Analysis of variations in hypoxia-pathway genes and mitochondrial DNA as prognostic markers in colorectal cancer patients

Haja Mohideen, Asan Meera Sahbi (2013) Analysis of variations in hypoxia-pathway genes and mitochondrial DNA as prognostic markers in colorectal cancer patients. Masters thesis, Memorial University of Newfoundland.

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Abstract

Colorectal cancer is a common malignancy, characterized by high incidence and mortality rates. Hypoxia induces angiogenesis, metastasis and aggressive tumour phenotype and hence promotes cancer progression. Similarly, dysfunctions in mitochondria have been shown to contribute to cancer progression. Therefore, in this thesis, genetic markers in both the hypoxia pathway genes and the mitochondrial DNA are hypothesized to be candidate genetic prognostic markers in colorectal cancer. -- The aim of this study is to test genetic markers that can predict outcome in colorectal cancer patients. This study consists of two projects: 1) the mitochondrial DNA variations project and 2) the hypoxia pathway Single Nucleotide Polymorphisms (SNPs) project. In the mitochondrial DNA (mtDNA) variations project, six mtDNA polymorphisms and the mtDNA copy number change were tested for their prognostic associations. However, none of the mtDNA markers selected was found to be associated with outcome. The hypoxia pathway SNPs project was done in two phases. In the first phase, 49 tagging SNPs from six hypoxia genes (HIF1A, HIF1B, HIF2A, LOX, MIF and CXCL12) were genotyped in a cohort of 272 colorectal cancer patients (cohort I). In the second phase, 77 tagging SNPs from seven hypoxia genes (HIF1A, HIF1B, HIF2A, HIF2B, HIF3A, LOX and CXCL12) were genotyped in a separate cohort of 536 colorectal cancer patients (cohort II). -- In phase I, the TT and AT genotypes of the HIF2A rs11125070 polymorphism was associated with increased disease free survival (DFS) in the multivariable model (p=0.004; HR=0.619; 95% CI: 0.446-0.859). In phase II, patients with TC and CC genotypes for the HIF2A rs4953352 polymorphism and patients with the GG genotype for the HIF2B rs12593988 polymorphism were associated with both reduced overall survival (OS) and DFS in multivariate models. However, the association of the HIF2A rs11125070 polymorphism with DFS detected in the phase I cohort was not replicated in the phase II patient cohort, suggesting this association was possibly a false-positive association. Similarly, association of the HIF2A rs4953352 polymorphism with OS and DFS detected in the phase II cohort failed to be detected in the phase I patient cohort, which may be due to the small sample size of cohort I. Association of the HIF2B rs12593988 polymorphism remains to be tested in another colorectal cancer cohort. -- In conclusion, this study shows no evidence of associations between majority of genetic markers in hypoxia pathway genes and mtDNA with prognosis in colorectal cancer. However, whether or not the HIF2B rs12593988 polymorphism is associated with prognosis needs to be confirmed by investigating other patient cohorts.

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