Mutational Characteristics of Primary Mucosal Melanoma: A Systematic Review.

BACKGROUND: Primary mucosal melanomas (PMMs) are rare and clinically heterogeneous, including head and neck (HNMs), vulvovaginal (VVMs), conjunctival (CjMs), anorectal (ARMs) and penile (PMs) melanomas. While the prognosis of advanced cutaneous melanoma has noticeably improved using treatments with immune checkpoint inhibitors (ICIs) and molecules targeting BRAF and MEK, few advances have been made for PMMs because of their poorer response to ICIs and their different genetic profile. This prompted us to conduct a systematic review of molecular studies of PMMs to clarify their pathogenesis and potential therapeutic targets. METHODS: All articles that examined gene mutations in PMMs were identified from the databases and selected based on predefined inclusion criteria. Mutation rate was calculated for all PMMs and each location group by relating the number of mutations identified to the total number of samples analysed. RESULTS: Among 1,581 studies identified, 88 were selected. Overall, the frequency of KIT, BRAF and NRAS mutation was 13.5%, 12.9% and 12.1%, respectively. KIT mutation ranged from 6.4% for CjMs to 16.6% for ARMs, BRAF mutation from 8.6% for ARMs to 31.1% for CjMs, and NRAS mutation from 6.2% for ARMs to 18.5% for CjMs. Among 101 other genes analysed, 33 had mutation rates over 10%, including TTN, TSC1, POM121, NF1, MTOR and SF3B1. CONCLUSION: In addition to BRAF, NRAS and KIT genes commonly studied, our systematic review identified significantly mutated genes that have already been associated (e.g., TSC1, mTOR, POLE or ATRX) or could be associated with (future) targeted therapies. PROSPERO ID: CRD42020185552.

Prognostic factors and incidence of primary mucosal melanoma: a population-based study in France.

Few population-based studies on the incidence and prognosis of primary mucosal melanoma (PMM) are available. The first objective was to evaluate disease-specific survival of PMM, overall and according to specific locations, and to identify prognostic factors. The second objective was to assess the global incidence of PMM compared to cutaneous melanoma and to specify the relative frequency of each affected location. A retrospective population-based study of incident PMM diagnosed between 2004 and 2014 was conducted, relying on the regional melanoma registry of the French Champagne-Ardenne region (1.34 million inhabitants). Thirty-nine cases were identified, including 17 head and neck (13 sinonasal and four oral), 12 vulvovaginal, six conjunctival, and four anorectal PMMs. Some 76.9% of cases were revealed by late symptoms. The median disease-specific survival time was 23.9 months and the five-year disease-specific survival rate was 31.8%. Univariate and multivariate analyses led to identification of primary tumour size and the presence of nodal or visceral macrometastases at diagnosis as adverse prognostic factors, while Breslow thickness and ulceration were unreported in 41% of cases and failed to display any prognostic value. Compared to other locations, conjunctival PMMs had a smaller tumour size and better prognosis. The annual incidence rate was 0.18/100,000 and the incidence ratio between PMM and cutaneous melanoma was 1/50. This population-based study confirms the rarity, delayed diagnosis, and severity of PMM, suggesting that improving prognosis will require specific, targeted therapies.

TERT promoter mutations in melanoma render TERT expression dependent on MAPK pathway activation.

The mechanism of telomerase re-activation in cancer had remained elusive until the discovery of frequent mutations in the promoter of the TERT gene that encodes the catalytic reverse transcriptase subunit of telomerase. We investigated the regulation of TERT expression in melanoma cell lines and our results show that promoter mutations render TERT expression dependent on MAPK activation due to oncogenic BRAF or NRAS mutations. Mutations in the TERT promoter create binding sites for ETS transcription factors. ETS1, expressed in melanoma cell lines, undergoes activating phosphorylation by ERK at Thr38 residue as a consequence of constitutively activated MAPK pathway. We demonstrate that ETS1 binds on the mutated TERT promoter leading to the re-expression of the gene. The inhibition of ETS1 resulted in reduced TERT expression. We provide evidence that the TERT promoter mutations provide a direct link between TERT expression and MAPK pathway activation due to BRAF or NRAS mutations via the transcription factor ETS1.

Parenchymal FLAIR hyperintensity before thrombolysis is a prognostic factor of ischemic stroke outcome at 3 Tesla.

BACKGROUND: The goal of the present study was to determine whether the presence or absence of parenchymal FLAIR hyperintensity alone, before thrombolysis, might be a predictive factor of ischemic stroke outcomes after the acute phase of stroke and at 3 months. MATERIALS AND METHODS: We retrospectively included 84 patients with an ischemic stroke between November 2007 and March 2012, who underwent 3T MRI, were treated by thrombolysis, and had medical follow-up at 3 months. Two readers analyzed parenchymal FLAIR visibility. Logistic regressions were performed for NIHSS difference (NIHSS at admission - NIHSS at the end of hospitalization) and for 3 months modified Ranking Score (mRS). Predictive values of positive parenchymal FLAIR for identifying poor outcome at discharge and at 3 months were estimated. RESULTS: Parenchymal FLAIR positivity was not predictive of NIHSS difference but it predicted poor outcome at 3 months (sensitivity: 0.49 [0.37-0.60], specificity: 0.69 [0.46-0.91], positive predictive value: 0.87 [0.76-0.98] and negative predictive value: 0.24 [0.12-0.36]). CONCLUSIONS: At 3 Tesla, the presence of a parenchymal hyperintense FLAIR signal before thrombolysis is predictive of a poor clinical outcome at 3 months.