Mutational Profile of Driver Genes in Brazilian Melanomas

Abstract

Purpose: Mutation testing of the key genes involved in melanoma oncogenesis is now mandatory for the application of targeted therapeutics. However, knowledge of the mutational profile of melanoma remains largely unknown in Brazil.

Patients and methods: In this study, we assessed the mutation status of melanoma driver genes BRAF, NRAS, TERT, KIT, and PDGFRA in a cohort of 459 patients attended at Barretos Cancer Hospital between 2001 and 2012. We used polymerase chain reaction followed by Sanger sequencing to analyze the hot spot mutations of BRAF exon 15 (V600E), NRAS (codons 12/13 and 61), TERT (promoter region), KIT (exons 9, 11, 13, and 17), and PDGFRA (exons 12, 14, and 18) in tumors. The mutational profile was investigated for associations with demographic, histopathologic, and clinical features of the disease.

Results: The nodular subtype was most frequent (38.9%) followed by the superficial spreading subtype (34.4%). The most frequent tumor location was in the limbs (50.0%). The mutation rates were 34.3% for TERT and 34.1% for BRAF followed by NRAS (7.9%), KIT (6.2%), and PDGFRA (2.9%). The BRAF (P = .014) and TERT (P = .006) mutations were associated with younger patients and with different anatomic locations, particularly in the trunk, for the superficial spreading and nodular subtypes, respectively (P = .0001 for both). PDGFRA mutations were associated with black skin color (P = .023) and TERT promoter mutations with an absence of ulceration (P = .037) and lower levels of lactate dehydrogenase. There was no association between patient survival rates and mutational status.

Conclusion: The similar mutational profile we observe in melanomas in Brazil compared with other populations will help to guide precision medicine in this country.

FIG 1

Mutational profile of 133 patients with melanoma.

FIG A1

Sequencing electropherograms. Hot spot mutations are exemplified.

FIG A2

Lollipop plots of driver mutations identified in BRAF, NRAS, TERT, KIT, and PDGFRA. aa, amino acids.