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 somatic alterations across cancer types and identify new potential therapeutic strategies to overcome drug resistance. We conducted an extensive analysis of genomics, transcriptomics, and clinical data retrieved from public repositories, including cBioPortal. Our comprehensive analysis examined 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 somatic alterations with survival, clinical and molecular features. Analysis of mutation frequencies across cancer types revealed that BRAFV600E represents approximately 90% of all alterations. While melanoma and thyroid carcinoma show the highest prevalence of mutations, followed by colorectal and non-small cell lung cancer in terms of absolute number of patients harboring 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. Comprehensive genomic profiling is critical for optimizing targeted therapy and overcoming drug resistance in -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.