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

Franciele Antonieta Bianchi Leidenz; Flavia Vasques Bittencourt; Williana Garcia Braga; Ellio Magno de Sá Araujo; Carolina Cavalieri Gomes; Vanessa de Fatima Bernardes; Eitan Friedman; Luiz De Marco

doi:10.5826/dpc.1401a50

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

Authors

Franciele Antonieta Bianchi Leidenz Departments of Surgery, School of Medicine, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
Flavia Vasques Bittencourt Departments of Medicine, School of Medicine, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
Williana Garcia Braga Departments of Surgery, School of Medicine, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
Ellio Magno de Sá Araujo Departments of Surgery, School of Medicine, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
Carolina Cavalieri Gomes Departments of Pathology, School of Medicine, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
Vanessa de Fatima Bernardes Departments of Pathology, School of Medicine, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
Eitan Friedman The Preventive Personalized Medicine Center, Assuta Medical Center and the Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel
Luiz De Marco Departments of Surgery, School of Medicine, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil

Keywords:

xeroderma pigmentosum, familial melanoma, XPC, MC1R, modifier genes

Abstract

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.

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