Abstract
BACKGROUND: RET fusions are significant oncogenic drivers, resulting from chromosomal rearrangements of the RET proto-oncogene with various partner genes. Understanding their structural characteristics is crucial for elucidating oncogenic potential and developing targeted therapies. METHODS: This study analyzed 21,023 tumor samples and 3716 peripheral blood samples from a Chinese pan-cancer cohort using DNA or RNA-targeted next-generation sequencing (NGS). 19,668 tissues underwent DNA-based fusion detection and 1355 NSCLC tissues underwent RNA-based fusion detection using a 733-gene panel. ctDNA-based targeted NGS was also performed on blood samples. RESULTS: RET fusions were detected in 1.027 % of tissue samples, predominantly lung and thyroid cancers. Compared to Western populations (87 % in intron 11), Chinese patients show a shift toward the exon 10-11 region, with 30.79 % in intron 10. RET rearrangements were classified into four categories (Simple Reciprocal Inversion, Co-Fusion, Single Fusion-Common, Single Fusion-Rare) with unique mutational profiles and tumor mutational burden scores. RNA-based NGS revealed some DNA-detected rearrangements might not undergo transcription, while Co-Fusion indicated potential simultaneous transcription of multiple RET fusions. An NSCLC patient with KIF5B-RET and ATRNL1-RET co-fusions achieved 15-month progression-free survival on RET-targeted therapy. CONCLUSION: This study underscores the importance of structural insights for developing targeted therapies against RET fusion-driven cancers and highlights the need for further investigation into complex RET fusion mechanisms to better understand RET-driven oncogenesis.