Variant-Specific Landscape of Mutual Exclusivity Among BRAF, EGFR, and KRAS Oncogenes in Human Cancer

In this cross-sectional study, we report the findings of our investigation into the mutual exclusivity (ME) and co-occurrence (CO) patterns of BRAF, KRAS, and EGFR mutations in human cancer. Our analysis acknowledges previously overlooked mutational subtypes with distinct clinical implications. Creating an automated R framework, we analyzed mutation data from 64807 unique cBioPortal samples, 1570 cell lines, and 2714 unique Belgian cancer samples. Consistently, across all three datasets, we observe that co-occurrence is less likely among class I BRAF, Hydrolysis KRAS, and Classical-like EGFR mutations. Bilateral variant-assigned CO matrices uncover novel inter-class and inter-type CO and ME scenarios, encompassing conventional and atypical mutations. Besides Class I BRAF, various mutation classes exhibit diverse CO patterns, justifying the need to refine mutational classifications. We provide a variant-specific database for precision oncology showcasing ME among three actionable oncogenes. These findings may guide the discovery of novel synthetically lethal interactions for targeted cancer therapy.