TERT Promoter Mutation as an Independent Prognostic Marker for Poor Prognosis MAPK Inhibitors-Treated Melanoma.

Pauline Blateau,Géraldine Chauchard,Estelle Laurent,Julie A Vendrell,Benoit Béganton,Etienne Coyaud,Jérôme Solassol,Vincent Ducros

doi:10.3390/cancers12082224

Abstract

Although the development of mitogen-activated protein kinase (MAPK) inhibitors has greatly improved the prognosis of BRAFV600 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 BRAF genotyping. Among co-occurring mutations, TERT 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 BRAFV600, there was a trend of longer PFS for patients harboring TERT 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 TERT 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 BRAFV600 melanoma under mitogen-activated protein kinase (MAPK) inhibitors.

Highlights

Over the past few years, the molecular characterization of melanomas has greatly improved, with an emphasis on alteration of cell signaling pathways [1,2]
When we compared the frequencies of co-occurring mutations variations between the BRAFV600 and BRAFWT patients, we only found a statistically significant difference between these two groups for NRAS (3.8% in BRAFV600 samples versus 44.4% in BRAFWT samples, p < 0.001) (Figure 2B)
We observed that specific TERT promoter mutation c.-124C>T displayed a statistically significant correlation with mitogen-activated protein kinase (MAPK) inhibitor treatment efficacy, in a subset of BRAFV600 melanoma patients that had poorer progression-free survival (PFS) and overall survival (OS)

Summary

Introduction

Over the past few years, the molecular characterization of melanomas has greatly improved, with an emphasis on alteration of cell signaling pathways [1,2]. 40% of patients with melanoma exhibit exon 15 BRAF mutations in cancer cells, resulting in constitutive activation of the mitogen-activated protein kinase (MAPK) cascade. Cancers 2020, 12, 2224 has significantly improved progression-free survival (PFS) and overall survival (OS) in melanoma patients harboring activating BRAF mutations [3]. Of 14 showed clinically significant improvements in OS in molecularly unselected populations of advanced significantly improved progression-free survival (PFS) and (OS). Recent data support the hypothesis thatoverall these survival therapies alsoinprovide clinical patients harboring activating. Immune checkpoint inhibitors benefit in melanoma patients with activating BRAF mutations [4]

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Discussion

Conclusion