Abstract 1668: Understanding cancer associated SNPs in the TERT-CLPTM1L locus through population genetics

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Abstract Telomeres form the ends of eukaryotic chromosomes and are vital in maintaining genetic integrity. 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 theTERT-CLPTM1L locus (5p15.33) associated with increased risk of several cancers, including glioma, basal cell carcinoma, testicular, pancreatic, breast and lung cancers, and possibly overall cancer risk. Our prior studies of common single nucleotide polymorphisms (SNPs) in the TERT gene region found low differentiation among populations and higher than expected levels of haplotype diversity in data from the Human Genome Diversity Panel (HGDP) and the International HapMap Project. In the current study we significantly expanded the population genetic analyses by utilizing data from the 1000 Genomes Project (2011 October release). Genetic variation from a total of 1092 individuals from 14 populations with European, East Asian, West African or American ancestry was evaluated. Data were acquired for 3468 variants in a 206kb region on 5p15.33, which included the TERT-CLPTM1L gene and flanking regions. The GLU genetics’ ld.tagzilla module was used for the tag analysis with a linkage disequilibrium (LD) pairwise r2 threshold of 0.8. Arlequin (3.5) and Genepop (4.1) packages were used to estimate diversity, LD, heterozygosity, and differentiation (FST) among populations. Pairwise LD was analyzed separately for the 4 ancestral groups (European, East Asian, West African and American) and used to select tag SNPs for each region. The 4 ancestral groups had differing LD patterns with the lowest level of LD occurring in individuals from Africa, as expected. These data were used to create the appropriate haplotype-tagging SNPs for the TERT-CLPTM1L region in each population; we present recommended tagging SNPs by ancestral group. The TERT-CLPTM1L gene region had low nucleotide diversity (mean 2 x 10−4) and differentiation among ancestral groups (90% of loci in this region had FST <0.10). The limited diversity in this region may be due to its critical role in telomere maintenance and chromosomal stability. The recently identified cancer associated SNPs in this region had differing genotype frequencies among ancestral groups. Variation in cancer associated alleles among ancestral groups may correlate to varying disease risks. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1668. doi:1538-7445.AM2012-1668