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 x 10-39; Region 3: rs2853677, P = 3.30 x 10-36 and PConditional = 2.36 x 10-8; Region 4: rs2736098, P = 3.87 x 10-12 and PConditional = 5.19 x 10-6, Region 5: rs13172201, P = 0.041 and PConditional = 2.04 x 10-6; and Region 6: rs10069690, P = 7.49 x 10-15 and PConditional = 5.35 x 10-7) and one in the neighboring CLPTM1L gene (Region 2: rs451360; P = 1.90 x 10-18 and PConditional = 7.06 x 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. ; Wang, Zhaoming Zhu, Bin Zhang, Mingfeng Parikh, Hemang Jia, Jinping Chung, Charles C Sampson, Joshua N Hoskins, Jason W Hutchinson, Amy Burdette, Laurie Ibrahim, Abdisamad Hautman, Christopher Raj, Preethi S Abnet, Christian C Adjei, Andrew A Ahlbom, Anders Albanes, Demetrius Allen, Naomi E Ambrosone, Christine B Aldrich, Melinda Amiano, Pilar Amos, Christopher Andersson, Ulrika Andriole, Gerald Jr Andrulis, Irene L Arici, Cecilia Arslan, Alan A Austin, Melissa A Baris, Dalsu Barkauskas, Donald A Bassig, Bryan A Beane Freeman, Laura E Berg, Christine D Berndt, Sonja I Bertazzi, Pier Alberto Biritwum, Richard B Black, Amanda Blot, William Boeing, Heiner Boffetta, Paolo Bolton, Kelly Boutron-Ruault, Marie-Christine Bracci, Paige M Brennan, Paul Brinton, Louise A Brotzman, Michelle Bueno-de-Mesquita, H Bas Buring, Julie E 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Stefano Prescott, Jennifer Pu, Xia Purdue, Mark P Qiao, You-Lin Rajaraman, Preetha Riboli, Elio Risch, Harvey A Rodabough, Rebecca J Rothman, Nathaniel Ruder, Avima M Ryu, Jeong-Seon Sanson, Marc Schned, Alan Schumacher, Fredrick R Schwartz, Ann G Schwartz, Kendra L Schwenn, Molly Scotlandi, Katia Seow, Adeline Serra, Consol Serra, Massimo Sesso, Howard D Severi, Gianluca Shen, Hongbing Shen, Min Shete, Sanjay Shiraishi, Kouya Shu, Xiao-Ou Siddiq, Afshan Sierrasesumaga, Luis Sierri, Sabina Loon Sihoe, Alan Dart Silverman, Debra T Simon, Matthias Southey, Melissa C Spector, Logan Spitz, Margaret Stampfer, Meir Stattin, Par Stern, Mariana C Stevens, Victoria L Stolzenberg-Solomon, Rachael Z Stram, Daniel O Strom, Sara S Su, Wu-Chou Sund, Malin Sung, Sook Whan Swerdlow, Anthony Tan, Wen Tanaka, Hideo Tang, Wei Tang, Ze-Zhang Tardon, Adonina Tay, Evelyn Taylor, Philip R Tettey, Yao Thomas, David M Tirabosco, Roberto Tjonneland, Anne Tobias, Geoffrey S Toro, Jorge R Travis, Ruth C 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NIH HHS/United States Human molecular genetics Hum Mol Genet. 2014 Jul 15. pii: ddu363.