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.
Original language | English |
---|---|
Pages (from-to) | 6616-33 |
Number of pages | 18 |
Journal | Human Molecular Genetics |
Volume | 23 |
Issue number | 24 |
DOIs | |
Publication status | Published - 15 Dec 2014 |
Keywords
- Alleles
- 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
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In: Human Molecular Genetics, Vol. 23, No. 24, 15.12.2014, p. 6616-33.
Research output: Contribution to journal › Article › Academic › peer-review
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
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AU - Zhang, Mingfeng
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AU - Chang-Claude, Jenny
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AU - Kamineni, Aruna
AU - Karagas, Margaret
AU - Khanna, Chand
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AU - Kim, Christopher
AU - Kim, In-Sam
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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
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AU - Ljungberg, Börje
AU - Lloreta, Josep
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AU - Peplonska, Beata
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AU - Seow, Adeline
AU - Serra, Consol
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AU - Severi, Gianluca
AU - Shen, Hongbing
AU - Shen, Min
AU - Shete, Sanjay
AU - Shiraishi, Kouya
AU - Shu, Xiao-Ou
AU - Siddiq, Afshan
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AU - Sierri, Sabina
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AU - Swerdlow, Anthony
AU - Tan, Wen
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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
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AU - Chanock, Stephen J
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AU - Shi, Jianxin
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N1 - 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.
PY - 2014/12/15
Y1 - 2014/12/15
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 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.
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 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.
KW - Alleles
KW - Chromosomes, Human, Pair 5
KW - Computational Biology
KW - DNA Methylation
KW - Epigenesis, Genetic
KW - Female
KW - Gene Expression Regulation, Neoplastic
KW - Gene Frequency
KW - Genetic Loci
KW - Genetic Predisposition to Disease
KW - Genome-Wide Association Study
KW - Humans
KW - Male
KW - Membrane Proteins
KW - Neoplasm Proteins
KW - Neoplasms
KW - Odds Ratio
KW - Polymorphism, Single Nucleotide
KW - Risk
KW - Telomerase
U2 - 10.1093/hmg/ddu363
DO - 10.1093/hmg/ddu363
M3 - Article
C2 - 25027329
SN - 0964-6906
VL - 23
SP - 6616
EP - 6633
JO - Human Molecular Genetics
JF - Human Molecular Genetics
IS - 24
ER -