Germline determinants of outcome and risk in colorectal cancer.
Doctoral thesis, UCL (University College London).
Genome-wide association studies (GWAS) have identified germline single nucleotide polymorphisms (SNPs) that are associated with colorectal cancer (CRC) susceptibility. This thesis applies the same approach to the identification of germline determinants of prognosis in CRC, attempts to verify potential susceptibility loci, and examines the relationship between SNPs and some forms of non-SNP based germline variation. The GWAS for prognosis used 931 patients enrolled in the VICTOR trial in the discovery phase, screening 309,200 autosomal SNPs for an association with disease-free survival (DFS). Following the application of selection filters based on statistical significance levels and performance of the genotyping, 40 SNPs were identified to be examined in further cohorts. The verification phase consisted of 1338 patients in the PETACC 3 trial and three population based cohorts: 899 patients from Scotland, 599 patients from Denmark, and 962 patients from Finland. The SNPs that came closest to genome-wide significance in stage 2 and 3 CRC was rs7556894, 15kb from Actin-related protein 2 (ARP2) on chromosome 2, part of the ARP2/3 complex essential for cell shape and motility, with p=8.96e-07. The impact on prognosis of rs7556894 was estimated as HR=1.52 (95% CI 1.17-1.96). Because of the failure to reach genome-wide significance (p<1e-07), two further approaches to the discovery phase are presented: the meta-analysis of two discovery cohorts to increase event rate and subject numbers and a GWAS for predictive markers for the benefit of adjuvant 5-FU chemotherapy. Formal verification of either approach was not undertaken as part of this thesis. Further loci were subjected to specific analyses of association with prognosis or CRC susceptibility: rs6983267 and the previously identified CRC susceptibility loci to a survival analysis, and not found to be associated; rs6687758, previously identified as a potential CRC risk locus to a susceptibility verification, confirming a significant association with HR=1.15, 95% CI 1.10-1.21, p=5.04e-08; and a variety of hypothesis driven potential risk loci to a screen for an association with CRC susceptibility, none was found but the LD relationship between tagSNPs and insertion/deletion polymorphisms appears to be the same as for ‘normal’ SNPs. Overall, the data presented in this thesis quantify further the contribution of germline variation to CRC susceptibility, exclude a major effect of such variation on prognosis, and verify rs6687758 as a further low-penetrance CRC susceptibility locus.
|Title:||Germline determinants of outcome and risk in colorectal cancer|
|Open access status:||An open access version is available from UCL Discovery|
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