Zhao Yi, Du Ruo, Chen Mingcong, Chen Zhiwei
Shanghai Lung Cancer Center, Shanghai Chest Hospital, Shanghai Jiaotong University, Shanghai 200030, China.
Department of thoracic radiotherapy, Taizhou Cancer Hospital, Zhejiang Cancer hospital Taizhou Branch, the University of Chinese Academy of Sciences, 317502, China.
Transl Oncol. 2025 May;55:102384. doi: 10.1016/j.tranon.2025.102384. Epub 2025 Apr 3.
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.
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.
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.
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.
RET融合是重要的致癌驱动因素，由RET原癌基因与各种伙伴基因的染色体重排产生。了解其结构特征对于阐明致癌潜力和开发靶向治疗至关重要。
本研究使用DNA或RNA靶向的下一代测序（NGS）分析了来自中国泛癌队列的21023份肿瘤样本和3716份外周血样本。19668份组织进行了基于DNA的融合检测，1355份非小细胞肺癌（NSCLC）组织使用733基因面板进行了基于RNA的融合检测。还对血液样本进行了基于循环肿瘤DNA（ctDNA）的靶向NGS。
在1.027%的组织样本中检测到RET融合，主要见于肺癌和甲状腺癌。与西方人群（内含子11中占87%）相比，中国患者的融合倾向于外显子10 - 11区域，内含子10中占30.79%。RET重排分为四类（简单相互倒位、共融合、单融合-常见、单融合-罕见），具有独特的突变谱和肿瘤突变负荷评分。基于RNA的NGS显示，一些基于DNA检测到的重排可能不会发生转录，而共融合表明可能同时转录多个RET融合。一名患有KIF5B-RET和ATRNL1-RET共融合的NSCLC患者接受RET靶向治疗后无进展生存期达15个月。
本研究强调了结构洞察对于开发针对RET融合驱动癌症的靶向治疗的重要性，并突出了进一步研究复杂RET融合机制以更好理解RET驱动的肿瘤发生的必要性。
