Large-Scale Cancer Genomic Analysis Reveals Significant Disparities between Microsatellite Instability and Tumor Mutational Burden

Abstract Background: Microsatellite instability (MSI) and tumor mutational burden (TMB) are predictive biomarkers for pan-cancer immunotherapy. The interrelationship between MSI-high (MSI-H) and TMB-high (TMB-H) in human cancers and their predictive value for immunotherapy in lung cancer remain unclear. Methods: We analyzed somatic mutation data from the Genomics Evidence Neoplasia Information Exchange (n = 46,320) to determine the relationship between MSI-H and TMB-H in human cancers using adjusted multivariate regression models. Patient survival was examined using the Cox proportional hazards model. The association between MSI and genetic mutations was assessed. Results: Patients (31–89%) with MSI-H had TMB-low phenotypes across 22 cancer types. Colorectal and stomach cancers showed the strongest association between TMB and MSI. TMB-H patients with lung cancer who received immunotherapy exhibited significantly higher overall survival [HR, 0.61; 95% confidence interval (CI), 0.44–0.86] and progression-free survival (HR, 0.65; 95% CI, 0.47–0.91) compared to the TMB-low group; no significant benefit was observed in the MSI-H group. Patients with TMB and MSI phenotypes showed further improvement in overall survival and PFS. We identified several mutated genes associated with MSI-H phenotypes, including known mismatch repair genes and novel mutated genes, such as ARID1A and ARID1B. Conclusions: Our results demonstrate that TMB-H and/or a combination of MSI-H can serve as biomarkers for immunotherapies in lung cancer. Impact: These findings suggest that distinct or combined biomarkers should be considered for immunotherapy in human cancers because notable discrepancies exist between MSI-H and TMB-H across different cancer types.