The fusion characteristics of RET fusion in pan-cancer among the Chinese population: A comprehensive genomic analysis

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.