The role of genetic factors in breast cancer aetiology

Breast cancer is the most common cancer in women and is also the leading cause of cancer<br/>mortality in women. There are several known risk factors for breast cancer including genetic<br/>factors which account for at least 25% of the incidence of breast cancer, although only a small<br/>proportion of this is a result of mutations in known high penetrance susceptibility genes. The<br/>majority of genetic risk is now thought to be due to common genetic variants, for example single<br/>nucleotide polymorphisms (SNPs). We investigated whether SNPs in candidate genes, with a<br/>biological reason for being of interest to study in relation to breast cancer, were correlated with<br/>the development of tumours with a certain phenotype, such as grade, lymph node involvement,<br/>oestrogen receptor status and the presence of distant metastases.<br/><br/>We genotyped 206 SNPs across 30 candidate genes in 1001 patients. Association was performed<br/>using Cochran-Armitage trend test and 2-by-3 tables of disease by genotype.<br/><br/>We replicated observations from previous studies such as the association of SNPs in FGFR2,<br/>TNRC9 and ATM with oestrogen receptor status and identified novel associations of SNPs in the<br/>oestrogen receptor gene and matrix metalloproteinase-9 gene (MMP-9) with grade and presence<br/>of distant metastasis respectively.<br/><br/>The function of two promoter SNPs in MMP-9 were further investigated using luciferase reporter<br/>gene assays. The C allele of rs3918242 had a 1.5 fold increase in MMP-9 expression in MDA-MB-<br/>231 cells and the A allele of rs3918241 showed a slight increase in MMP-9 expression in MCF-7<br/>and NIH-3T3 cell lines although not significant.<br/><br/>The novel results identified need to be replicated for validation but this study provides evidence<br/>that common genetic variants play a role in predisposing to certain tumour types.

Name dc:type.qualificationname

Ph.D.

Level dc:type.qualificationlevel

doctoral

Grantor dc:publisher.institution

University of Southampton

Year dc:date.issued

2010

Author dc:creator

• Hammond, Victoria Naomi

Advisor dc:contributor.advisor

• Eccles, Diana