Characterization of population-based variation and putative functional elements for the multiple-cancer susceptibility loci at 5p15.33

Background: TERT encodes the telomerase reverse transcriptase, which is responsible for maintaining telomere ends by addition of (TTAGGG) (n) nucleotide repeats at the telomere. Recent genome-wide association studies have found common genetic variants at the TERT-CLPTM1L locus (5p15.33) associated with an increased risk of several cancers. Results: Data were acquired for 1627 variants in 1092 unrelated individuals from 14 populations within the 1000 Genomes Project. We assessed the population genetics of the 5p15.33 region, including recombination hotspots, diversity, heterozygosity, differentiation among populations, and potential functional impacts. There were significantly lower polymorphism rates, divergence, and heterozygosity for the coding variants, particularly for non-synonymous sites, compared with non-coding and silent changes. Many of the cancer-associated SNPs had differing genotype frequencies among ancestral groups and were associated with potential regulatory changes. Conclusions: Surrogate SNPs in linkage disequilibrium with the majority of cancer-associated SNPs were functional variants with a likely role in regulation of TERT and/or CLPTM1L. Our findings highlight several SNPs that future studies should prioritize for evaluation of functional consequences.