Feng Junnan, Li Yan, Wei Bing, Guo Lei, Li Weihua, Xia Qingxin, Zhao Chengzhi, Zheng Jiawen, Zhao Jiuzhou, Sun Rui, Guo Yongjun, Brcic Luka, Hakozaki Taiki, Ying Jianming, Ma Jie
Department of Molecular Pathology, Clinical Pathology Center, The Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China.
Henan Key Laboratory of Molecular Pathology, Zhengzhou, China.
Transl Lung Cancer Res. 2022 Apr;11(4):617-631. doi: 10.21037/tlcr-22-202.
Rearranged during transfection () rearrangement has been identified as one of the crucial oncogenic drivers in non-small cell lung cancer (NSCLC). Recently, two highly selective inhibitors have been approved by the US Food and Drug Administration and demonstrated remarkable responses. However, the clinical characteristics, outcomes and optimal diagnostic method of -rearrangements are not well understood. This study sought to evaluate the prevalence and characteristics of rearrangement, identify an effective diagnostic method for it, and correlate its presence with outcomes.
A total of 9,431 Chinese NSCLCs from two cancer centers who have undertaken targeted DNA-NGS were enrolled and 167 -positive cases were screened. Non-canonical rearrangements were confirmed by targeted RNA-NGS. If material was sufficient, positive cases were analyzed by fluorescence in situ hybridization (FISH) (n=30) and immunohistochemistry (IHC) (n=57). Clinicopathologic characteristics, molecular profiling and treatment outcomes of rearrangement were evaluated.
The prevalence of rearrangement was 1.52% (138/9,101) in unfiltered cases and 8.79% (29/330) in ///-negative cases. rearrangement was common in females, never smokers, and lung adenocarcinoma patients. Additionally, 40.3% of stage IV -rearranged NSCLC patients developed brain metastases. was the most common concurrent mutation, and 8 patients harbored concurrent driver oncogenic alterations, including (N=5), (N=2), and (N=1). Non-canonical fusion partners were identified in 13.8% (23/167) of cases by DNA-based NGS, and RNA-based NGS identified 3 new partners (, , and ). The concordance of FISH and NGS was 83.3% (25/30), while the concordance of IHC and NGS was only 28.1% (16/57). Both IHC and FISH demonstrated lower sensitivity for /other- fusions. The subgroup had significantly longer progression-free survival than the subgroup, both after chemotherapy (23 9.7 months; P=0.014).
rearrangement occurs in 1.52% of Chinese NSCLCs and has identifiable clinicopathologic characteristics. IHC has a low sensitivity, disavowing its use in routine practice. While NGS and FISH has good performance in identifying rearrangement. Both IHC and FISH demonstrated lower sensitivity for /others- fusions. Clinical benefit with chemotherapy is different between - and fusion patients, optimal treatment should be considered when selecting therapies for patients with -rearranged lung cancers.
转染重排（RET）重排已被确定为非小细胞肺癌（NSCLC）中关键的致癌驱动因素之一。最近，两种高度选择性RET抑制剂已获美国食品药品监督管理局批准，并显示出显著疗效。然而，RET重排的临床特征、结局及最佳诊断方法尚不清楚。本研究旨在评估RET重排的发生率及特征，确定其有效诊断方法，并将其存在情况与结局相关联。
纳入来自两个癌症中心的9431例接受靶向DNA二代测序（NGS）的中国NSCLC患者，并筛选出167例RET阳性病例。通过靶向RNA-NGS确认非经典RET重排。若材料充足，对阳性病例进行荧光原位杂交（FISH）分析（n=30）和免疫组织化学（IHC）分析（n=57）。评估RET重排的临床病理特征、分子图谱及治疗结局。
未筛选病例中RET重排的发生率为1.52%（138/9101），在///阴性病例中为8.79%（29/330）。RET重排在女性、从不吸烟者及肺腺癌患者中常见。此外，40.3%的IV期RET重排NSCLC患者发生脑转移。KRAS是最常见的共发突变，8例患者存在共发驱动致癌改变，包括KRAS（N=5）、NRAS（N=2）和BRAF（N=1）。基于DNA的NGS在13.8%（23/167）的病例中鉴定出非经典融合伴侣，基于RNA的NGS鉴定出3个新伴侣（SLC4A1、FAM131B和MAGI2）。FISH与NGS的一致性为83.3%（25/30），而IHC与NGS的一致性仅为28.1%（16/57）。IHC和FISH对RET/其他融合的敏感性均较低。RET亚组化疗后的无进展生存期明显长于非RET亚组（23对9.7个月；P=0.014）。
RET重排在1.52%的中国NSCLC患者中发生，具有可识别的临床病理特征。RET IHC敏感性低，不适合在常规实践中使用。而NGS和FISH在鉴定RET重排方面表现良好。IHC和FISH对RET/其他融合的敏感性均较低。RET融合和非RET融合患者化疗的临床获益不同，为RET重排肺癌患者选择治疗方案时应考虑最佳治疗方法。
