Wang Shuhang, Li Qin, Ma Peiwen, Fang Yuan, Yu Yue, Jiang Ning, Miao Huilei, Tang Qiyu, Yang Yuqi, Xing Shujun, Chen Rongrong, Yi Xin, Li Ning
Clinical Cancer Centre, National Cancer Centre/National Clinical Research Centre for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
Geneplus-Beijing Institute, Beijing, China.
Front Mol Biosci. 2022 Mar 11;9:831382. doi: 10.3389/fmolb.2022.831382. eCollection 2022.
KRAS is the most commonly mutated oncogene in human cancers. Targeted therapy and immunotherapy for this gene have made remarkable progress in recent years. However, comprehensive molecular landscape analysis of KRAS in rare tumors is lacking. Retrospective analysis was performed on clinical samples from patients with rare tumors collected between September 2015 and September 2021, using hybrid-capture-based next-generation sequencing for genomic profiling and immunohistochemistry assay for PD-L1. Of the 3,453 patients included in analysis, KRAS mutations were identified in 8.7% patients in overall; mutation rate and mutation subtypes varied widely across tumor systems and subtypes. KRAS mutations included 21 missense mutations, of which G12D (29.2%), G12V (24.6%), and G13D (10.8%) were most common. Interestingly, KRAS G12C was observed in 0.6% patients overall, and in 5.7% of sarcomatoid carcinoma of the lung and 5.4% of clear cell ovarian cancer tumors, but none in small-bowel cancer tumors. 31.8% KRAS mutations and 36.4% KRAS G12C mutations co-occurred with other targetable alterations. No significant correlation was observed between TMB-H, MSI-H, PD-L1 status, and KRAS mutation status, which may be related to the high proportion of G12D. This study is the first KRAS mutation landscape study in rare tumors of large sample size in China and worldwide. Our results suggest that targeted therapy and immunotherapy are both feasible, albeit complex, in these patients. This information may have significant impact on the operation of clinical trials for rare tumor patients with KRAS mutations in China.
KRAS是人类癌症中最常见的突变癌基因。近年来，针对该基因的靶向治疗和免疫治疗取得了显著进展。然而，在罕见肿瘤中缺乏对KRAS的全面分子特征分析。对2015年9月至2021年9月期间收集的罕见肿瘤患者的临床样本进行回顾性分析，采用基于杂交捕获的下一代测序进行基因组分析，并采用免疫组织化学法检测PD-L1。在纳入分析的3453例患者中，总体上8.7%的患者检测到KRAS突变；不同肿瘤系统和亚型的突变率和突变亚型差异很大。KRAS突变包括21种错义突变，其中G12D（29.2%）、G12V（24.6%）和G13D（10.8%）最为常见。有趣的是，总体上0.6%的患者检测到KRAS G12C突变，在肺肉瘤样癌患者中该突变率为5.7%，在透明细胞卵巢癌患者中为5.4%，但在小肠癌患者中未检测到。31.8%的KRAS突变和36.4%的KRAS G12C突变与其他可靶向改变同时出现。未观察到肿瘤突变负荷高（TMB-H）、微卫星高度不稳定（MSI-H）、PD-L1状态与KRAS突变状态之间存在显著相关性，这可能与G12D的高比例有关。本研究是中国乃至全球首次针对大样本量罕见肿瘤的KRAS突变特征研究。我们的结果表明，在这些患者中，靶向治疗和免疫治疗虽然复杂，但都是可行的。这些信息可能会对中国KRAS突变的罕见肿瘤患者的临床试验开展产生重大影响。
