The analysis of BRAF fusions characteristics in Chinese solid tumor patients.

Abstract

e15073 Background: BRAF encodes a RAF kinase, which signal downstream of RAS and activate the MAPK pathway, and has emerged as a major oncogenic driver and a potential therapy target. BRAF V600E base substitution is an approved target for the BRAF inhibitors in solid tumors. BRAF gene fusions represent a different mechanism of BRAF activation. BRAF fusions have shown responses to MEK inhibitors and non-specific RAF inhibitors (eg, sorafenib) in Melanoma (NCCN). We sought to analysis of BRAF fusions characteristics in Chinese solid tumor patients to explore the possibility of therapeutic intervention in solid tumors. Methods: We comprehensively characterized BRAF fusions from next-generation sequencing (NGS) data from May 2019 to January 2023 in 80083 various solid tumors. Considering the characteristics of the receptor tyrosine kinase, we focused on the BRAF fusions which contain the kinase domain. Results: A total of 164 unique cases (70.1% (115/164) glioma and 29.9% (49/164) non-glioma with BRAF fusions) were identified. The non-glioma cohort consisted up mainly lung tumors (49%, 24/49), colorectal tumors (18.4%, 9/49), pancreatic tumors (10.2%,5/49), melanoma (9.2%, 4/49) and biliary tumors (4.1%, 2/49). In the glioma cohort, the median age of the 115 patients was 12 with a range of 0–66; 43 (37.4%) of the patients were female and 72 (62.6%) were male. On the other hand, the median age was 64 with a range of 33–82; 23 (46.9%) of the patients were female and 26 (53.10%) were male in the non-glioma cohort. In the glioma cohort, 82.4% of the partners were KIAA1549. However, the most common fusion partners were AGK (14.04%), TRIM24(14.0%), SND1(12.28%), TPK1(8.77%) in the non-glioma cohort. These BRAF fusions comprised 49 unique 5′ fusion partners, of which 51% (25) were known and 49.0% (24) were novel. 14 novel partners were TMEM176B, HMBOX1, SEMA3E, LOC441204, PDE4D, DENND2A, STIM1, TNS3, PRRC2B, BCR, MET, COL4A3BP, TPM4, ZBTB16 and 10 novel partners were intergenic region. 130 patients with BRAF fusions could be evaluated for concurrent mutations. Of interest is that no KRAS and BRAF V600E mutations were identified in the 130 cases. Conclusions: BRAF fusions were detected in 0.2% (164/80083) of Chinese solid tumor patients. 70.1% of BRAF fusion positive cases were diagnosed with glioma and 29.9% were diagnosed with non-glioma. 14 novel BRAF fusion partners were discovered. BRAF fusion is an important driver genomic alteration and occur in a mutually exclusive pattern with other activating mutations in the MAP kinase signaling pathway. BRAF fusion targeted therapies should be further explored in solid tumors.