Journal
INTERNATIONAL JOURNAL OF CANCER
Volume 151, Issue 8, Pages 1382-1393Publisher
WILEY
DOI: 10.1002/ijc.34119
Keywords
microsatellite instability; mismatch repair; next-generation sequencing; tumor mutation burden
Categories
Funding
- Beijing Municipal Administration of Hospitals' Youth Program [QML20171107]
- Capital's Funds for Health Improvement and Research [2018-2-1023]
- National Natural Science Foundation of China [31870805, 81502643, 82073312]
- Science Foundation of Peking University Cancer Hospital [2022-1]
- Third Round of Public Welfare Development and Reform Pilot Projects of Beijing Municipal Medical Research Institutes [2019-1]
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A novel method combining MSI score, MMR mutation status and TMB level was developed to identify MSI status from NGS data. High MSI was found in 1.84% of samples across 30 cancer types in Chinese patients, and was associated with high TMB, PD-L1 expression and tumor-infiltrating immune cells.
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.
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