Date of Award

January 2023

Document Type

Open Access Thesis

Degree Name

Master of Public Health (MPH)

Department

School of Public Health

First Advisor

Andrew T. DeWan

Abstract

Colorectal cancer (CRC) is one of the most common incident cancers in developed countries. Though the majority of colorectal cancer cases do not arise in individuals with inherited pathogenic mutations or a family history of CRC, there is a substantial heritable component of colorectal cancer. Thus, there is a critical need to incorporate genetic risk factors into overall CRC risk assessment to ultimately improve the efficacy of current screening strategies and optimize precision medicine approaches.

Presented here is a polygenic risk score (PRS) utilizing 79 genetic variants for colorectal cancer. The PRS was generated using genome-wide significant single nucleotide polymorphisms (SNPs) as identified from a meta-analysis of genome-wide association studies (GWAS) among individuals of European and east Asian genetic ancestry (100,204 caases and 154,587 controls). This PRS was then applied to 9,304 colorectal cancer cases and 477,902 controls from the UK Biobank (UKB) of multiple different races/ethnicites.

There was a statistically significant difference in mean PRS value in white, black, and Asian subpopulations, indicating acceptable discriminatory accuracy with regards to CRC case-control status. The greatest discriminatory accuracy was demonstrated among white participants, followed by Asian participants. Due to the reference population from which the PRS was constructed consisting only of European and east Asian genetic ancestry, the PRS demonstrated reduced predictive power among black participants. The combination of a significant difference in mean PRS value, but relatively poor predictive power among this subpopulation is indicative of the genetic generalizability gap of colorectal cancer. Therefore, it is essential to explore other risk-associated SNPs specific to African ancestry to further elucidate the unique genetic etiology of CRC.

Comments

This is an Open Access Thesis.

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