Family-based whole-exome sequencing identifies rare variants potentially related to cutaneous melanoma predisposition in Brazilian melanoma-prone families

PLoS One. 2022 Jan 27;17(1):e0262419. doi: 10.1371/journal.pone.0262419. eCollection 2022.


Genetic predisposition accounts for nearly 10% of all melanoma cases and has been associated with a dozen moderate- to high-penetrance genes, including CDKN2A, CDK4, POT1 and BAP1. However, in most melanoma-prone families, the genetic etiology of cancer predisposition remains undetermined. The goal of this study was to identify rare genomic variants associated with cutaneous melanoma susceptibility in melanoma-prone families. Whole-exome sequencing was performed in 2 affected individuals of 5 melanoma-prone families negative for mutations in CDKN2A and CDK4, the major cutaneous melanoma risk genes. A total of 288 rare coding variants shared by the affected relatives of each family were identified, including 7 loss-of-function variants. By performing in silico analyses of gene function, biological pathways, and variant pathogenicity prediction, we underscored the putative role of several genes for melanoma risk, including previously described genes such as MYO7A and WRN, as well as new putative candidates, such as SERPINB4, HRNR, and NOP10. In conclusion, our data revealed rare germline variants in melanoma-prone families contributing with a novel set of potential candidate genes to be further investigated in future studies.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Brazil
  • Exome Sequencing / methods
  • Female
  • Genetic Predisposition to Disease / genetics*
  • Genotype
  • Humans
  • Male
  • Melanoma / genetics*
  • Melanoma, Cutaneous Malignant
  • Middle Aged
  • Mutation / genetics*
  • Pedigree
  • Penetrance
  • Skin Neoplasms / genetics*

Grants and funding

GTT, SJS and DMC were funded by Fundação de Amparo à Pesquisa do Estado de São Paulo, grant number 2014/50943-1, Conselho Nacional de Desenvolvimento Científico e Tecnológico, grant number 465682/2014-6 and CAPES - 88887.136405/2017-00. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.