Abstract 5455: Large-scale cancer genomic analysis reveals significant disparities between microsatellite instability and tumor mutational burden
Authors: Choi Jungyoon , Kim Jung Sun , Park Kyong Hwa , Guo Xingyi , Kim Yeul Hong 
Published: June 2023

Abstract
Microsatellite instability (MSI) and tumor mutational burden (TMB) are efficacy biomarkers for cancer immunotherapies, with both MSI-high and TMB-high considered hypermutator phenotypes that predict better drug responses. However, the inter-relationship between these biomarkers has not been well-investigated. Herein, we conducted a large-scale cancer genomic analysis to characterize patterns of distribution between MSI-high and TMB-high across 22 human cancer types, and identify mutated genes that may contribute to MSI-high cancers.We analyzed somatic mutation data from the Genomics Evidence Neoplasia Information Exchange (GENIE; n=49,496) to characterize gene mutations and patterns of distribution between MSI and TMB for each cancer. Associations between TMB and MSI were evaluated using multivariable linear regression models adjusted for age at sequencing report, sex, race, sequencing center, and histological subtype. Associations between MSI and gene mutations were evaluated using multivariable logistic regression models adjusted for the above mentioned covariates and TMB.Our analysis revealed that considerable differences in the prevalence of MSI-high and TMB-high by cancer types. The moderate differences were observed in cancers with the top prevalence of MSI-high/TMB-high, such as 31.1%/28.7% in endometrial cancer, 18.4%/17.7% in colorectal cancer, and 17.2%/12.2% in stomach cancer, while most other cancers showed high differences of prevalence (&gt;10%). Notably, MSI-high patients were observed to have a substantial proportion of TMB-low phenotypes ranging from 31% to 89% among these cancer types, likely indicating distinct drug responses compared to TMB-high phenotypes. Association analyses between TMB and MSI for these cancers showed the strongest associations in colorectal cancer (P=4.0 × 10-255) and stomach cancer (P=6.2 × 10-60), while marginal or no associations were observed in several cancers including head and neck cancer (P=0.08) and hepatocellular carcinoma (P=0.15). In addition, we identified several mutated genes associated with MSI-high phenotypes, including known mismatch repair genes (e.g., MSH3, POLD1, MLH1, and MSH6) and novel mutated genes (e.g., RNF43, ARID1A, ARID1B, NOTCH3, SMARCA4, KMT2C, and CREBBP), in endometrial cancer (n=32 genes), in colorectal cancer (n=29 genes) and in stomach cancer (n=18 genes), at a Bonferroni-corrected P &lt; 0.05.Our study revealed large discrepancies in prevalence between MSI-high and TMB-high in many cancer types, highlighting the need to consider distinct or combined biomarkers for immunotherapies. Our study also identified novel mutated genes associated with MSI-high cancers, providing additional insights into MSI-high carcinogenesis and candidate genetic biomarkers to screen patients for potential immunotherapy.
Citation Format: Jungyoon Choi, Jung Sun Kim, Kyong Hwa Park, Xingyi Guo, Yeul Hong Kim. Large-scale cancer genomic analysis reveals significant disparities between microsatellite instability and tumor mutational burden. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5455.