Abstract A20: Identification of new promising germline variants in melanoma-prone patients

Background: Melanoma is a highly aggressive skin cancer; approximately 10% of melanomas are caused by germline mutations, mainly affecting the p16 isoform of the CDKN2A gene (responsible for up to 40% of the familial melanoma). Other genes exhibiting moderate- to high-penetrant mutations have been recently associated with melanoma susceptibility but in low frequency. Therefore, the majority of the melanoma-prone patients remain without the identification of genetic etiology. Objective: In order to find new genes potentially related to melanoma predisposition, we performed whole-exome sequencing of 10 affected individuals from 5 unrelated families. All patients were negative for CDKN2A/CDK4/TERT promoter/MITF (E318K) mutations. Materials and Methods: Melanoma-prone patients were ascertained based on either the classical criteria for familial melanoma syndrome or based on evidence of a strong genetic predisposition (occurrence of ≥2 primary melanomas). Whole-exome sequencing was performed using the Ion Proton Sequencer (Life Technologies). Our experimental design was performed using at least 20x each base pair sequencing as confidence pattern and the most interesting variants were prioritized, when identified on the two probands from the same family, using the VarSeq software 1.4.2. Once we obtained the most interesting germline rare variants we designed a panel for the validation of these variants through the target sequencing (Ion Proton Thermo Fisher Scientific Inc). Results: We identified 214 rare nonsynonymous variants. We selected a set with 63 rare germline variants potentially damaging the protein function and associated to important cellular pathways to perform validation (4 LoF variants classified as frameshift). All variants were validated by resequencing using probes specifically designed for the rare selected variants; some of them already associated to melanoma, skin pigmentation, melanoma, and/or cancer susceptibility. Conclusion: This study provides new knowledge about melanoma predisposition in the Brazilian population, in which the risk is smaller to develop this disease than in other populations, and also highlighted possible new risk factor or predisposition genes for hereditary melanoma syndrome. Citation Format: Felipe Fidalgo, Luciana Facure, Bruna Barros, Renan Valieris, Giovana Torrezan, Bianca de Sa, Amanda Nobrega, Maria Isabel Achatz, Joao Duprat, Carla Rosenberg, Sandro Souza, Ana Krepischi, Dirce Maria Carraro. Identification of new promising germline variants in melanoma-prone patients [abstract]. In: Proceedings of the AACR International Conference held in cooperation with the Latin American Cooperative Oncology Group (LACOG) on Translational Cancer Medicine; May 4-6, 2017; Sao Paulo, Brazil. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(1_Suppl):Abstract nr A20.