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Increased genetic risk for melanoma can occur in the context of germline pathogenic variants in high-penetrance genes, such as CDKN2A and CDK4 , risk variants in low- to moderate-penetrance genes ( MC1R and MITF ), and possibly due to variants in emerging genes, such as ACD , TERF2IP, and TERT . We aimed to identify germline variants in high- and low- to moderate-penetrance melanoma risk genes in Brazilian patients with clinical criteria for familial melanoma syndrome. We selected patients with three or more melanomas or melanoma patients from families with three tumors (melanoma and pancreatic cancer) in first- or second-degree relatives. Genetic testing was performed with a nine-gene panel ( ACD , BAP1 , CDK4 , CDKN2A , POT1 , TERT , TERF2IP , MC1R, and MITF ). In 36 patients, we identified 2 (5.6%) with germline pathogenic variants in CDKN2A and BAP1 and 4 (11.1%) with variants of uncertain significance in the high-penetrance genes. MC1R variants were found in 86.5%, and both red hair color variants and unknown risk variants were enriched in patients compared to a control group. The low frequency of germline pathogenic variants in the high-penetrance genes and the high prevalence of MC1R variants found in our cohort show the importance of the MC1R genotype in determining the risk of melanoma in the Brazilian melanoma-prone families.

Genetic predisposition accounts for nearly 10% of all melanoma cases and has been associated with a dozen moderate- to high-penetrance genes, including CDKN2A, CDK4, POT1 and BAP1. However, in most melanoma-prone families, the genetic etiology of cancer predisposition remains undetermined. The goal of this study was to identify rare genomic variants associated with cutaneous melanoma susceptibility in melanoma-prone families. Whole-exome sequencing was performed in 2 affected individuals of 5 melanoma-prone families negative for mutations in CDKN2A and CDK4, the major cutaneous melanoma risk genes. A total of 288 rare coding variants shared by the affected relatives of each family were identified, including 7 loss-of-function variants. By performing in silico analyses of gene function, biological pathways, and variant pathogenicity prediction, we underscored the putative role of several genes for melanoma risk, including previously described genes such as MYO7A and WRN, as well as new putative candidates, such as SERPINB4, HRNR, and NOP10. In conclusion, our data revealed rare germline variants in melanoma-prone families contributing with a novel set of potential candidate genes to be further investigated in future studies., Competing Interests: The authors have declared that no competing interests exist.

Background: BRCA1 associated-protein 1 (BAP1) tumor predisposition syndrome is associated with an increased risk for malignant mesotheliomas, uveal and cutaneous melanomas, renal cell carcinomas, and singular cutaneous lesions. The latter are referred to as BAP1-inactivated melanocytic tumors (BIMTs). When multiple BIMTs manifest, they are considered potential markers of germline BAP1 mutations., Case Presentation: Here, we report a novel pathogenic BAP1 germline variant in a family with a history of BIMTs, cutaneous melanomas, and mesotheliomas. We also describe singular pathological aspects of the patient's BIMT lesions and their correlation with dermoscopic and reflectance confocal microscopy findings., Conclusions: This knowledge is crucial for the recognition of BIMTs by dermatologists and pathologists, allowing the determination of appropriate management for high-risk patients, such as genetic investigations and screening for potentially aggressive tumors.

Aim: This work evaluates a possible causative role for germline copy number variants (CNVs) in melanoma predisposition., Patients & Methods: A total of 41 melanoma-prone Brazilian patients were investigated for CNVs using 850K single nucleotide polymorphism arrays., Results: Ten rare CNVs were identified in nine patients, comprising 54 known genes, mostly related to cancer. In silico analyses revealed gene enrichment for cellular development and growth, and proliferation, highlighting five genes directly associated with the melanoma phenotype (ANGPT1, IDH1, PDE5A, HIST1H1B and GCNT2)., Conclusion: Patients harboring rare CNVs exhibited a decreased age of disease onset, in addition to an overall higher skin cancer predisposition. Our findings suggest that rare CNVs contribute to melanoma susceptibility, and should be taken into account when investigating cancer risk factors.

Melanoma and pancreatic cancer are two low frequency types of cancer. In this study, three patients who developed both melanoma and intraepithelial neoplasia of the pancreas were tested for CDKN2A mutations and deletions, and investigated for rare germline copy number variations (CNVs). The three patients were negative for CDKN2A point mutations and intragenic deletions. One of these patients carried two large (>300 kb) germline CNVs, both genomic duplications affecting coding sequences that are not copy number variable in the population. A second patient exhibited loss of the entire Y chromosome, an event probably coincidental related to his advanced age (79 years-old). Our data pinpoint that rare germline CNVs harboring genes can contribute to the cancer predisposition of melanoma and intraepithelial neoplasia of the pancreas., (Copyright © 2014. Published by Elsevier Inc.)