Multiple tumor phenotypes and malignant melanoma: the role of genetic testing for MITF, PTEN and CDKN2A

It is well known that synchronous and/or metachronous multiple primary melanomas (MPMs) occur in clearly hereditary settings as well as in familial and sporadic settings. However, no evidence exists about their co-occurrence in patients with multiple cancer phenotypes, a setting in which genetic susceptibility plays a significant role. Inside the multiple tumor phenotypes, multiple primary melanomas occurring in familial or sporadic settings constitute an interesting case study for the analysis of cancer susceptibility. In this study, we focused on the co-existence of MPMs and other types of tumors evaluating the genetic characterization underlying the context of high susceptibility to the development of multiple cancer phenotypes. We retrospectively evaluated the prevalence of benign and malignant neoplasms occurred in a group of 49 patients with multiple primary melanomas (MPMs) and compared the results with a group of 58 randomly age- and gender matched controls with single primary melanoma (SPM) and a group of 52 age- and gender randomly matched healthy patients. Mutational analysis of specific genes was performed when clinical data and family history were suggestive for familial/hereditary setting. Individuals affected by MPMs were distinguished by a statistically significant higher mutation frequency and a higher prevalence of other neoplasms. Of 27 diagnosed malignancies, basal cell carcinoma was the most frequent (n=10, 37.1%), followed by colorectal adenocarcinoma (n=5, 18.5%) and prostate adenocarcinoma (n=3, 11.1%). In addition to malignances, we also detected 10 benign tumors. Genetic testing revealed germline mutations affecting PTEN, MITF E318K, CDKN2A, MC1R genes. Our data highlight the importance of strict cancer surveillance in individuals with MPMs and the role of appropriate genetic counseling and testing in selected patients. Selected candidates should undergo genetic testing, not only for CDKN2a, CDK4, MC1R, but also for MITF E318K and PTEN, in ordeto plan personalized clinical and instrumental screenings and follow-up strategies; the latter must be assessed basing on mutational status: it is prudent to have a heightened level of suspicion in the clinical management of mutation carriers.