克服SEPTIN14低表达以在RNA测序中检测EGFR-SEPTIN14融合

EGFR-SEPTIN14 fusion is a rare but clinically significant oncogenic event, occurring in approximately 3-4% of glioblastoma (GBM) cases. This fusion retains the tyrosine kinase domain of EGFR fused to the coiled-coil domain of SEPTIN14 but is often undetected by RNA sequencing (RNA-seq) due to minimal SEPTIN14 expression outside the testis. To overcome this limitation, we developed a novel detection approach that leverages soft-clipped reads mapped to EGFR with perfect matches to SEPTIN14 sequences, enabling detection even in the absence of SEPTIN14 transcript reads. Using this method, we identified EGFR-SEPTIN14 fusion in positive controls, samples with DNA-based evidence, and additional previously undetected cases in the SNUH cohort. These GBM samples exhibited characteristic oncogenic mutation profiles, including TERT promoter mutation, EGFR amplification, and CDKN2A/B deletions, which may as markers indirectly indicating fusion presence. Notably, one fusion-positive patient treated with erlotinib showed a partial response, suggesting potential sensitivity to EGFR tyrosine kinase inhibitors. Application of our approach to the TCGA-GBM dataset also identified novel positive samples with similar mutation profiles, demonstrating scalability to whole transcriptome data. Overall, our strategy increased detection sensitivity 66.7%, addressing a key limitation of current RNA-seq fusion detection tools and supporting recognition of EGFR-SEPTIN14 fusion as an additional actionable oncogenic driver in solid tumors.