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.
Patients with late stage resected cutaneous melanoma have poor overall survival (OS) and experience irreversible adverse events from systemic therapy.,There is a clinical need to identify biomarkers to predict outcome.,Performing germline/tumour whole-exome sequencing of 44 stage III/IV melanoma patients we identified pathogenic germline mutations in CDKN2A, CDK4, ATM, POLH, MRE11A, RECQL4 and XPC, affecting 7/44 patients.,These mutations were associated with poor OS (p = 0.0082).,We confirmed our findings in The Cancer Genome Atlas (TCGA) human skin cutaneous melanoma cohort where we identified pathogenic variants in 40/455 patients (p = 0.0203).,Combining these cohorts (n = 499) further strengthened these findings showing germline carriers had worse OS (p = 0.0009).,Additionally, we determined whether tumour mutation burden (TMB) or BRAF status were prognostic markers of survival.,Low TMB rate (< 20 Mut/Mb; p = 0.0034) and BRAF p.V600 mutation (p = 0.0355) were associated with worse progression-free survival.,Combining these biomarkers indicated that V600 mutant patients had significantly lower TMB (p = 0.0155).,This was confirmed in the TCGA (n = 443, p = 0.0007).,Integrative analysis showed germline mutation status conferred the highest risk (HR 5.2, 95% CI 1.72-15.7).,Stage IV (HR 2.5, 0.74-8.6) and low TMB (HR 2.3, 0.57-9.4) were similar, whereas BRAF V600 status was the weakest prognostic biomarker (HR 1.5, 95% CI 0.44-5.2).