Background: Melanoma is a highly heterogeneous neoplasia in which transcriptional profile encodes much of the biological diversity that determines tumor progression and therapeutic response. To refine its molecular stratification and profiles characterization, we conducted an in silico transcriptomic analysis. Methods: Public microarray datasets from the GEO and ArrayExpress were examined, and the E-MTAB-6697 expression dataset was selected. We used a K-Means clustering algorithm to stratify 194 tumor samples into expression-driven subgroups and analyzed each one to define their transcriptional and biological profiles. Differential expression analysis between identified clusters and controls was performed. Additionally, we applied Weighted-Gene correlation analysis to identify coordinated expression hubs in the tumor dataset and tested the resulting modules for correlation with the identified clusters. Results: Unsupervised clustering of melanoma transcriptomic profiles identified three distinct molecular subtypes characterized by divergent biological programs. While all clusters shared the dysregulation of pathways involved in epidermal differentiation, immune response, and lipid metabolism, they diverged in proliferation, phenotypic plasticity, metabolic adaptation, and apoptotic regulation. Cluster A was characterized by enrichment in DNA replication, repair, and mitochondrial metabolism modules, suggesting a proliferative yet genomically stable state. Cluster B showed enrichment in immune and cytokine signaling pathways alongside reduced proliferative activity, consistent with a quiescent or transitional phenotype. Cluster C displayed coordinated enrichment in cell-cycle, DNA-maintenance, and neuroectodermal reprogramming pathways, indicating a highly plastic and proliferative subtype. Despite these molecular distinctions, all clusters retained an “immunologically hot” profile (IPS 7–8), indicating potential responsiveness to immunotherapy. Conclusions: These findings provide an overview of the functional characteristics of melanoma heterogeneity and identify biological processes that could be targeted by drugs for the development of tailored therapies for each subtype. Nevertheless, future studies in independent clinically annotated cohorts would be required.

Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal malignancies, with a rising incidence and a poor prognosis that largely reflects late-stage diagnosis. Although most cases are sporadic, approximately 5–10% of PDACs occur in the context of inherited cancer susceptibility, including hereditary pancreatic cancer (HPC) syndromes and familial pancreatic cancer (FPC). Germline pathogenic variants in genes involved in DNA damage repair, cell-cycle regulation, and genomic stability—such as BRCA1, BRCA2, PALB2, ATM, CDKN2A, STK11, mismatch repair genes, and TP53—contribute to PDAC risk and may influence disease biology. This review provides an overview of the genetic landscape of hereditary and FPC, focusing on established cancer predisposition syndromes and emerging susceptibility genes. Current evidence regarding the prevalence, penetrance, and clinical relevance of germline pathogenic variants (PGVs) is summarized, together with the challenges associated with identifying individuals at increased risk. Contemporary recommendations for germline genetic testing, including the use of multigene panel approaches and limitations in real-world implementation, are also discussed. In addition, surveillance strategies for PDAC in high-risk individuals (HRI) are reviewed, and the available data on the outcomes and limitations of surveillance programs are examined. Finally, the therapeutic implications of inherited alterations, particularly in DNA repair-deficient PDAC, are outlined with reference to genotype-informed systemic treatment approaches.

Background: Sotorasib, a KRAS G12C inhibitor, is approved for treating non-small cell lung cancer (NSCLC) and has shown a distinct safety profile in randomized clinical trials (RCTs). However, post-marketing pharmacovigilance is crucial to identify real-world safety signals including sex-specific differences that may not be evident in controlled trial settings. Methods: This analysis reviewed 845 individual case safety reports (ICSRs) from the EudraVigilance (EV) database between 1 January 2021, and 8 April 2025, involving NSCLC patients treated with sotorasib. Adverse drug reactions (ADRs) were assessed by sex, seriousness, outcome, and system organ class (SOC). Disproportionality analyses were conducted to detect sex-specific safety signals, and results were compared with data from the CodeBreaK200 RCT by using a two-proportion z-test. Results: Among the ICSRs, 49.2% involved male and 40.1% female patients. Serious ADRs accounted for 47.5% of cases, with females at higher risk (relative risk [RR] = 1.31; 95% confidence interval (CI): 1.22–1.40; p < 0.0001). The most frequently reported SOCs were neoplasms (15.8%), gastrointestinal disorders (15.3%), and hepatobiliary disorders (11.5%). Four sex-specific safety signals were identified: women had a significantly increased risk of cholestasis (RR = 3.37) and hepatotoxicity (RR = 3.01), while men were less likely to report decreased appetite (RR = 0.20) and rash (RR = 0.14). Real-world data showed lower reporting of diarrhea, fatigue, nausea, and liver enzyme elevations (p < 0.0001). Conclusions: Real-world pharmacovigilance supports the RCT findings and highlights sex-specific risks, thus emphasizing the importance of sex-aware monitoring and personalized toxicity management.