Transcriptome and Network Dissection of Microsatellite Stable and Highly Instable Colorectal Cancer

Abstract

Background: Colorectal cancer (CRC) is one of the most common cancers worldwide with high number of mortality every year. Microsatellite instability (MSI) is a considerable feature of CRC which affects prognosis and treatment. High level of MSI or MSI-high (MSI-H) colorectal cancer has better prognosis and immunotherapy response, while microsatellite stable (MSS) CRC has better response to 5-fluorouracil (5-FU)-based chemotherapy. More studies are needed, specifically on MSS CRC which has worse prognosis, to further reveal biological differences and similarities between MSS and MSI colorectal cancer, which may equip us with the knowledge to develop more promising therapeutic approaches to target both types or be more effective for each type. Methods: We aimed to find affected biological processes and their regulators in both type, MSS and MSI-H, of CRC; as well as reveal specific ones in each type. We applied meta-and network analysis on freely available transcriptome data in MSS and MSI-H colorectal cancer from gene expression omnibus (GEO) database to detect common differentially expressed genes (DEGs) and critical biological processes and predict their most significant regulators. Results: Our results demonstrate considerable up and downregulation in cell cycle and lipid catabolism processes, respectively; and introduced MYC and FOXM1 as two central and upstream regulators of DEGs in both type of CRC. Chemokine-mediated processes displayed up-regulation in MSI-H type, while metastasis-related processes showed more activation in MSS CRC. Additionally, DACH1 and TP53 were detected as two important transcription factors that differentially expressed just in MSS and MSI-H, respectively. Conclusion: Our results can explain why MSI and MSS CRC display different immunotherapy response, prognosis, and metastasis feature. Moreover, our predicted upstream regulators in the regulatory networks may be promising therapeutic targets.

A New Prognostic and Therapeutic Immune-related Risk Signature of Colorectal Cancer

“…MSI CRC has a better responsiveness to ICB therapy, while MSS CRC is more effective in 5-uorouracil treatment. As for the differences in prognosis and therapy between MSI-H and MSS CRC, more studies are required to dissect the differences in biological pathways and regulation between these two subtypes of CRC (21). Understanding the relevant immune genes involved in the MSS regulation can help us nd appropriate methods and provide a reliable reference for the diagnosis and treatment of immunotherapy-unresponsive patients.…”