Genome-wide analyses to identify biomarkers of toxicity in the treatment of advanced colorectal cancer

Watts, Katie 2023. Genome-wide analyses to identify biomarkers of toxicity in the treatment of advanced colorectal cancer. PhD Thesis, Cardiff University. Item availability restricted.

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Abstract

Background Chemotherapies administered at normal therapeutic dosages can cause significant side-effects and may result in early treatment discontinuation. Inter-individual variation in toxicity highlights the need for biomarkers to personalise treatment. Inherited genetic variants are increasingly being recognised to cause chemotherapyinduced toxicity. Aim I sought such biomarkers by conducting genome-wide association studies, together with gene and gene set analyses, for ten toxicities in 1800 patients with advanced colorectal cancer (CRC) treated with oxaliplatin and fluoropyrimidine chemotherapy ± cetuximab. Materials and Methods Patients were from the MRC COIN and COIN-B trials. 385 received folinic acid, fluorouracil and oxaliplatin (FOLFOX), 360 FOLFOX + cetuximab, 707 capecitabine and oxaliplatin (XELOX) and 348 XELOX + cetuximab. Common and low-frequency single nucleotide polymorphisms (SNPs), genes and gene sets that reached genome-wide or suggestive significance were replicated in independent patient groups, clinical trial cohorts and participants from the UK Biobank and Genomics England. Meta-analyses were also performed to increase power. Results rs13260246 at 8q21.13 was significantly associated with vomiting in patients treated with XELOX (Odds Ratio [OR]=5.0, 95% Confidence Interval [CI]=3.0-8.3, P=9.8x10- 10) but failed independent replication. SNPs at 139 loci had suggestive associations for toxicities and lead SNPs at five were replicated. rs6783836 in ST6GAL1 was associated with hand‐foot syndrome (HFS) in patients treated with XELOX (OR=3.1, 95% CI=2.1‐4.6, P=4.3x10‐8) and ST6GAL1 was associated with type-2 diabetes (a risk factor for HFS). A low-frequency nonsynonymous variant in the antigen processing 1 signature region was suggestive of an association with sepsis (OR=6.1, 95% CI=3.0-12.8, P=1.2x10-6). rs4760830 in TRHDE was associated with diarrhoea in patients treated with capecitabine (OR=0.6, 95% CI=0.50-0.72, P=4.8x10-8). In MAGMA gene analyses, MROH5 was significantly associated with neutropenia (P=6.6x10-7) and was independently replicated.

Item Type:	Thesis (PhD)
Date Type:	Completion
Status:	Unpublished
Schools:	Medicine
Funders:	Cardiff University School of Medicine Studentship
Date of First Compliant Deposit:	23 October 2023
Last Modified:	24 Oct 2023 11:23
URI:	https://orca.cardiff.ac.uk/id/eprint/163425

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