Imputation and subset-based association analysis across different cancer types identifies multiple independent risk loci in the TERT-CLPTM1L region on chromosome 5p15.33.

Hum Mol Genet
Authors
Keywords
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.

Year of Publication
2014
Journal
Hum Mol Genet
Volume
23
Issue
24
Pages
6616-33
Date Published
2014 Dec 15
ISSN
1460-2083
URL
DOI
10.1093/hmg/ddu363
PubMed ID
25027329
PubMed Central ID
PMC4240198
Links
Grant list
P50 CA091846 / CA / NCI NIH HHS / United States
P30 CA016672 / CA / NCI NIH HHS / United States
P30 CA015704 / CA / NCI NIH HHS / United States
P50 CA062924 / CA / NCI NIH HHS / United States
R01 CA092447 / CA / NCI NIH HHS / United States
G1000143 / Medical Research Council / United Kingdom
UM1 CA173640 / CA / NCI NIH HHS / United States
K07 CA172294 / CA / NCI NIH HHS / United States
14136 / Cancer Research UK / United Kingdom
P50 CA097257 / CA / NCI NIH HHS / United States
G0401527 / Medical Research Council / United Kingdom
P30 CA015083 / CA / NCI NIH HHS / United States
R01 CA154823 / CA / NCI NIH HHS / United States
U10 CA180899 / CA / NCI NIH HHS / United States
UM1 CA182910 / CA / NCI NIH HHS / United States
HHSN261200800001E / CA / NCI NIH HHS / United States
R01 CA052689 / CA / NCI NIH HHS / United States
UM1 CA182876 / CA / NCI NIH HHS / United States