Hypermutation in Microsatellite Stable Cancers

Abstract

Cancer stands as one of the deadliest diseases worldwide, claiming a significant number of lives. It's a complex condition influenced by various factors, including physical, chemical, and biological carcinogens. Cancer can be broadly categorized into genetic or somatic forms, with somatic cancer involving DNA changes or damage as a primary cause. Hypermutation, characterized by an excessive number of mutations in cancer cells, further divides into microsatellite instability (MSI-High and MSI-Low) and microsatellite stability (MSS). In recent years, immunotherapy has emerged as a promising and relatively low side-effect approach to cancer treatment. Recent findings reported promising results of immunotherapy in MSI. This study focuses on MSS samples with higher mutation burden has potential for immunotherapy. To achieve this, we examined hypermutated cancers, including UCEC, COAD, READ, PAAD, STAD, UCS and ESCA, utilizing TCGA data. This analysis includes transcriptomic and differential gene expression analysis using cBioPortal and the edgeR package in R for Next-Generation Sequencing (NGS) data. Among the key mutations contributing to MSS, the POLE gene mutation emerged as a major player, alongside other reported mutations like APC R1114* and ZNHIT6 R258*. This study incorporated a total of 42 hypermutated samples. From this analysis, we uncovered common upregulations in genes like DKK4, FGF20, and HMX2 corelated to POLE mutations, as well as TSIX, GNG4, GSTM1, ALDH1A1, and CPS1 corelated to APC mutations. Additionally, HOXC5 and LMO3 were upregulated corelated to ZNHIT6 mutations. Conversely, downregulation was observed in AKR1B10 and AKR1C2 corelated to POLE mutations, HOMER2 and FGF19 corelated to APC mutations, and IHH, UGT2B7, and OGDHL due to ZNHIT6 mutations. Furthermore, a differential expression analysis conducted in UCEC, STAD, and CRC identified MUC5AC and CXCL5 as genes involved in inflammation and apoptosis. Pathway analysis revealed their potential connection to the IL-17 signaling pathway and immune response. Therefore, this study suggests that the upregulation and downregulation of common genes in CRC and UCEC, along with the interaction of MUC5AC and CXCL5 with the IL-17 pathway, could serve as promising biomarkers for immunotherapy