S. Narayanan1, T. Kawaguchi1, L. Yan1, X. Peng1, Q. Qi1, K. Takabe1 1Roswell Park Cancer Institute,Surgical Oncology,Buffalo, NY, USA
Introduction: Microsatellite instability (MSI) occurs via inactivation of DNA mismatch repair genes resulting in impaired DNA repair function with subsequent accumulation of abnormal genes. Heterogeneity in MSI status is common in colon cancers and has been demonstrated to be an independent predictor of survival, with MSI-high tumors having a better overall prognosis. Previous studies have correlated upregulation of DNA repair genes with increased ability for tumors to metastasize and with chemotherapy and radiation resistance, thereby resulting in poorer survival. We, thus, hypothesized that low expression of DNA repair genes would result in improved survival secondary to increased MSI.
Methods: The Cancer Genome Atlas (TCGA) was used to evaluate a cohort of 283 patients with colorectal cancer. RNA sequence gene expression quantification data for colon cancer was retrieved from the Genomics Data Commons (GDC) data portal. Gene expression levels were derived using normalization methods provided in the DESeq2 package and designated as low or high. The expression of DNA repair genes was then compared between MSI-High and Microsatellite stable (MSS) cohorts. Overall survival for patients for each DNA repair gene was determined via Kaplan-Meier analysis.
Results: We found that low expression of several DNA repair genes correlated with high levels of microsatellite instability. Some of these were the expected mismatch repair genes- MLH1 (p< 0.0001), PMS1 (p= 0.002), PMS2 (p< 0.0001) and MLH3 (p=0.036). However, others were double stranded break DNA repair genes such as ATM (p< 0.0001), PRKDC (p< 0.0001), ATR (p< 0.0001) and BRCA2 (p= 0.0081). Significantly improved overall survival was demonstrated in patients with low expression of ATM (p= 0.04), MLH1 (p= 0.028), PMS2 (p= 0.003) and MLH 3 (p= 0.0029). There was a trend towards improved survival in patients with low expression of BRCA2 and ATR without achieving statistical significance.
Conclusion: In this analysis of patients with colorectal cancer we found that diminished expression of several DNA repair genes correlated with increased microsatellite instability even those that were not known mismatch repair (MMR) genes. However, improvement in survival primarily correlated with MMR-deficiency and with low expression of other DNA repair genes to a lesser extent. This phenomenon may relate to the increased immunogenicity of tumors with genomic instability and may have implications for further development of immunotherapy targets in the future.