Date of Award
January 2023
Document Type
Open Access Thesis
Degree Name
Master of Public Health (MPH)
Department
School of Public Health
First Advisor
Caroline Johnson
Abstract
Early-onset colorectal cancer (EO-CRC) occurring in individuals under age 50 is rapidly increasing globally. In comparison, later-onset colorectal cancer (LO-CRC) incidence has decreased or remained stable over recent years. Despite these increases in EO-CRC incidence, the etiology of EO-CRC is largely unknown. This study aimed to compare the metabolomes of EO-CRC (N=53) and LO-CRC (N=314) patients from a cohort of 367 patients using patient matched samples of stages I-IV tumor and healthy colon tissue. Hydrophilic interaction liquid chromatography mass spectrometry (HILIC-MS) and reversed phase liquid chromatography mass spectrometry (RPLC-MS)-based untargeted metabolomics were applied to identify features present in the samples, and these were matched to an in-house library of metabolites. Pathway analyses were conducted using MetaboAnalyst software, and signaling networks were explored using Ingenuity Pathway Analysis (QIAGEN IPA).
Between the two groups, 131 metabolites were similarly dysregulated. Two metabolites, fructose 1,6-bisphosphate and 4-hydroxy-3-methoxyphenylacetic acid, were unique to EO-CRC samples. There were similarities between EO- and LO-CRC in enrichment of pathways, including enrichment of purine metabolism and aminoacyl-tRNA biosynthesis. However, LO-CRC uniquely showed enrichment of arginine biosynthesis. In EO-CRC tumors, evidence of resilience to oxidative stress was observed through unique activation of glutathione peroxidase as a result of ERK1/2 and growth hormone activation. This appeared to reduce lipid hyperoxides and free hydrogen peroxide, allowing cells to survive, where, in a normal cellular environment, they should fail. For LO-CRC tumors, we observed coordinated networks of pro-carcinogenic molecules, including nitric oxide synthase, and immune responses, which are likely contributing to tumor cell proliferation that may be distinct from EO-CRC.
Recommended Citation
Janak, Allison Paige, "Identifying Aberrant Metabolism And Underlying Biology In Colorectal Cancer Tumors Between Early- And Later-Onset Samples" (2023). Public Health Theses. 2272.
https://elischolar.library.yale.edu/ysphtdl/2272
This Article is Open Access
Comments
This is an Open Access Thesis.