Author ORCID Identifier
https://orcid.org/0009-0003-1025-5330
Date of Graduation
5-2026
Document Type
Thesis (MS)
Program Affiliation
Biomedical Sciences
Degree Name
Masters of Science (MS)
Advisor/Committee Chair
Raghu Kalluri, MD, Ph.D.
Committee Member
Kunal Rai, Ph.D.
Committee Member
Scott Kopetz, MD, Ph.D.
Committee Member
Stephanie Watowich, Ph.D.
Committee Member
Xiling Shen, Ph.D.
Abstract
Colorectal cancer (CRC) is one of the most common malignancies in the United States. CRC can arise from the left or right side of the colon, and these anatomical subtypes have historically been associated with distinct developmental pathways, mutational profiles, and tumor microenvironment (TME). Left‐sided CRC (LCRC) typically follows the classical adenoma– carcinoma sequence and is characterized by recurrent mutations in APC, TP53, and KRAS, whereas many right‐sided CRC (RCRC) tumors arise from the serrated neoplasia pathway and are frequently associated with microsatellite instability (MSI) and BRAF mutations. We evaluated whether primary tumor location or microsatellite instability status is the dominant determinant of genomic and immunologic heterogeneity in CRC. We identified differentially mutated genes and T cell subtypes between tumor subgroups. While limited differences in oncogenic mutation frequencies and immune cell composition were observed between LCRC and RCRC, MSS status emerged as a stronger predictor of genomic alterations and immune phenotypes. MSI CRC primary tumors showed enrichment of oncogenic mutations in WNT signaling-associated genes, such as RNF43, and exhibited increased proportions of exhausted CD8+ T cells. In contrast, MSS CRC tumors were enriched for oncogenic mutations in APC, P53 and KRAS, and contained higher proportions of naïve CD4+ T cells. Finally, compared to MSS RNF43 WT primary tumors, MSI RNF43 Mutant primary tumors had fewer CD4+ naïve T cells. Conversely, compared to MSI RNF43 WT primary tumors, MSI RNF43 Mutant primary tumors had more CD4+ naïve T cells. Together, these findings indicate that MSS Status is a more influential predictor of an immunosuppressive TME compared to primary tumor anatomical location and MSI RNF43 Mutant CRC tumors exhibit a unique TME.
Recommended Citation
Gates, Ryan, "Genetic Defects and Tumor Microenvironment Associated with Left-Sided and Right-Sided Colorectal Cancer" (2026). Dissertations & Theses (Open Access). 1517.
https://digitalcommons.library.tmc.edu/utgsbs_dissertations/1517
Keywords
scRNA-seq, WES, Colorectal Cancer, T-cell, Immunotherapy
Included in
Bioinformatics Commons, Cancer Biology Commons, Computational Biology Commons, Genetics Commons, Genomics Commons, Immunopathology Commons, Immunotherapy Commons