Table_1_Concurrent RAS and RAS/BRAF V600E Variants in Colorectal Cancer: More Frequent Than Expected? A Case Report.docx

The assessment of RAS and BRAF mutational status is one of the main steps in the diagnostic and therapeutic algorithm of metastatic colorectal cancer (mCRC). Multiple mutations in the BRAF and RAS pathway are described as a rare event, with concurrent variants in KRAS and BRAF genes observed in approximately 0.05% of mCRC cases. Here, we report data from a case series affected by high-risk stage III and stage IV CRC and tested for RAS and BRAF mutation, treated at our Medical Oncology Unit. The analysis of KRAS, NRAS (codons 12, 13, 59, 61, 117, 146), and BRAF (codon 600) hotspot variants was performed in 161 CRC tumors from August 2018 to September 2021 and revealed three (1.8%) patients showing mutations in both KRAS and BRAF (V600E), including two cases with earlier CRC and one with metastatic disease. We also identified one patient (0.6%) with a mutation in both KRAS and NRAS genes and another one (0.6%) with a double KRAS mutation. Notably, the latter was characterized by aggressive behavior and poor clinical outcome. The mutational status, pathological features, and clinical history of these five CRC cases are described. Overall, this study case series adds evidence to the limited available literature concerning both the epidemiological and clinical aspects of CRC cases characterized by the presence of concurrent RAS/BRAF variants. Future multicentric studies will be required to increase the sample size and provide additional value to results observed so far in order to improve clinical management of this subgroup of CRC patients.

RAS与BRAF基因突变状态评估是转移性结直肠癌（metastatic colorectal cancer, mCRC）诊疗流程中的核心步骤之一。BRAF及RAS通路的多重突变属于罕见事件，其中KRAS与BRAF基因共突变在约0.05%的mCRC病例中被观测到。本研究报告了2018年8月至2021年9月期间，于我科肿瘤内科就诊的161例高危III期及IV期结直肠癌患者的相关数据，所有受试者均接受了RAS与BRAF基因突变检测。本研究对KRAS、NRAS（密码子12、13、59、61、117、146）及BRAF（密码子600）的热点突变进行分析后，共发现3例（占比1.8%）患者同时携带KRAS与BRAF（V600E）突变，其中2例为早期结直肠癌患者，1例为转移性结直肠癌患者。此外，本研究还检出1例（0.6%）同时携带KRAS与NRAS基因突变的患者，以及1例（0.6%）携带双KRAS突变的患者。值得注意的是，该双KRAS突变患者表现出侵袭性临床行为与不良预后。本研究对这5例结直肠癌患者的基因突变状态、病理特征及临床病史进行了详细描述。总体而言，本病例系列研究为现有关于携带共突变RAS/BRAF变异的结直肠癌患者的流行病学与临床特征的有限文献补充了新证据。未来需开展多中心研究以扩大样本量，进一步验证现有研究结果，从而优化该亚型结直肠癌患者的临床诊疗管理。