The clinical, genomic, and transcriptomic landscape of BRAF mutant cancers

Abstract Background BRAF mutations are classified into 4 molecularly distinct groups, and Class 1 (V600) mutant tumors are treated with targeted therapies. Effective treatment has not been established for Class 2/3 or BRAF Fusions. We investigated whether BRAF mutation class differed according to clinical, genomic, and transcriptomic variables in cancer patients. Methods Using the AACR GENIE (v.12) cancer database, the distribution of BRAF mutation class in adult cancer patients was analyzed according to sex, age, primary race, and tumor type. Genomic alteration data and transcriptomic analysis was performed using The Cancer Genome Atlas. Results BRAF mutations were identified in 9515 (6.2%) samples among 153,834, with melanoma (31%), CRC (20.7%), and NSCLC (13.9%) being the most frequent cancer types. Class 1 harbored co-mutations outside of the MAPK pathway (TERT, RFN43) vs Class 2/3 mutations (RAS, NF1). Across all tumour types, Class 2/3 were enriched for alterations in genes involved in UV response and WNT/β-catenin. Pathway analysis revealed enrichment of WNT/β-catenin and Hedgehog signaling in non-V600 mutated CRC. Males had a higher proportion of Class 3 mutations vs. females (17.4% vs 12.3% q = 0.003). Non-V600 mutations were generally more common in older patients (aged 60+) vs younger (38% vs 15% p<0.0001), except in CRC (15% vs 30% q = 0.0001). Black race was associated with non-V600 BRAF alterations (OR: 1.58; p<0.0001). Conclusions Class 2/3 BRAF are more present in Black, male patients with co-mutations outside of the MAPK pathway, likely requiring additional oncogenic input for tumorigenesis. Improving access to NGS and trial enrollment will help development of targeted therapies for non-V600 BRAF mutations. Statement of Translational Relevance BRAF mutations are classified in 4 categories based on molecular characteristics, but only Class 1 BRAF V600 have effective targeted treatment strategies. With increasing access to next-generation sequencing, oncologists are more frequently uncovering non-V600 BRAF mutations, where there remains a scarcity of effective therapies. Responsiveness to MAPK pathway inhibitors differs according to BRAF mutation class and primary tumor type. For this reason, we sought to determine whether key demographic, genomic, and transcriptomic differences existed between classes. This cross-sectional study analyzes the largest dataset of BRAF-mutated cancers to date. Our findings propose insights to optimize clinical trial design and patient selection in the pursuit of developing effective treatment strategies for patients whose tumors harbor non-V600 BRAF mutations. This study also offers insights into the potential of targeting alternative pathways in addition to the MAPK pathway as part of combinatorial treatment strategies.