Genetic and clinico-demographic factors with and without time-varying associations with survival outcomes in colorectal cancer

Yu, Yajun (2022) Genetic and clinico-demographic factors with and without time-varying associations with survival outcomes in colorectal cancer. Doctoral (PhD) thesis, Memorial University of Newfoundland.

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Abstract

Predicting the risk of outcomes (e.g., death, tumor recurrence/metastasis) as well as when a patient has such high risks are important, as this information can guide the disease management and patient care in colorectal cancer. However, current established prognostic markers in colorectal cancer predicting such risks are not sufficient to stratify patients into appropriate risk groups, suggesting the need for additional prognostic markers. In addition, there are no established prognostic markers that can tell whether a patient has high outcome risk in different time frames following diagnosis. The main aim of this research was to examine the relationship between genetic/clinico-demographic factors and clinical outcomes in colorectal cancer and to identify factors that associated with patient outcomes with or without time-varying associations. To this end, I examined ~4.7 million SNPs and hundreds of CNVs/INDELs for their associations with outcomes in colorectal cancer. My results showed that a number of CNVs/INDELs in BRM-741, TGFBR3, FILIP1L, STEAP2, RP11-143P4.2, and a SNP (rs7314075) in WBP11 are associated with time to outcome events in colorectal cancer. Further, two CNVs in PDLIM3 and GUSBP1 were identified to be associated with patient outcomes within the first ~3 years post-diagnosis, but not after that (i.e., candidate early-outcome markers); another three variants (rs817090, rs11064732, and rs200143895) were found to be associated with patient outcomes after 5 years post-diagnosis, but not before that (i.e., candidate lateoutcome markers). I also examined a set of baseline clinico-demographic factors, where a number of them were identified to be associated with outcomes in colorectal cancer, including those that have time-varying associations. By investigating a long follow up data, I was also able to examine the long term survival characteristics in this disease. This comprehensive research described a detailed picture of genetic and clinicodemographic factors with and without time-varying associations with clinical outcomes in colorectal cancer. It provided a set of variants/factors as candidate markers predicting outcome risks for colorectal cancer patients, including candidate early- or late-outcome markers. These factors, once their prognostic value is validated, can be used to guide patients’ treatment and clinical care, and improve their survival times.

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