Authors: Trenton M. Gibson, Brett E Pickett
Mentors: Brett E Pickett
Insitution: Brigham Young University
Lynch Syndrome, formerly known as Hereditary Non-Polyposis Colorectal Cancer, is an autosomal dominant condition characterized by non-functional DNA mismatch repair genes, leading to mismatch repair deficiency (dMMR). Individuals with dMMR have an increased risk of developing cancerous tumors with microsatellite instability (MSI). The aim of this study was to investigate significant perturbations in gene expression among different dMMR variants within Lynch Syndrome, specifically focusing on variants in the PMS2, MLH1, and MSH2 loci. We obtained 55 public RNA-seq human colorectal tumor samples with specific germline dMMR mutations and 20 samples of healthy colorectal epithelium from the GENE Expression Omnibus (GEO). These samples were subjected to a robust RNA-seq data preprocessing and analytical workflow, which involved quality control, trimming, read pseudomapping and quantification using Salmon, identification of significant differentially expressed genes using edgeR, and gene ontology enrichment analysis using Camera. Signaling pathway impact analysis (SPIA) was employed to assess gene pathway perturbations. Our results revealed that tumor samples from individuals with germline mutations in the PMS2 MMR gene exhibited transcriptomic profiles indicating upregulation in pathways related to intrinsic and extrinsic prothrombin activation, fibrinolysis, and uPA/uPAR-mediated signaling, in comparison to other tumor and healthy samples. Previous research has established a correlation between these pathways and tumor growth, invasiveness, and metastasis. These findings provide a foundation for further research to explore the interactions between PMS2 and these pathways in influencing tumor development.