High-throughput sequencing identifies 3 novel susceptibility genes for hereditary melanoma

Catarina Campos, Sofia Fragoso, Rafael Luís, Filipe Pinto, Cheila Brito, Susana Esteves, Margarida Pataco, Sidónia Santos, Patrícia Machado, João B. Vicente, Joaninha Costa Rosa, Branca M. Cavaco, Cecília Moura, Marta Pojo

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10 Citations (Scopus)
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Cutaneous melanoma is one of the most aggressive human cancers due to its high invasiveness. Germline mutations in high-risk melanoma susceptibility genes have been associated with development hereditary melanoma; however, most genetic culprits remain elusive. To unravel novel susceptibility genes for hereditary melanoma, we performed whole exome sequencing (WES) on eight patients with multiple primary melanomas, high number of nevi, and negative for high and intermediate-risk germline mutations. Thirteen new potentially pathogenic variants were identified after bioinformatics analysis and validation. CDH23, ARHGEF40, and BRD9 were identified as the most promising susceptibility genes in hereditary melanoma. In silico analysis of CDH23 and ARHGEF40 variants provided clues for altered protein structure and function associated with the identified mutations. Then, we also evaluated the clinical value of CDH23, ARHGEF40, and BRD9 expression in sporadic melanoma by using the TCGA dataset (n = 461). No differences were observed in BRD9 expression between melanoma and normal skin samples, nor with melanoma stage, whereas ARHGEF40 was found overexpressed, and CDH23 was downregulated and its loss was associated with worse survival. Altogether, these results reveal three novel genes with clinical relevance in hereditary and sporadic melanoma.

Original languageEnglish
Article number403
Issue number4
Publication statusPublished - Apr 2020


  • Cutaneous melanoma
  • Germline mutations
  • Hereditary melanoma
  • WES


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