Genomic landscape of microsatellite instability in Chinese tumors: A comparison of Chinese and TCGA cohorts

Abstract Microsatellite instability (MSI) is an important biomarker for predicting the response to immunotherapy and prognosis that mainly results from a defective DNA mismatch repair (MMR) system and strongly correlates with high tumor mutation burden (TMB). Herein, we developed a novel method that integrates MSI score, MMR mutation status and TMB level to identify MSI status from next‐generation sequencing (NGS) data. The novel method displays a sensitivity of 96.80%, a specificity of 99.96% and an overall accuracy of 99.89%, compared to current standards. Using our novel method, we analyzed 11 395 Chinese patients across 30 cancer types. High microsatellite instability (MSI‐H) was detected in 210 (1.84%) samples in 18 of 30 cancer types assessed. Mutations in ACVR2A (73%), KMT2D (68%), KMT2B (66%) and MMR‐related genes ( MLH1 , MSH2 , MSH6 and PMS2 ) were enriched in MSI‐H samples. Furthermore, MSI‐H samples were more likely to have high TMB ( P < .01), high PD‐L1 expression ( P < .05) and more tumor‐infiltrating immune cells than microsatellite‐stable (MSS) samples. Compared to the TCGA patients, the prevalence of MSI‐H in the Chinese cohort was significantly lower in colorectal, gastric and pancreatic cancer, while significantly higher in urinary and prostate cancer. Mutations in ACVR2A (73% vs 28%, P < .01) and MMR‐related genes (51.4% vs 21.3%, P < .01) were significantly higher in the Chinese population. Thus, our study suggests the fraction of MSI‐H attributable to MMR inactivation mutations were lower in European than in Chinese patients, while the proportion of MSI‐H due to other events may be higher.