Familial Melanoma Phenotype With Xeroderma Pigmentosum Group C (XP-C) Genotype - The Putative Role of MC1R Polymorphism as Modifier

• Main Authors: Franciele Antonieta Bianchi Leidenz (Author), Flavia Vasques Bittencourt (Author), Williana Garcia Braga (Author), Ellio Magno de Sá Araujo (Author), Carolina Cavalieri Gomes (Author), Vanessa de Fatima Bernardes (Author), Eitan Friedman (Author), Luiz De Marco (Author)
• Format: Book
• Published: Mattioli1885, 2024-01-01T00:00:00Z.
• Subjects: article
• Online Access: Connect to this object online.

Summary

Introduction: Xeroderma pigmentosum (XP), a rare inherited condition, hallmarked by extreme sensitivity to sun exposure resulting in multiple skin cancers and non-malignant skin alterations is attributed to homozygous inactivating pathogenic variants (PVs) in DNA repair genes, predominantly the XPC gene. Objectives: Report a unique phenotypic expression of mutant XPC allele that may be compatible with a putative modifier role for MC1R polymorphism. Methods: A family of 13 siblings, seven of whom were diagnosed with at least one cutaneous  melanoma (N = 53) and non-melanoma skin cancers (N = 9) was studied. Of seven melanoma-affected cases, five consented for genetic analysis. CDKN2A revealed no PV in any case and subsequent whole-exome sequencing (WES) identified a rare homozygous missense PV (c.919C>T; p.Arg307Trp) in exon 8 of the XPC gene in all affected individuals. Notably, XPC PV carriers who co-harbored the p.I155T MC1R variant (N = 3) exhibited larger number of tumors, deeper Breslow indexes, higher rates of invasive melanomas and earlier age at diagnosis compared with non MC1R variant carriers (N = 2). Conclusions: Familial malignant melanoma phenotype may, in fact, be an unusual clinical presentation of XPC, and MC1R may be a genetic modifier of penetrance and phenotype of mutant XPC alleles.

Item Description

10.5826/dpc.1401a50
2160-9381