| Summary: | Although the development of mitogen-activated protein kinase (MAPK) inhibitors has greatly improved the prognosis of <i>BRAF</i><sup>V600</sup> cutaneous melanomas, the identification of molecular indicators for mutated patients at risk of early progression remains a major issue. Using an amplicon-based next-generation-sequencing (NGS) assay that targets cancer-related genes, we investigated co-occurring alterations in 89 melanoma samples. We analyzed both their association with clinicopathological variables and clinical significance in terms of progression-free survival (PFS) and overall survival (OS) according to <i>BRAF</i> genotyping. Among co-occurring mutations, <i>TERT</i> promoter was the most frequently mutated gene. Although no significant difference in PFS was observed in the presence or absence of co-occurring alterations to <i>BRAF</i><sup>V600</sup>, there was a trend of longer PFS for patients harboring <i>TERT</i> c.-124C>T mutation. Of most interest, this mutation is an independent marker of good prognosis in subgroups of patients with poor prognosis (presence of brain metastasis and elevated level of lactate dehydrogenase, LDH). Moreover, combination of elevated LDH level, presence of brain metastasis, and <i>TERT</i> c.-124C>T mutation was identified as the best fit model for predicting clinical outcome. Our work revealed the potential interest of c.-124C>T status determination in order to refine the prognosis of <i>BRAF</i><sup>V600</sup> melanoma under mitogen-activated protein kinase (MAPK) inhibitors.
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