Abstract
BackgroundThe p.E318K variant of the Melanocyte Inducing Transcription Factor (MITF) has been implicated in genetic predisposition to melanoma as an intermediate penetrance allele. However, the impact of this variant on clinico-phenotypic, as well as on dermoscopic patterns features of affected patients is not entirely defined. The purpose of our study was to assess the association between the p.E318K germline variant and clinic-phenotypical features of MITF+ compared to non-carriers (MITF−), including dermoscopic findings of melanomas and dysplastic nevi.Methodswe retrospectively analyzed a consecutive series of 1386 patients recruited between 2000 and 2017 who underwent genetic testing for CDKN2A, CDK4, MC1R and MITF germline variants in our laboratory for diagnostic/research purposes. The patients were probands of melanoma-prone families and apparently sporadic single or multiple primary melanoma patients. For all, we collected clinical, pathological information and dermoscopic images of the histopathologically diagnosed melanomas and dysplastic nevi, when available.ResultsAfter excluding patients positive for CDKN2A/CDK4 pathogenic variants and those affected by non-cutaneous melanomas, our study cohort comprised 984 cutaneous melanoma patients, 22 MITF+ and 962 MITF−. MITF+ were more likely to develop dysplastic nevi and multiple primary melanomas. Nodular melanoma was more common in MITF+ patients (32% compared to 19% in MITF−). MITF+ patients showed more frequently dysplastic nevi and melanomas with uncommon dermoscopic patterns (unspecific), as opposed to MITF− patients, whose most prevalent pattern was the multicomponent.ConclusionsMITF+ patients tend to develop melanomas and dysplastic nevi with histopathological features, frequency and dermoscopic patterns often different from those prevalent in MITF− patients. Our results emphasize the importance of melanoma prevention programs for MITF+ patients, including dermatologic surveillance with digital follow-up.
Highlights
The p.E318K variant of the Melanocyte Inducing Transcription Factor (MITF) has been implicated in genetic predisposition to melanoma as an intermediate penetrance allele
Multiple primary melanoma (MPM) patients (5% compared to 2% in single melanoma patients)
In our study cohort, the prevalence of the p.E318K germline variant in Cyclin Dependent Kinase Inhibitor 2A (CDKN2A)/Cyclin-Dependent Kinase 4 (CDK4)-negative patients was 2.2%, slightly higher than we previously reported in a smaller series of melanoma patients (1.8%) [13], but in line with Spanish (1.9%) [14], French (2.8%) [6], Australian (3.4–3.6%) [16] and American (2.8%) [12] studies
Summary
The p.E318K variant of the Melanocyte Inducing Transcription Factor (MITF) has been implicated in genetic predisposition to melanoma as an intermediate penetrance allele. A number of novel candidate melanoma predisposition genes, in addition to the well know high penetrance genes such as Cyclin Dependent Kinase Inhibitor 2A (CDKN2A), Cyclin-Dependent Kinase 4 (CDK4) and low-penetrance genes such as Melanocortin 1 Receptor (MC1R) have been uncovered in the last few years These include genes involved in DNA replication (telomere maintenance) or repair, such as Telomere Reverse Transcriptase (TERT), Protection of Telomeres 1 (POT1), Adrenocortical Dysplasia (ACD), Telomeric RepeatBinding Factor-2 (TERF2) Interacting Protein (TERF2IP), and Breast Cancer Gene 1 (BRCA1)-Associated Protein 1 (BAP1). The p.E318K variant of MITF in melanoma and renal carcinoma cells severely impaired SUMOylation of MITF, resulting in an increased transcription of HIF1A and other genes compared to wild-type MITF. The p.E318K variant allows cancer cells to activate a pseudohypoxic response or aerobic glycolysis and this “Warburg effect” predispose to cancer progression and metastasis [10]
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