Identifying genetic biomarkers of survival for colorectal cancer

Wills, Christopher 2023. Identifying genetic biomarkers of survival for colorectal cancer. PhD Thesis, Cardiff University. Item availability restricted.

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Abstract

Background Clinical stage is the only routinely used marker of survival from colorectal cancer (CRC). Other factors thought to influence prognosis include the location of the primary tumour and the patient’s germline and the tumour’s somatic genetic profile. Aims of my thesis To examine inherited variation as a determinant of patient outcome with further analyses stratified by primary tumour site and mitogen-activated protein kinase (MAPK) activation status. To consider whether known somatic prognostic mutations might mask novel candidate loci. Materials and Methods I performed a genome-wide association study (GWAS), gene and gene-set analyses for survival in 1,926 patients with advanced CRC from the COIN and COIN-B clinical trials with replication in 5,675 patients from the Study of Colorectal Cancer in Scotland (SOCCS), 16,964 patients from the International Survival Analysis in Colorectal cancer Consortium and 5,078 patients with CRC from the UK Biobank. To understand underlying mechanism(s), I performed expression analyses both by variant and transcriptome-wide, and investigated the relationship between expression in colorectal tumours and survival in patients from The Human Protein Atlas. Results In COIN and COIN-B, the most significant SNP associated with survival was rs79612564 in ERBB4 (hazard ratio [HR]=1.24, 95% confidence interval [CI]=1.16–1.32, P=1.9x10−7) which was replicated in stage-IV patients from SOCCS (P=2.1x10−2); mechanistically, patients with high ERBB4 expression in their colon adenocarcinomas had worse survival (HR=1.50, 95% CI=1.1–1.9, P=4.6x10−2). When stratifying by primary tumour location, rs76011559 replicated in patients with proximal tumours (COIN, COIN-B and UK Biobank combined HR=1.53, 95% CI=1.19-1.86, P=7.5x10-7) and rs12273047 replicated in patients with rectal tumours (HR=1.27, 95% CI=1.09-1.46, P=4.1x10-7). PI4K2B associated with survival in patients with distal cancers (P=2.1x10-6) and increased PI4K2B expression in colorectal tumours was associated with improved survival (P=9.6x10-5). RASAL2, encoding a RAS GTPase-activating protein, was the most significant gene associated with survival in patients with MAPK-activated CRCs (P=2.0x10−5) with further analyses revealing pathway specificity. Finally, rs11062901 in PARP11 was a novel biomarker of survival when unmasked from known somatic prognostic factors (HR=1.99, 95% CI=1.5-2.5, P=4.5x10-8) and supported by gene (P=1.4x10-6) and transcriptome-wide (P=1.1x10-5) analyses. Conclusions My data identify novel loci potentially associated with survival from CRC, together with mechanistic insights, many of which were mediated by changes in gene expression.

Item Type:	Thesis (PhD)
Date Type:	Completion
Status:	Unpublished
Schools:	Medicine
Date of First Compliant Deposit:	9 October 2023
Last Modified:	11 Oct 2023 09:32
URI:	https://orca.cardiff.ac.uk/id/eprint/163073

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