Use this URL to cite or link to this record in EThOS: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.587693
Title: Functional analysis of low-moderate risk susceptibility genes emerging from pathway based approaches and genome wide association studies in epithelial ovarian cancer
Author: Notaridou, M.
Awarding Body: University College London (University of London)
Current Institution: University College London (University of London)
Date of Award: 2013
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Abstract:
Pathway based and genome wide association studies aim to identify alleles of low/moderate risk that may account for the development of EOC not attributed to high risk susceptibility genes. The aim of this study was to investigate the functional role of low/moderate susceptibility SNPs and candidate genes that emerge from candidate gene approaches and GWAS using tumour tissues or appropriate models from the proposed cells of origin for EOC, normal Ovarian Surface Epithelium (NOSE), Fallopian Tube Epithelium (FTE) respectively. Part of this study focused in establishing NOSE, FTE and EOC cell lines to study differential expression of candidate genes in post-GWAS functional characterisation studies. Additionally, I have established 3D FTE cultures and propose they more closely resemble the in vivo characteristics than 2D cultures. A candidate gene approach has identified nine candidate genes. I tested 301 invasive EOC tumours and found frequent LOH for tagging SNPs in those genes. LOH was associated with worse survival for AXIN2, CASP5, RRBBP8 and AIFM2 but the result for AXIN2, CASP5 and AIFM2 were associated with stage. Additionally, one SNP in STAG3 showed significant preferential loss of the common allele. Six loci containing susceptibility SNPs were identified in an ovarian cancer GWAS. I found compelling evidence for the somatic role of several genes within these loci in EOC development based on their differential expression between normal (NOSE & FTE) and EOC cell lines. These genes included PVT1, SP2, CBX1, PNPO, HAUS8, USE1, SKAP1, MERIT40 and members of the HOXB family of genes with an observed gain of function role and TIPARP and BNC2 with an observed loss of function role in EOC development. Additionally, I found weak associations of susceptibility SNPs’ genotypes with CBX1, SNX11, SP2 and HOXD1 expression and compelling evidence of genotype specific methylation of HOXB5 using non tumour samples. I further knocked down MERIT40 in EOC cell lines to study the potential role of the gene in EOC development. I found that MERIT40 depletion led to increased accumulation of spontaneous DNA damage and cell cycle arrest characterised by reduction in ploidy of the mucinous EOC cell line EFO27. This study provides functional evidence that GWAS are powerful tools for identifying novel genes implicated with EOC and that further functional investigation of GWAS identified loci leads to a better understanding of the molecular players involved in EOC initiation, development and survival.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.587693  DOI: Not available
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