Mannisto S135, Marina N136, Mastrangelo G137, Matsuo K138, McGlynn KA2, McKean-Cowdin R80,McNeill LH139, McWilliams RR140, Melin BS10, Meltzer PS88, Mensah JE3, Miao X141, Michaud DS142, Mondul AM2, Moore LE2, Muir K143, Niwa S27, Olson SH144, Orr N145, Panico S146, Park JY147, Patel AV54, Patino-Garcia A122, Pavanello S137, Peeters PH148, Peplonska B149, Peters U90, Petersen GM140, Picci P86, Pike MC150, Porru S13, Prescott J50, Pu X80, Purdue MP2, Qiao YL151, Rajaraman P2, Riboli E152, Risch HA153, Rodabough RJ90, Rothman N2, Ruder AM30, Ryu JS154, Sanson M53, Schned A9, Schumacher FR82, Schwartz AG155, Schwartz KL156, Schwenn M157, Scotlandi K86, Seow A126, Serra C158, Serra M86, Sesso HD29, Severi G71, Shen H96, Shen M2, Shete S159, Shiraishi K114, Shu XO7, Siddiq A160, Sierrasesumaga L122, Sierri S161, Sihoe AD162,Silverman DT2, Simon M163, Southey MC164, Spector L165, Spitz M166, Stampfer M133, Stattin P130, Stern MC82, Stevens VL54, Stolzenberg-Solomon RZ2,Stram DO82, Strom SS167, Su WC168, Sund M169, Sung SW170, Swerdlow A171, Tan W127, Tanaka H99, Tang W2, Tang ZZ51, Tardon A172, Tay E3, Taylor PR2,Tettey Y3, Thomas DM173, Tirabosco R174, Tjonneland A175, Tobias GS2, Toro JR2, Travis RC5, Trichopoulos D176, Troisi R2, Truelove A27, Tsai YH177,Tucker MA2, Tumino R178, Van Den Berg D82, Van Den Eeden SK179, Vermeulen R180, Vineis P181, Visvanathan K89, Vogel U182, Wang C2, Wang C37, Wang J183, Wang SS184, Weiderpass E185, Weinstein SJ2, Wentzensen N2, Wheeler W70, White E90, Wiencke JK186, Wolk A187, Wolpin BM61, Wong MP188,Wrensch M186, Wu C127, Wu T141, Wu X80, Wu YL189, Wunder JS11, Xiang YB64, Xu J190, Yang HP2, Yang PC97, Yatabe Y191, Ye Y80, Yeboah ED3, Yin Z81,Ying C126, Yu CJ168, Yu K2, Yuan JM192, Zanetti KA56, Zeleniuch-Jacquotte A193, Zheng W7, Zhou B81, Mirabello L2, Savage SA2, Kraft P194, Chanock SJ1,Yeager M1, Landi MT2, Shi J2, Chatterjee N2, Amundadottir LT195.
Genome-wide association studies (GWAS) have mapped risk alleles for at least ten 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 (ASSET) 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 (SNPs): five in the TERT gene (region 1: rs7726159, P=2.10x10-39; region 3: rs2853677, P=3.30x10-36 and PConditional=2.36x10-8; region 4: rs2736098, P=3.87x10-12 and PConditional=5.19x10-6, region 5: rs13172201, P=0.041 and PConditional=2.04x10-6; and region 6: rs10069690, P=7.49x10-15 and PConditional=5.35x10-7) and one in the neighboring CLPTM1L gene (region 2: rs451360; P=1.90x10-18 and PConditional=7.06x10-16). 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.
Published by Oxford University Press 2014. This work is written by (a) US Government employee(s) and is in the public domain in the US.
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