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In-depth Investigation of Genetic Region Identifies Mechanism that Contributes to Cancer Susceptibility

Posted on May 01, 2017

Map of TERT and CLPTM1L region. (Brown, Amundadottir et al. Nat. Commun. 2017)

Investigators in the Laboratory of Translational Genomics have identified a genetic variant in a multi-cancer risk locus at chromosome 5p15.33 that explains, at least in part, the molecular mechanism through which this variant influences cancer risk. Genome-wide association studies (GWAS) have revealed up to seven independent cancer susceptibility loci in a small genomic region on chromosome 5p15.33, that includes the TERT and CLPTM1L genes. Specifically, variation in one of these loci (Region 2 in the CLPTM1L gene) has been found to increase risk of pancreatic cancer and testicular cancer, while decreasing risk of lung cancer and melanoma.

Laufey Amundadottir, Ph.D., Kevin Brown, Ph.D., and colleagues conducted fine-mapping analyses of Region 2 across these four cancers and identified rs36115365 as a functional variant that influences TERT expression, telomerase activity, and telomere length in an allele specific manner, via binding of the zinc finger transcription factor ZNF148 to the C allele at rs36115365.

The authors noted that future work should focus on identifying additional mechanisms of action at other risk loci in the region, as well as investigations to explain the contributions of deleterious and protective alleles at these loci for different cancers.

Reference: Brown, Amundadottir et al. Functional characterization of a multi-cancer risk locus on chr5p15.33 reveals regulation of TERT by ZNF148. Nat. Commun. April 27, 2017. DOI: 10.1038/ncomms15034