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. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement The work performed by the Centre for Human Genetics (Belgium) was co-funded by the Wetenschappelijk Fonds Willy Gepts of the UZ Brussel/VUB and the UZ Brussel Foundation. Oleg Timofeev had received the following: The Federal Ministry of Education and Research (BMBF) grant 161L0279A and German Research Foundation (DFG) grant Ti1028/2-1. Maxim Noeparast had receivedFonds Wetenschappelijk Onderzoek (FWO) -Vlaanderen, Belgium 12Y0120N. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Ethical approval was obtained by the Medical Ethics Committee of UZ Brussel/VUB for studying NGS data from Belgian diagnostic cancer patients (EC-2023-040). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes The R script developed during this study can be found at .