Abstract PO001: Association of DNA repair genes with tumor mutational burden and microsatellite instability
Authors: Ding Jason , Patel Nihir 
Published: February 2021

Abstract
Background: DNA repair is a critical process to maintain DNA integrity. It is conducted by distinct pathways of genes, many of whose alterations are thought to result in genomic instability and subsequent hypermutability and contribute to tumorigenesis. Microsatellite Instability (MSI) and Tumor Mutation Burden (TMB) are considered as good prognostics biomarkers and efficacy predictors for immunotherapy and chemotherapy. However, there has been little characterization of the association between these pathways and TMB/MSI in cancer. This study aims to further understand the DNA repair genes, their pathways, and evaluate the contribution of their alteration to MSI and TMB.
Method: We systematically analyzed 282 DNA repair genes involved in 20 DNA repair pathways. The DNA repair genes were evaluated for mutations based on 274 sequenced tumor samples from the TCGA database. The functional impact of these mutations was analyzed, and only damaging mutations were used for the subsequent analysis. The most frequently mutated genes were identified. The association between the damaging mutations and TMB/MSI status was calculated for each gene, and the significant genes were selected and subject to further pathway enrichment analysis. We also compared the gene expression between TMB high and low as well as between MSI high and MSI-Low/MSS for these genes respectively based on RNAseq expression data of these tumor samples. The potential associations between DNA repair gene expression and two phenotypes - genomic microsatellite status and TMB tumor mutation burden - were evaluated
Results: 94 genes were identified to be significantly mutated in TMB high, including all of the 26 genes that were significant in MSI. The genes are enriched in multiple pathways, including Fanconi anemia, Base excision repair and Mismatch repair. At the expression level, 28 genes are significantly downregulated in TMB-High samples while 35 genes in MSI, suggesting that the inactivation of these genes might be mediated by the epigenetic abnormalities such as promoter methylation. The genes are enriched in pathways, including base excision repair. Finally, 9 genes were identified that significantly mutated in TMB high samples as compare to MSI samples. Loss of function mutations in these genes, such as POLE, will result in an ultra-mutated phenotype consisting of unusually high mutation rates. Contradicting the notion that POLE mutation is associated with an MSS phenotype in endometrial cancer and are mutually exclusive with the complete loss of MMR, we found 8 MSI samples with POLE mutation, 5 of which have MMR mutations.
Conclusions: The study investigated mutations in DNA repair genes associated with TMB and MSI. We identified and compared genes significantly altered in TMB and MSI. We also found genes pointing to a potential mechanism that induces ultra-mutated in a subset of a cancer patients with intact MMR, which can serve as a potential biomarker for immunotherapy efficacy linked with high TMB.
Citation Format: Jason Ding, Nihir Patel. Association of DNA repair genes with tumor mutational burden and microsatellite instability [abstract]. In: Proceedings of the AACR Virtual Special Conference: Endometrial Cancer: New Biology Driving Research and Treatment; 2020 Nov 9-10. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(3_Suppl):Abstract nr PO001.