Searching for genetic variants associated with survival in patients with metastatic colorectal cancer

Summers, Matthew G. ORCID: https://orcid.org/0000-0001-6387-124X 2019. Searching for genetic variants associated with survival in patients with metastatic colorectal cancer. PhD Thesis, Cardiff University. Item availability restricted.

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Abstract

Background Colorectal cancer (CRC) is the third most commonly diagnosed cancer and fourth highest cause of cancer-related death worldwide. Although the five-year survival rate for patients with early stage CRC is high (∼92%), it is considerably decreased (∼12%) for metastatic CRC (mCRC). A number of somatic prognostic factors are established for CRC, but few germline prognostic biomarkers have been identified. Materials and methods Survival analyses were stratified by somatic mutation and MSI status, and GWAS analyses for germline variants were performed on data from 2671 patients from the COIN and COIN-B clinical trials, followed by in silico functional analyses of four germline variants significantly associated with survival and validation analyses for three of these variants. Results Mutations in KRAS (HR 1.45, 95% CI 1.30-1.61, P=1.9x10-11), BRAF (HR 2.31, 95% CI 1.85- 2.87, P=7.8x10-14), NRAS (HR 1.44, 95% CI 1.09-1.90, P=0.01) and MSI-positive tumours (HR 1.86, 95% CI 1.22-2.83, P=4.0x10-3) were found to confer poor prognosis. Two SNPs (rs9356458 at 6q27 and rs17560791 at 2q35) of genome-wide significance (P< 5.0x10-8) and two (rs241477 at 14q31.3 and rs4074683 at 7p11.2) suggestive of association (P< 1.0x10-5) with survival were identified. These variants did not replicate in validation analyses, possibly due to overinflated effect sizes caused by winner’s curse in the discovery set, or through clinicopathological differences between the study and validation cohorts. Conclusion The work presented in this thesis has identified somatic mutations in four oncogenes and tumour MSI status as being significantly associated with survival in mCRC patients. Four novel germline variants were also identified as potential candidate prognostic biomarkers for mCRC. Further work is required using larger validation cohorts of stage-matched patients with similar clinical and prognostic covariates to determine whether these variants can be validated as robust prognostic biomarkers for mCRC. ii

Item Type:	Thesis (PhD)
Date Type:	Completion
Status:	Unpublished
Schools:	Medicine
Date of First Compliant Deposit:	28 May 2020
Last Modified:	07 Nov 2022 10:05
URI:	https://orca.cardiff.ac.uk/id/eprint/131129

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