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Title: Germline determinants of 5-fluorouracil drug toxicity and patient survival in colorectal cancer
Author: Rosmarin, Daniel Norris
Awarding Body: University of Oxford
Current Institution: University of Oxford
Date of Award: 2013
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Despite a decade of publications investigating the effect of germline polymorphisms on both toxicity related to treatment with 5-fluorouracil-based (5-FU) chemotherapy and prognosis following diagnosis with colorectal cancer (CRC), few genetic biomarkers have been identified convincingly. For 5-FU toxicity and CRC prognosis, in four results chapters, this thesis aims to validate previously-reported genetic biomarkers, identify new markers, determine the mechanistic basis of associated polymorphisms, and expand upon methods in the field. The first three results chapters investigate genetic biomarkers for the prediction of toxicity caused by 5-FU-based treatment, particularly for the 5-FU prodrug capecitabine (Xeloda®, Roche). In the first, a systematic review and meta-analysis is performed for all variants that have been previously studied for an association with toxicity caused by any 5-FU-based drug regimen. 16 studies are analysed, including 36 previously-studied variants. Four variants show strong evidence of affecting a patient’s risk of global (any) 5-FU-related toxicity upon analysis of both the existing data and over 900 patients from the QUASAR2 trial of capecitabine +/- bevacizumab (Avastin®, Roche/Genentech): DPYD 2846, DPYD *2A, TYMS 5’VNTR and TYMS 3’UTR. Next, 1,456 polymorphisms in 25 genes involved in the activation, action or degradation of 5-FU are investigated in 1,046 patients from QUASAR2. At a Bonferroni-corrected p-value threshold of 3.43e-05, three novel associations with capecitabine-related toxicity are identified in DPYD (rs12132152, rs7548189, A551T) and the previously-identified TYMS 5’VNTR and 3’UTR toxicity polymorphisms are refined to a tagging SNP (rs2612091) downstream of TYMS and intronic to the adjacent ENOSF1, the latter of which appears to be functional. Finally, a genome-wide investigation of 4.77 million directly genotyped or imputed SNPs identifies one variant (rs2093152 on chr20) as significantly associated with capecitabine-related diarrhoea (p<5e-08), though no associations meet this threshold for global toxicity. In the study of CRC prognosis, a severe left truncation to the VICTOR trial is defined and shown to probably reduce statistical power but not bias effect estimates. Applying standard and novel genome-wide analysis approaches, a set of 43 SNPs are prioritised for future work. With over one million new CRC cases annually, this work helps define biomarkers that could become broadly applicable in the clinical setting.
Supervisor: Tomlinson, Ian; Johnstone, Elaine; Midgley, Rachel Sponsor: Keasbey Memorial Foundation
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Mathematical biology ; Medical Sciences ; Clinical genetics ; Gene medicine ; Biology (medical sciences) ; Genetics (medical sciences) ; Gastroenterology ; Oncology ; Pharmacology ; Enzymes ; Molecular genetics ; Mathematical genetics and bioinformatics (statistics) ; Computationally-intensive statistics ; Bioinformatics (technology) ; Bioinformatics (biochemistry) ; Bioinformatics (life sciences) ; Biology ; Genetics (life sciences) ; Metabolism ; 5-fluorouracil ; cancer ; colorectal cancer ; toxicity ; survival ; toxgnostics ; genetics ; drug personalisation ; drug personalization ; diarrhoea ; association study ; chemotherapy ; neutropaenia ; thrombocytopaenia