Rare missense variants in POT1 predispose to familial cutaneous malignant melanoma

Abstract

Although CDKN2A is the most frequent high-risk melanoma susceptibility gene, the underlying genetic factors for most melanoma-prone families remain unknown. Using whole exome sequencing, we identified a rare variant that arose as a founder mutation in the telomere shelterin POT1 gene (g.7:124493086 C>T, Ser270Asn) in five unrelated melanoma-prone families from Romagna, Italy. Carriers of this variant had increased telomere length and elevated fragile telomeres suggesting that this variant perturbs telomere maintenance. Two additional rare POT1 variants were identified in all cases sequenced in two other Italian families, yielding a frequency of POT1 variants comparable to that of CDKN2A mutations in this population. These variants were not found in public databases or in 2,038 genotyped Italian controls. We also identified two rare recurrent POT1 variants in American and French familial melanoma cases. Our findings suggest that POT1 is a major susceptibility gene for familial melanoma in several populations.

Multiple primary melanomas (MPMs) and criteria for genetic assessment: MultiMEL, a multicenter study of the Italian Melanoma Intergroup

“…However, most of the participating centers perform genetic counseling and dermatologic examinations for patients coming from other areas. Rare mutations in novel melanoma susceptibility genes, including a founder mutation in POT1 in families from the Italian region Emilia-Romagna, have been identified [31][32][33][34][35][36] but were not tested. However, such mutations occur in less than 10% of melanoma families with a yet unknown genetic prevalence in the studied populations.…”

“…[27][28][29][30] Novel melanoma susceptibility genes have also been identified, but their geographic prevalence and penetrance has yet to be established. [31][32][33][34][35][36] The aim of our study was to carry out a nationwide evaluation of the mutation rate of melanoma susceptibility genes CDKN2A, CDK4, and MITF and associated features in patients with MPM to establish whether, even in the absence of family history, MPM may be added as a criterion to update the national recommendations for genetic testing for hereditary melanoma.…”

Whole exome sequencing reveals a C-terminal germline variant in CEBPA-associated acute myeloid leukemia: 45-year follow up of a large family

“…The procedure used has been described previously. 17,18 Briefly, 1.1 mg of genomic DNA was extracted by standard methods from low-passage cultured fibroblasts (IV.1, IV.4 and III.2) or from lymphocytes (III.5 and III.8). Pretreatment leukemic cells were not available for any of the tested AML patients; all testing was performed on healthy tissue and diseased cells were not available for testing.…”

Whole exome sequencing in families at high risk for Hodgkin lymphoma: identification of a predisposing mutation in the KDR gene

“…20 Details of the bioinformatics pipeline for variant alignment and calling used in this study appear in the Online Supplementary Methods. Annotation of each variant locus was made via a custom software pipeline based on public data sources described in the Online Supplementary Methods.…”

“…37 Interestingly, we did not find shared variants in the three genes (KLHDC8B, NPAT, and ACAN) previously identified in high-risk HL families, [16][17][18] while we observed the POT1 rs202187871 variant also reported in a high-risk melanoma family. 20 Given the large total number of genes (2383) with family-shared variants that we identified, we also conducted pathway analyses using two independent tools, Ingenuity Variant Analysis (IVA) 38 Supplementary Table S6F). We did not observe significant enrichment in kinase activities or in cell division processes or in Kelch gene families (Online Supplementary Table S6B).…”