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 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., Beane Freeman LE., Berg CD., Berndt SI., Bertazzi PA., Biritwum RB., Black A., Blot W., Boeing H., Boffetta P., Bolton K., Boutron-Ruault M-C., Bracci PM., Brennan P., Brinton LA., Brotzman M., Bueno-de-Mesquita HB., Buring JE., Butler MA., 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., Crawford ED., Cussenot O., Davis FG., De Vivo I., Deng X., Ding T., Dinney CP., Di Stefano AL., Diver WR., Duell EJ., Elena JW., Fan J-H., Feigelson HS., Feychting M., Figueroa JD., Flanagan AM., Fraumeni JF., Freedman ND., Fridley BL., Fuchs CS., Gago-Dominguez M., Gallinger S., Gao Y-T., Gapstur SM., Garcia-Closas M., Garcia-Closas R., Gastier-Foster JM., Gaziano JM., Gerhard DS., Giffen CA., Giles GG., Gillanders EM., Giovannucci EL., Goggins M., Gokgoz N., Goldstein AM., Gonzalez C., Gorlick R., Greene MH., Gross M., Grossman HB., 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., Hosgood HD., Hsiao C-F., Hsing AW., Hsiung CA., 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 JH., Kim YH., Kim Y-C., Kim YT., Kang CH., Jung YJ., 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., Lindstrom S., Linet MS., Lissowska J., Liu J., Ljungberg B., Lloreta J., Lu D., Ma J., Malats N., Mannisto 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 JY., 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., Loon Sihoe AD., 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 SW., 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 MP., 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 MT., Shi J., Chatterjee N., Amundadottir LT.
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.