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

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.

References

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Published

2024-01-31

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Original Article

How to Cite

1.
Familial Melanoma Phenotype With Xeroderma Pigmentosum Group C (XP-C) Genotype - The Putative Role of MC1R Polymorphism as Modifier. Dermatol Pract Concept [Internet]. 2024 Jan. 31 [cited 2024 Jul. 13];14(1):e2024050. Available from: https://dpcj.org/index.php/dpc/article/view/3558

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