Unraveling <i>BRAF</i> alterations: molecular insights to circumvent therapeutic resistance across cancer types

<b>Aim:</b> As intrinsic resistance - often driven by concurrent genomic alterations in tumor suppressor genes or oncogenes - remains a major challenge in oncology, this work aimed to comprehensively analyze <i>BRAF</i> somatic alterations across cancer types and identify new potential therapeutic strategies to overcome drug resistance. <b>Methods:</b> We conducted an extensive analysis of genomics, transcriptomics, and clinical data retrieved from public repositories, including cBioPortal. Our comprehensive analysis examined <i>BRAF</i> alterations [point mutations, structural variants (SVs) and copy number alteration] in more than 217,000 tumor samples across 120 distinct tumor types from primary and metastatic sites in both adult and pediatric cohorts, focusing on mutual exclusivity and co-occurrence of mutations in other oncogenes or tumor suppressors. The work also explores the association of <i>BRAF</i> somatic alterations with survival, clinical and molecular features. <b>Results:</b> Analysis of mutation frequencies across cancer types revealed that BRAFV600E represents approximately 90% of all <i>BRAF</i> alterations. While melanoma and thyroid carcinoma show the highest prevalence of <i>BRAF</i> mutations, followed by colorectal and non-small cell lung cancer in terms of absolute number of patients harboring <i>BRAF</i> mutations worldwide, notably high mutation frequencies were identified in rare malignancies, including hairy-cell leukemia, ganglioglioma, and serous borderline ovarian tumors. The comprehensive analysis of genomic profiling data across these tumors uncovered distinct patterns of co-occurring and mutually exclusive alterations in oncogenes and tumor suppressor genes, illuminating resistance mechanisms and suggesting novel therapeutic combinations. <b>Conclusion:</b> Comprehensive genomic profiling is critical for optimizing targeted therapy and overcoming drug resistance in <i>BRAF</i>-mutated cancers. The identification of co-occurring alterations provides opportunities for rational combination therapies, emphasizing the importance of detailed mutation profiling in developing effective treatment strategies across diverse cancer types.