Newly identified melanoma susceptibility genes in families highlight the importance of the telomere in melanoma carcinogenesis and prognosis
Melanoma is a cancer predominantly of pale-skinned peoples. Within pale-skinned populations, those with genetically determined phenotypes such as red hair, freckles and large numbers of melanocytic naevi are especially at risk. The identification of high penetrance germline mutations in CDKN2A led to a recognition that control of cell proliferation by the process of senescence 1 is a crucial factor in melanoma prevention. We report further evolution in our understanding of this process resulting from identification of the role for genetic variation in the telomerase reverse transcriptase gene (TERT) in melanoma carcinogenesis and prognosis.
Genome wide association studies (GWAS) were performed in melanoma cases and healthy controls ascertained in many centres across Europe and Australia by the GenoMEL consortium. Whole exomic sequencing was also carried out in multiple case melanoma families; identified mutations were validated by functional studies and by screening for the identified mutations in population-ascertained melanoma cases and controls.
Of the 16 susceptibility genetic loci identified via GWAS, the majority were related to pigmentation or number of naevi, but several were related to senescence via telomere function (TERT2 and PARP1). Critical variants in the TERT region were in strong linkage disequilibrium with SNPs shown to be associated with telomere length in the germline3. Further, a PARP1 variant was also shown to be associated with survival from melanoma in a collaboration with the BioGenoMEL genetics consortium showing that germline variation may moderate host-tumour interaction and therefore melanoma survival (paper submitted). Exomic and Sanger sequencing in the high risk families identified an inherited promoter mutation in the TERT gene as recently described 4 and mutations in a further new family of genes related to senescence (paper currently submitted).
Germline genetic variation associated with melanoma risk has identified the pathway controlling cell senescence/telomere function as crucial to melanoma development.
Supported primarily by Cancer Research UK and NIH. BioGenoMEL has benefitted from a grant from YCR.
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3. Bojesen SE, Pooley KA, Johnatty SE, et al. Multiple independent variants at the TERT locus are associated with telomere length and risks of breast and ovarian cancer. Nat Genet 2013; 45:371-84, 384e1-2.
4. Horn S, Figl A, Rachakonda PS, et al. TERT promoter mutations in familial and sporadic melanoma. Science 2013; 339:959-61.