Abstract
Cutaneous malignant melanoma (CMM) is one of the most common skin cancers worldwide. CMM pathogenesis involves genetic and environmental factors. Recent studies have led to the identification of new genes involved in CMM susceptibility: beyond CDKN2A and CDK4, BAP1, POT1, and MITF were recently identified as potential high-risk melanoma susceptibility genes. This study is aimed to evaluate the genetic predisposition to CMM in patients from central Italy. From 1998 to 2017, genetic testing was performed in 888 cases with multiple primary melanoma and/or familial melanoma. Genetic analyses included the sequencing CDKN2A, CDK4, BAP1, POT1, and MITF in 202 cases, and of only CDKN2A and CDK4 codon 24 in 686 patients. By the evaluation of the personal and familial history, patients were divided in two clinical categories: “low significance” and “high significance” cases. 128 patients (72% belonging to the “high significance” category, 28% belonging to the “low significance” category) were found to carry a DNA change defined as pathogenic, likely pathogenic, variant of unknown significance (VUS)-favoring pathogenic or VUS. It is important to verify the genetic predisposition in CMM patients for an early diagnosis of further melanomas and/or other tumors associated with the characterized genotype.
Highlights
Cutaneous malignant melanoma (CMM) is one of the most common skin cancers worldwide [1]
128/888 (14%) of cases were found to carry a DNA variant defined as Pathogenic (P), Likely Pathogenic (LP), variant of unknown significance (VUS)-favoring pathogenic (VUS-3B), or VUS
98 cases carried a variant in cyclin-dependent kinase inhibitor 2A (CDKN2A), 10 in MITF, 9 in cyclin-dependent kinases-4 (CDK4), 9 in BAP1 in 2 in POT1
Summary
Cutaneous malignant melanoma (CMM) is one of the most common skin cancers worldwide [1]. Among the susceptibility genetic factors, germline alterations of the cyclin-dependent kinase inhibitor 2A (CDKN2A) gene are the most recognized cause of CMM hereditability within populations of different geographic areas [6]. P16INK4A and p16γ encode structurally related isoforms known to function as inhibitors of the CDK4 kinase, while p14ARF includes an alternate first exon located 20 Kb upstream of the remainder of the gene. This isoform functions as a stabilizer of the tumor suppressor protein p53 as it can sequester the E3 ubiquitin-protein ligase MDM2, a protein responsible for the degradation of p53 [8]. Somatic CDKN2A loss, by deletions or by promoter’s hypermethylation, has been shown to be a significant event in a number of cancer types [8]
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