Sequence variants at the TERT-CLPTM1L locus associate with many cancer types

Abstract

The common sequence variants that have recently been associated with cancer risk are particular to a single cancer type or at most two. Following up on our genome-wide scan of basal cell carcinoma, we found that rs401681[C] on chromosome 5p15.33 satisfied our threshold for genome-wide significance (OR = 1.25, P = 3.7 x 10(-12)). We tested rs401681 for association with 16 additional cancer types in over 30,000 cancer cases and 45,000 controls and found association with lung cancer (OR = 1.15, P = 7.2 x 10(-8)) and urinary bladder, prostate and cervix cancer (ORs = 1.07-1.31, all P < 4 x 10(-4)). However, rs401681[C] seems to confer protection against cutaneous melanoma (OR = 0.88, P = 8.0 x 10(-4)). Notably, most of these cancer types have a strong environmental component to their risk. Investigation of the region led us to rs2736098[A], which showed stronger association with some cancer types. However, neither variant could fully account for the association of the other. rs2736098 corresponds to A305A in the telomerase reverse transcriptase (TERT) protein and rs401681 is in an intron of the CLPTM1L gene.

Figure 1

A schematic view of the association results and LD-structure in a region on chromosome 5p15.33. A) The pair-wise correlation structure in a 200 kb interval (1.225 – 1.425 Mb, NCBI B36) on chromosome 5. The upper plot shows pair-wise D′ for 100 common SNPs (with MAF > 5%) from the HapMap (v22) CEU dataset. The lower plot shows the corresponding r² values. B) Estimated recombination rates (saRR) in cM/Mb from the HapMap Phase II data. C) Location of known genes in the region. D) Schematic view of the association with BCC in the Icelandic sample set consisting of cases genotyped by chip or in silico (blue dots). Red triangle shows the location of rs2736098 and corresponding significance of association to BCC, testing for the HapMap CEU markers absent on the chip for individuals directly genotyped on chip.