Abstract
The MITF-E318K variant has been implicated in genetic predisposition to cutaneous melanoma. We addressed the occurrence of MITF-E318K and its association with germline status of CDKN2A and MC1R genes in a hospital-based series of 248 melanoma patients including cohorts of multiple, familial, pediatric, sporadic and melanoma associated with other tumors. Seven MITF-E318K carriers were identified, spanning every group except the pediatric patients. Three carriers showed mutated CDKN2A, five displayed MC1R variants, while the sporadic carrier revealed no variants. Germline/tumor whole exome sequencing for this carrier revealed germline variants of unknown significance in ATM and FANCI genes and, in four BRAF-V600E metastases, somatic loss of the MITF wild-type allele, amplification of MITF-E318K and deletion of a 9p21.3 chromosomal region including CDKN2A and MTAP. In silico analysis of tumors from MITF-E318K melanoma carriers in the TCGA Pan-Cancer-Atlas dataset confirmed the association with BRAF mutation and 9p21.3 deletion revealing a common genetic pattern. MTAP was the gene deleted at homozygous level in the highest number of patients. These results support the utility of both germline and tumor genome analysis to define tumor groups providing enhanced information for clinical strategies and highlight the importance of melanoma prevention programs for MITF-E318K patients.
Highlights
The microphthalmia-associated transcription factor (MITF) is a master regulator of melanocytes
We addressed the occurrence of MITF-E318K and its association with germline status of Cyclin Dependent Kinase Inhibitor 2A gene (CDKN2A) and Melanocortin-1 Receptor (MC1R) genes in a hospital-based series of 248 melanoma patients including cohorts of multiple, familial, pediatric, sporadic and melanoma associated with other tumors
We report the occurrence of the MITF-E318K germline variant in 7/248 cutaneous melanoma (CM) patients of a hospital-based cohort, which was screened for the germline status of CDKN2A and MC1R predisposition genes, and included multiple (n = 78), familiar (n = 74), sporadic (n = 59), patients diagnosed for melanoma and other tumors (n = 15), and pediatric cases (n = 22)
Summary
The microphthalmia-associated transcription factor (MITF) is a master regulator of melanocytes. The critical role of MITF and the complexity of its regulatory effects become evident in melanoma, where high MITF expression is associated with a differentiated and proliferative phenotype, whereas low MITF expression with dedifferentiation and invasion, and with cell senescence [3,4,5]. MITF plays a complex role in the response to targeted therapies given that both increased as well as decreased MITF expression can mediate resistance to BRAF and MEK inhibitor therapy [7,8]. Recent evidence indicates that MITF can impact the anti-melanoma immune responses [9]. As a reaction to stimuli from the microenvironment, melanoma cells can dynamically switch between invasive (MITF-low) and proliferative (MITF-high) phenotypes to promote cell plasticity, tumor heterogeneity and resistance to therapy [3,10]
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