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

Area of Science:

• Oncology
• Genomics
• Immunotherapy

Background:

• Microsatellite instability (MSI) and tumor mutational burden (TMB) are established predictive biomarkers for pan-cancer immunotherapy.
• The precise relationship between MSI-high (MSI-H) and TMB-high (TMB-H) phenotypes and their combined predictive utility in lung cancer immunotherapy remains incompletely understood.

Purpose of the Study:

• To investigate the interrelationship between MSI-H and TMB-H across diverse human cancers.
• To evaluate the predictive value of MSI-H and TMB-H, individually and in combination, for immunotherapy response in lung cancer.

Main Methods:

• Analysis of somatic mutation data from 46,320 patients via the Genomics Evidence Neoplasia Information Exchange.
• Utilized adjusted multivariate regression models to assess the MSI-H and TMB-H relationship.
• Employed Cox proportional hazards models to examine patient survival and the association between MSI and genetic mutations.

Main Results:

• A significant proportion of MSI-H patients (31-89%) exhibited TMB-low phenotypes across 22 cancer types, highlighting discrepancies.
• Lung cancer patients with TMB-H receiving immunotherapy showed improved overall survival and progression-free survival compared to TMB-low patients.
• Combined TMB and MSI phenotypes further enhanced survival outcomes; novel mutated genes like ARID1A and ARID1B were identified in MSI-H phenotypes.

Conclusions:

• TMB-H and/or MSI-H serve as valuable biomarkers for predicting immunotherapy efficacy in lung cancer.
• Distinct or combined biomarker strategies are recommended for immunotherapy selection due to observed discrepancies between MSI-H and TMB-H across cancer types.