Targeted Serum Metabolomics for Noninvasive Detection of Colorectal Neoplasia

Fitzgerald, Liam Warren

Targeted Serum Metabolomics for Noninvasive Detection of Colorectal Neoplasia

dc.contributor.advisor	Bathe, Oliver
dc.contributor.author	Fitzgerald, Liam Warren
dc.contributor.committeemember	Orton, Dennis
dc.contributor.committeemember	Kopciuk, Karen
dc.contributor.committeemember	Vogel, Hans
dc.date	2023-11
dc.date.accessioned	2023-08-23T19:57:46Z
dc.date.available	2023-08-23T19:57:46Z
dc.date.issued	2023-08
dc.description.abstract	Background: Early detection of colorectal cancer (CRC) and its precursor lesions improves CRC-related mortality and reduces disease incidence. However, due to limitations of currently available screening modalities, patient adherence to screening is low. A reliable and inexpensive blood test represents a promising solution to this problem. Our group has previously demonstrated that there are distinct metabolic perturbations in CRC and adenomatous polyps which are measurable in the blood. However, a targeted metabolomic approach is needed to uncover reliable meta-biomarkers for CRC, adenomatous polyps, and serrated polyps. Methods: A targeted metabolomic assay (Biocrates MxP® Quant 500) was used to analyze our discovery set of sera from patients with CRC of all stage (N=111), adenoma (N=63), sessile serrated adenoma (SSA; N=62), and age- and sex-matched disease-free controls (DFC; N=154). Orthogonal partial least squares discriminant analysis (OPLS-DA) and machine learning (ML) were used to derive signatures comprised of metabolite concentration ratios which discriminate between CRC, adenoma, SSA, and DFCs. A large, representative validation cohort (N=838) was also analyzed to test our meta-biomarkers. Results: Two signatures for CRC were derived from OPLS-DA and ML and comprised of 21 and 16 metabolite ratios, respectively. OPLS-DA signatures for adenoma and SSA were comprised of 23 and 56 metabolite ratios, respectively. All models performed well based on 7-fold internal cross-validation, with receiver operating characteristic (ROC) analysis demonstrating areas under the curve (AUC) greater than 0.85. Importantly, external validation confirmed the reliability of our meta-biomarkers, with sensitivities as high as 92-100% for CRC and 80-85% for adenoma and SSA being possible. Conclusion: Our meta-biomarkers discovered using targeted metabolomics demonstrated excellent performance based on internal and external validation. Of significance, our signatures exhibit superior sensitivity compared to other readily available screening modalities such as stool tests.
dc.identifier.citation	Fitzgerald, L. W. (2023). Targeted serum metabolomics for noninvasive detection of colorectal neoplasia (Master's thesis, University of Calgary, Calgary, Canada). Retrieved from https://prism.ucalgary.ca.
dc.identifier.uri	https://hdl.handle.net/1880/116881
dc.identifier.uri	https://dx.doi.org/10.11575/PRISM/41723
dc.language.iso	en
dc.publisher.faculty	Graduate Studies
dc.publisher.institution	University of Calgary
dc.rights	University of Calgary graduate students retain copyright ownership and moral rights for their thesis. You may use this material in any way that is permitted by the Copyright Act or through licensing that has been assigned to the document. For uses that are not allowable under copyright legislation or licensing, you are required to seek permission.
dc.subject	Colorectal cancer
dc.subject	Screening
dc.subject	Metabolomics
dc.subject	Bioinformatics
dc.subject	Cancer biomarker
dc.subject.classification	Medicine and Surgery
dc.subject.classification	Bioinformatics
dc.subject.classification	Oncology
dc.title	Targeted Serum Metabolomics for Noninvasive Detection of Colorectal Neoplasia
dc.type	master thesis
thesis.degree.discipline	Medicine – Medical Sciences
thesis.degree.grantor	University of Calgary
thesis.degree.name	Master of Science (MSc)
ucalgary.thesis.accesssetbystudent	I require a thesis withhold – I need to delay the release of my thesis due to a patent application, and other reasons outlined in the link above. I have/will need to submit a thesis withhold application.