TERT Promoter Mutations are Associated with Visceral Spreading in Melanoma of the Trunk.

Simona Osella-Abate,Rajiv Kumar,Francesco Lisa,Paola Cassoni,Rebecca Senetta,Eduardo Nagore,Susana Puig S,Vittoria Coppola,Esperanza Manrique-Silva,Jasna Metovic,Barbara Pasini,Simone Ribero,Luca Bertero,Sara Mariani,Maria Fierro

doi:10.3390/cancers11040452

Abstract

Survival predictions are currently determined on the basis of NRAS/BRAF mutations, even though TERT promoter mutations have been recently associated with a poor prognosis in stage I-II melanomas. Usually, it is not recommended to perform a mutational test on primary melanoma, as the results do not always reflect the mutational status of metastases. In particular, trunk melanomas have been reported to have an unfavourable prognosis. A series of 105 advanced melanoma patients were analysed by TERT promoter Sanger sequencing. Univariate/multivariate binary logistic regression models were performed using progression to a visceral site as the dependent variable and patient/tumour characteristics as covariates. Performance of the model was assessed in an external independent primary melanoma patients’ dataset. Male gender (odds ratio (OR), 344; 95% CI, 1.12–10.6; p = 0.031), AJCC (American Joint Committee on Cancer) classification (OR, 022; 95% CI, 0.07–0.67; p = 0.008), SLNB (Sentinel Lymph Node Biopsy) status (OR, 3.05; 95% CI, 1.06–8.78; p = 0.039) and TERT-mutated trunk lesions (OR, 3.78; 95% CI, 1.35–10.6; p = 0.011) were significantly associated with the risk of developing a visceral spreading as first site of progression using multivariate logistic regression analysis. These results were confirmed in the external validation control group. Therefore, in trunk primary melanomas, due to their high risk of progression to visceral sites, we encourage somatic TERT mutation analysis at diagnosis to identify those patients who would potentially benefit from a more intensive follow-up protocol and a prompt initiation of therapy.

Highlights

Genetic testing for targetable somatic mutations is considered mandatory by the EuropeanGuidelines in the context of diagnosis, treatment and follow-up of cutaneous melanomas in patients with advanced disease, and highly recommended in high-risk resected disease [1]
The majority of melanomas appeared on the trunk (n = 41, 39.1%)
To test the reproducibility of the association between TERT promoter mutation in trunk site with visceral metastases as first site of progression, we investigated its performance in data collected from 83 stage II primary melanoma patients all progressed to a metastatic stage recruited in Valencia by the Instituto Valenciano de Oncologia

Summary

Introduction

Genetic testing for targetable somatic mutations is considered mandatory by the EuropeanGuidelines in the context of diagnosis, treatment and follow-up of cutaneous melanomas in patients with advanced disease (unresectable stage III or stage IV), and highly recommended in high-risk resected disease (stage IIC or stages IIIB–IIIC) [1]. In BRAF wild type tumours, alternative mutations occurring at NRAS and c-Kit genes must be tested. Tumour heterogeneity in advanced stage melanoma has important implications for molecular testing and treatment. It is not recommended to test for BRAF mutations in primary cutaneous melanoma unless these data are required to guide systemic therapy in advanced stages. Several studies suggest that detection of a wild type BRAF (B-Raf proto-oncogene) in the primary tumour may not necessarily reflect the BRAF mutation status of metastases [4,5]. Patients often come to our attention with advanced stages, progressing either after a positive or a negative sentinel lymph node (SLN), or directly from a primary to a distant metastatic site [6,7]

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