Genetic characterization of suspected hereditary melanoma in a Central Italy cohort

Abstract

Approximately 5–12% of cutaneous melanomas arise in a familial context, suggesting hereditary predisposition. Our analysis aims to investigate the clinical and genetic background of melanoma patients living in the Lazio area with a personal and/or family history of melanoma or other cancers. We retrospectively collected data of patients affected by melanoma and addressed to genetic evaluation by using CE-IVD Next Generation Sequencing (NGS) ClinEX pro kit (4bases) on Illumina NovaSeq6000 covering 45 target regions that includes 38 melanoma cancer predisposition genes using Geneyx pipeline. Over a period of 18 months, 40 Caucasian patients received a genetic evaluation and were included in our molecular study; of these, 55% were females, 80% were native to, and 98% resided in the Lazio area. The median age of diagnosis of melanoma was 48 years (IQR, 36–62). Half of the diagnosed melanoma were localized at the trunk (48%) and superficial spreading melanoma was the prevalent histotype (64%). A personal history of additional primary tumors (second to fifth) was found in 70%, 47.5%, 17.5%, 12.5% patients, respectively. The most represented second tumor was melanoma, diagnosed in 47.5% patients, followed by non-melanoma skin cancer ( n = 5, 12.5%) and colorectal cancer ( n = 4, 10%). Germline NGS analysis revealed 22.5% patients with pathogenic (P) or likely pathogenic (LP) variants, including both high and moderate-low penetrance genes for melanoma. Variants of uncertain significance (VUS) and Red Hair Color (RHC) variants were detected in 42.5% and 7.5% of individuals, respectively, while the remaining 27.5% had a negative genetic test. MC1R was the most involved gene (20%), affected by VUS and RHC variants. The eligibility criteria adopted by our group identified a positive genetic testing in 22.5% of evaluated patients, disclosing P and LP variants, especially in CDKN2A. The high proportion of VUS (42.5%), the clinical relevance of which remains unknown, warrants further investigation.The eligibility criteria adopted by our group identified a positive genetic testing in 22.5% of evaluated patients, disclosing P and LP variants, especially in CDKN2A. The high proportion of VUS (42.5%), the clinical relevance of which remains unknown, warrants further investigation.