Open AccessFamily-based whole-exome sequencing identifies rare variants potentially related to cutaneous melanoma predisposition in Brazilian melanoma-prone families
Author(s) -
Felipe Fidalgo,
Giovana Tardin Torrezan,
Bianca Costa Soares de Sá,
Bruna Durães de Figueiredo Barros,
Luciana Facure Moredo,
Renan Valieris,
Sandro J. de Souza,
João Pereira Duprat,
Ana Cristina Victorino Krepischi,
Dirce Maria Carraro
Publication year - 2022
Publication title -
plos one
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.99
H-Index - 332
ISSN - 1932-6203
DOI - 10.1371/journal.pone.0262419
Subject(s) - exome sequencing , melanoma , exome , genetic predisposition , genetics , biology , medicine , computational biology , mutation , gene
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.