Abstract
Germline CDKN2A mutations occur in 40 % of 3-or-more case melanoma families while mutations of CDK4, BAP1, and genes involved in telomere function (ACD, TERF2IP,POT1), have also been implicated in melanomagenesis. Mutation of the promoter of the telomerase reverse transcriptase (TERT) gene (c.−57 T>G variant) has been reported in one family. We tested for the TERT promoter variant in 675 multicase families wild-type for the known high penetrance familial melanoma genes, 1863 UK population-based melanoma cases and 529 controls. Germline lymphocyte telomere length was estimated in carriers. The c.−57 T>G TERT promoter variant was identified in one 7-case family with multiple primaries and early age of onset (earliest, 15 years) but not among population cases or controls. One family member had multiple primary melanomas, basal cell carcinomas and a bladder tumour. The blood leukocyte telomere length of a carrier was similar to wild-type cases. We provide evidence confirming that a rare promoter variant of TERT (c.−57 T>G) is associated with high penetrance, early onset melanoma and potentially other cancers, and explains <1 % of UK melanoma multicase families. The identification of POT1 and TERT germline mutations highlights the importance of telomere integrity in melanoma biology.Electronic supplementary materialThe online version of this article (doi:10.1007/s10689-015-9841-9) contains supplementary material, which is available to authorized users.
Highlights
Cutaneous melanoma occurs predominantly in the genetically predisposed, i.e. white-skinned individuals with skin that burns with UV exposure, and who are prone to develop melanocytic naevi [2, 3]
In order to estimate the prevalence of germline telomerase reverse transcriptase (TERT) promoter mutations in population-ascertained melanoma cases, we screened blood-derived DNA from 1863 cases and 529 controls recruited to the Leeds Melanoma Case–Control study [17]
The c.-57 T[G TERT promoter variant was identified in the proband of a single 7-case UK family and subsequently in a sibling (Fig. 1)
Summary
Cutaneous melanoma occurs predominantly in the genetically predisposed, i.e. white-skinned individuals with skin that burns with UV exposure, and who are prone to develop melanocytic naevi [2, 3]. Clustering of melanoma in families points to rare high-penetrance dominantly inherited mutations. The most frequently mutated high-penetrance melanoma susceptibility gene is CDKN2A (cyclin-dependent kinase inhibitor 2A), which encodes tumour suppressors p16 and p14ARF. The proportion of families with identifiable CDKN2A mutations varies geographically, being lower in countries with high ambient solar ultraviolet radiation populated by fair-skinned people [5]. CDKN2A mutation carriers tend to have multiple primary melanomas, early onset melanoma and an increased risk of developing pancreatic cancer [5] and have been shown to have an increased risk of tobacco associated cancers in respiratory and digestive tissues [6, 7]. A very small proportion (\1 %) of families worldwide have been reported with mutations in the CDK4 (Cyclin-dependent kinase 4) gene at a key p16-binding residue [8]
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