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 CLPTM1Lgene(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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 6616-6633 |
| Number of pages | 18 |
| Journal | Human molecular genetics |
| Volume | 23 |
| Issue number | 24 |
| DOIs | |
| State | Published - Nov 15 2014 |
ASJC Scopus subject areas
- Molecular Biology
- Genetics
- Genetics(clinical)
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In: Human molecular genetics, Vol. 23, No. 24, 15.11.2014, p. 6616-6633.
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TY - JOUR
T1 - Imputation and subset-based association analysis across different cancer types identifies multiple independent risk loci in the TERT-CLPTM1L region on chromosome 5p15.33
AU - Wang, Zhaoming
AU - Zhu, Bin
AU - Zhang, Mingfeng
AU - Parikh, Hemang
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AU - Hoskins, Jason W.
AU - Hutchinson, Amy
AU - Burdette, Laurie
AU - Ibrahim, Abdisamad
AU - Hautman, Christopher
AU - Raj, Preethi S.
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AU - Adjei, Andrew A.
AU - Ahlbom, Anders
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AU - Aldrich, Melinda
AU - Amiano, Pilar
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AU - Andersson, Ulrika
AU - Gerald Andriole, G. A.
AU - Andrulis, Irene L.
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AU - Freeman, Laura E.Beane
AU - Berg, Christine D.
AU - Berndt, Sonja I.
AU - Bertazzi, Pier Alberto
AU - Biritwum, Richard B.
AU - Black, Amanda
AU - Blot, William
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AU - Brennan, Paul
AU - Brinton, Louise A.
AU - Brotzman, Michelle
AU - Bueno-de-Mesquita, H. Bas
AU - Buring, Julie E.
AU - Butler, Mary Ann
AU - Cai, Qiuyin
AU - Cancel-Tassin, Geraldine
AU - Canzian, Federico
AU - Cao, Guangwen
AU - Caporaso, Neil E.
AU - Carrato, Alfredo
AU - Carreon, Tania
AU - Carta, Angela
AU - Chang, Gee Chen
AU - Chang, I. Shou
AU - Chang-Claude, Jenny
AU - Che, Xu
AU - Chen, Chien Jen
AU - Chen, Chih Yi
AU - Chen, Chung Hsing
AU - Chen, Constance
AU - Chen, Kuan Yu
AU - Chen, Yuh Min
AU - Chokkalingam, Anand P.
AU - Chu, Lisa W.
AU - Clavel-Chapelon, Francoise
AU - Colditz, Graham A.
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AU - Conti, David
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AU - Cortessis, Victoria K.
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AU - Fan, Jin Hu
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AU - Feychting, Maria
AU - Figueroa, Jonine D.
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AU - Fraumeni, Joseph F.
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AU - Fridley, Brooke L.
AU - Fuchs, Charles S.
AU - Gago-Dominguez, Manuela
AU - Gallinger, Steven
AU - Gao, Yu Tang
AU - Gapstur, Susan M.
AU - Garcia-Closas, Montserrat
AU - Garcia-Closas, Reina
AU - Gastier-Foster, Julie M.
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AU - Gonzalez, Carlos
AU - Gorlick, Richard
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AU - Haiman, Christopher A.
AU - Hallmans, Goran
AU - Hankinson, Susan E.
AU - Harris, Curtis C.
AU - Hartge, Patricia
AU - Hattinger, Claudia
AU - Hayes, Richard B.
AU - He, Qincheng
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AU - Hoffman-Bolton, Judith
AU - Hohensee, Chancellor
AU - Holly, Elizabeth A.
AU - Hong, Yun Chul
AU - Hoover, Robert N.
AU - Dean Hosgood, H.
AU - Hsiao, Chin Fu
AU - Hsing, Ann W.
AU - Hsiung, Chao Agnes
AU - Hu, Nan
AU - Hu, Wei
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AU - Huang, Ming Shyan
AU - Hunter, David J.
AU - Inskip, Peter D.
AU - Ito, Hidemi
AU - Jacobs, Eric J.
AU - Jacobs, Kevin B.
AU - Jenab, Mazda
AU - Ji, Bu Tian
AU - Johansen, Christoffer
AU - Johansson, Mattias
AU - Johnson, Alison
AU - Kaaks, Rudolf
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AU - Kamineni, Aruna
AU - Karagas, Margaret
AU - Khanna, Chand
AU - Khaw, Kay Tee
AU - Kim, Christopher
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AU - Kim, Jin Hee
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AU - Kim, Young Tae
AU - Kang, Chang Hyun
AU - Jung, Yoo Jin
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AU - Klein, Alison P.
AU - Klein, Robert
AU - Kogevinas, Manolis
AU - Koh, Woon Puay
AU - Kohno, Takashi
AU - Kolonel, Laurence N.
AU - Kooperberg, Charles
AU - Kratz, Christian P.
AU - Krogh, Vittorio
AU - Kunitoh, Hideo
AU - Kurtz, Robert C.
AU - Kurucu, Nilgun
AU - Lan, Qing
AU - Lathrop, Mark
AU - Lau, Ching C.
AU - Lecanda, Fernando
AU - Lee, Kyoung Mu
AU - Lee, Maxwell P.
AU - Marchand, Loic Le
AU - Lerner, Seth P.
AU - Li, Donghui
AU - Liao, Linda M.
AU - Lim, Wei Yen
AU - Lin, Dongxin
AU - Lin, Jie
AU - Lindstrom, Sara
AU - Linet, Martha S.
AU - Lissowska, Jolanta
AU - Liu, Jianjun
AU - Ljungberg, Börje
AU - Lloreta, Josep
AU - Lu, Daru
AU - Ma, Jing
AU - Malats, Nuria
AU - Mannisto, Satu
AU - Marina, Neyssa
AU - Mastrangelo, Giuseppe
AU - Matsuo, Keitaro
AU - McGlynn, Katherine A.
AU - McKean-Cowdin, Roberta
AU - McNeil, Lorna H.
AU - McWilliams, Robert R.
AU - Melin, Beatrice S.
AU - Meltzer, Paul S.
AU - Mensah, James E.
AU - Miao, Xiaoping
AU - Michaud, Dominique S.
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AU - Olson, Sara H.
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AU - Park, Jae Yong
AU - Patel, Alpa V.
AU - Patino-Garcia, Ana
AU - Pavanello, Sofia
AU - Peeters, Petra H.M.
AU - Peplonska, Beata
AU - Peters, Ulrike
AU - Petersen, Gloria M.
AU - Picci, Piero
AU - Pike, Malcolm C.
AU - Porru, Stefano
AU - Prescott, Jennifer
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AU - Qiao, You Lin
AU - Rajaraman, Preetha
AU - Riboli, Elio
AU - Risch, Harvey A.
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AU - Rothman, Nathaniel
AU - Ruder, Avima M.
AU - Ryu, Jeong Seon
AU - Sanson, Marc
AU - Schned, Alan
AU - Schumacher, Fredrick R.
AU - Schwartz, Ann G.
AU - Schwartz, Kendra L.
AU - Schwenn, Molly
AU - Scotlandi, Katia
AU - Seow, Adeline
AU - Serra, Consol
AU - Serra, Massimo
AU - Sesso, Howard D.
AU - Severi, Gianluca
AU - Shen, Hongbing
AU - Shen, Min
AU - Shete, Sanjay
AU - Shiraishi, Kouya
AU - Shu, Xiao Ou
AU - Siddiq, Afshan
AU - Sierrasesumaga, Luis
AU - Sierri, Sabina
AU - Sihoe, Alan Dart Loon
AU - Silverman, Debra T.
AU - Simon, Matthias
AU - Southey, Melissa C.
AU - Spector, Logan
AU - Spitz, Margaret
AU - Stampfer, Meir
AU - Stattin, Par
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AU - Stevens, Victoria L.
AU - Stolzenberg-Solomon, Rachael Z.
AU - Stram, Daniel O.
AU - Strom, Sara S.
AU - Su, Wu Chou
AU - Sund, Malin
AU - Sung, Sook Whan
AU - Swerdlow, Anthony
AU - Tan, Wen
AU - Tanaka, Hideo
AU - Tang, Wei
AU - Tang, Ze Zhang
AU - Tardon, Adonina
AU - Tay, Evelyn
AU - Taylor, Philip R.
AU - Tettey, Yao
AU - Thomas, David M.
AU - Tirabosco, Roberto
AU - Tjonneland, Anne
AU - Tobias, Geoffrey S.
AU - Toro, Jorge R.
AU - Travis, Ruth C.
AU - Trichopoulos, Dimitrios
AU - Troisi, Rebecca
AU - Truelove, Ann
AU - Tsai, Ying Huang
AU - Tucker, Margaret A.
AU - Tumino, Rosario
AU - Van Den Berg, David
AU - Van Den Eeden, Stephen K.
AU - Vermeulen, Roel
AU - Vineis, Paolo
AU - Visvanathan, Kala
AU - Vogel, Ulla
AU - Wang, Chaoyu
AU - Wang, Chengfeng
AU - Wang, Junwen
AU - Wang, Sophia S.
AU - Weiderpass, Elisabete
AU - Weinstein, Stephanie J.
AU - Wentzensen, Nicolas
AU - Wheeler, William
AU - White, Emily
AU - Wiencke, John K.
AU - Wolk, Alicja
AU - Wolpin, Brian M.
AU - Wong, Maria Pik
AU - Wrensch, Margaret
AU - Wu, Chen
AU - Wu, Tangchun
AU - Wu, Xifeng
AU - Wu, Yi Long
AU - Wunder, Jay S.
AU - Xiang, Yong Bing
AU - Xu, Jun
AU - Yang, Hannah P.
AU - Yang, Pan Chyr
AU - Yatabe, Yasushi
AU - Ye, Yuanqing
AU - Yeboah, Edward D.
AU - Yin, Zhihua
AU - Ying, Chen
AU - Yu, Chong Jen
AU - Yu, Kai
AU - Yuan, Jian Min
AU - Zanetti, Krista A.
AU - Zeleniuch-Jacquotte, Anne
AU - Zheng, Wei
AU - Zhou, Baosen
AU - Mirabello, Lisa
AU - Savage, Sharon A.
AU - Kraft, Peter
AU - Chanock, Stephen J.
AU - Yeager, Meredith
AU - Landi, Maria Terese
AU - Shi, Jianxin
AU - Chatterjee, Nilanjan
AU - Amundadottir, Laufey T.
N1 - Funding Information: This work was supported by the Intramural Research Program and by contract number HHSN261200800001E of the US National Institutes of Health (NIH), National Cancer Institute. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services nor does mention of trade names, commercial products or organizations imply endorsement by the U.S. Government. Additional funding acknowledgements are listed in Supplementary Material. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.
PY - 2014/11/15
Y1 - 2014/11/15
N2 - 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 CLPTM1Lgene(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.
AB - 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 CLPTM1Lgene(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.
UR - http://www.scopus.com/inward/record.url?scp=84938138638&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84938138638&partnerID=8YFLogxK
U2 - 10.1093/hmg/ddu363
DO - 10.1093/hmg/ddu363
M3 - Article
C2 - 25027329
AN - SCOPUS:84938138638
SN - 0964-6906
VL - 23
SP - 6616
EP - 6633
JO - Human molecular genetics
JF - Human molecular genetics
IS - 24
ER -