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Identifying genetic biomarkers of response to treatment for advanced colorectal cancer

Gray, Victoria 2021. Identifying genetic biomarkers of response to treatment for advanced colorectal cancer. PhD Thesis, Cardiff University.
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Background Although there are tumour-based biomarkers of response to chemotherapy and cetuximab, there is a lack of germline predictive biomarkers. I sought such biomarkers by analysing patients from the COIN and COIN-B clinical trials who received oxaliplatin and fluoropyrimidine chemotherapy ± cetuximab for advanced colorectal cancer (aCRC). Patients and Methods 2,244 blood DNA samples were genotyped on whole genome arrays and imputed for 5 million common genetic variants (SNPs); 1,649 patients had data on response at 12 weeks and 1,948 had data on overall survival (OS). SNPs in pattern recognition proteins (PRPs) were analysed by Cox regression. Univariate and multivariate genome-wide association studies (GWASs) for response to oxaliplatin and fluoropyrimidine-based chemotherapy were performed. To identify predictive biomarkers for cetuximab, I performed exploratory factor analyses (including RAS[KRAS and NRAS] mutational status and type of chemotherapy) and univariate and multivariate GWASs in 319 patients with RAS wild-type CRCs. Results Loss of function SNPs in PRP genes were not associated with benefit from oxaliplatinbased chemotherapy. Genome wide analyses identified five loci suggestive of association (P<1x10-5) with response to chemotherapy and SNPs at 10p15.3 (WDR37 and an eQTL for IDI1) influenced OS (lead SNP rs2086382, HR=0.77, 95% CI=0.65- 0.92, P=3.0x10-3). RAS mutation status was predictive for response to cetuximab (PInteraction<0.01); 71% of patients with RAS wild-type CRCs responded to chemotherapy plus cetuximab versus 61% without cetuximab (OR=1.61, 95% CI=1.19–2.19, P<0.01). Although not genome-wide significant, rs12054810 (eQTL for ISCO1, P=3.0x10-6), rs142144203 (RNLS, P=9.7x10-6), rs73200904 (PCDH9, P=5.7x10-6) and rs131850 (P=7.7x10-6) genotypes showed evidence for an association with response to cetuximab.

Item Type: Thesis (PhD)
Date Type: Completion
Status: Unpublished
Schools: Medicine
Date of First Compliant Deposit: 11 February 2022
Last Modified: 11 Feb 2022 10:05

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