Comprehensive analysis of BRCA1/2 mutations, "BRCAness" and PARP inhibitors in melanoma

The BRCA1 and BRCA2 genes encode critical proteins in the homologous recombination (HR) DNA repair pathway. While their role in hereditary breast and ovarian cancer syndromes is well established, recent evidence suggests a more nuanced role in other malignancies, including melanoma, where homologous recombination deficiency (HRD) occurs in 18-57 % of cases. This review is the first to comprehensively synthesize current findings on epidemiology and molecular mechanisms, while investigating potential predictive biomarkers, diagnostic implications, and therapeutic relevance of BRCA1/2 mutations in melanoma. We conducted an in-depth analysis of risk ratio (RR) in individuals with BRCA1 and BRCA2 mutations separately, across both traditionally linked cancers and various skin cancer types. Particular focus was given to melanoma, critically evaluating conflicting evidence suggesting a risk ratio ranging from 1.44 to 3.31, with variation between BRCA1 and BRCA2 carriers. Importantly, we explore the concept of "BRCAness" in melanoma-the phenotypic state where tumors display HR repair defects similar to BRCA-mutant cancers despite lacking BRCA1/2 alterations-alongside its predictive and therapeutic value. We assess the clinical promise of PARP inhibitors in common melanoma subtypes, both as monotherapy and combined with immunotherapy, alkylating agents, and MAPK-targeting agents. Resistance mechanisms, hematologic and gastrointestinal toxicities, and financial disparities are discussed as barriers to sustained treatment. Understanding the intersection of homologous recombination dysfunction and melanoma biology may refine diagnostic stratification, enhance prognostic accuracy, and enable rational integration of PARP inhibitors and targeted therapies into future treatment paradigms for melanoma patients.