Imputation and subset-based association analysis across different cancer
types identifies multiple independent risk loci in the TERT-CLPTM1L
region on chromosome 5p15.33
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 P-Conditional =
2.36 x 10(-8); Region 4: rs2736098, P = 3.87 x 10(-12) and P-Conditional
= 5.19 x 10(-6), Region 5: rs13172201, P = 0.041 and P-Conditional =
2.04 x 10(-6); and Region 6: rs10069690, P = 7.49 x 10 215 and
P-Conditional = 5.35 x 10(-7)) and one in the neighboring CLPTM1L
gene(Region 2: rs451360; P = 1.90 x 10(-18) and P-Conditional = 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
