Correlation between MSI, TMB, and RAS gene mutation in solid tumors.

Abstract

2624 Background: RAS gene family encodes a protein that is a member of the small GTPase super family and plays an important role in the regulation of cell proliferation and promoting oncogenic events. Studies have reported that RAS gene shows a high mutation frequency in lung cancer, colorectal cancer and pancreatic cancer. However, the relation between RAS-mutant and RAS-wild type tumors in tumor mutation burden (TMB) and microsatellite instability (MSI) remain unclear in pan-cancer. Methods: We retrospectively analyzed 15188 Chinese patients with pan-cancer from laboratory of Simcere Diagnosis (Nanjing, China) during 2019-2021. Somatic mutations in tumor samples were assessed by next-generation sequencing (NGS). We evaluated RAS (KRAS, NRAS and HRAS) mutation frequency, TMB and MSI in RAS-mutant and RAS wild-type tumors. Results: RAS mutations were detected in 2663 (17.5%) samples, including 88.7% of KRAS mutations, 9.1% of NRAS mutations and 3.5% of HRAS mutations. The top 6 frequently cancers were colorectal cancer (829, 31.1%), lung cancer (747, 28.1%), pancreatic cancer (358, 13.4%), biliary tract cancer (210, 7.9%), liver cancer (78, 2.9%), and gastric cancer (73, 2.7%). We found that the incidence of MSI-H in patients with RAS-mutant solid tumors was 3.3% and the frequency of MSI-H was significantly higher in RAS-mutant gastric cancer than that in RAS wild-type (RAS-MUT vs RAS-WT, 20.5% vs 3.5%, p < 0.001). Contrary to our assumption, it was not observed in colorectal cancer (RAS-MUT vs RAS-WT, 5.8% vs 6.9%). In the analysis of TMB, RAS gene mutation was associated with higher TMB (P < 0.01). 27.4% of RAS-mutant gastric cancer and 10.8% RAS wild-type gastric cancer were classified as TMB-H (TMB ≥10 muts/Mb) (P＜0.01), while 13.4% of RAS-mutant colorectal cancer was TMB-H, with no significant difference between RAS wild-type. However, we did not observe a close association between MSI, TMB and RAS gene mutations in lung cancer, pancreatic cancer, biliary tract cancer, and liver cancer. Conclusions: We analyzed RAS gene mutations in Chinese patients with solid tumor. Our data showed that RAS mutations were associated with TMB-H and MSI-H in solid tumors, especially gastric cancer. In colorectal cancer, RAS mutations were associated with higher TMB, but not TMB-H. It was showed that RAS mutations in specific cancer types, such as gastric cancer and colorectal cancer, may be related to the efficacy of immunotherapy.