The role of genetic factors in breast cancer aetiology

Abstract

Breast cancer is the most common cancer in women and is also the leading cause of cancer
mortality in women. There are several known risk factors for breast cancer including genetic
factors which account for at least 25% of the incidence of breast cancer, although only a small
proportion of this is a result of mutations in known high penetrance susceptibility genes. The
majority of genetic risk is now thought to be due to common genetic variants, for example single
nucleotide polymorphisms (SNPs). We investigated whether SNPs in candidate genes, with a
biological reason for being of interest to study in relation to breast cancer, were correlated with
the development of tumours with a certain phenotype, such as grade, lymph node involvement,
oestrogen receptor status and the presence of distant metastases.

We genotyped 206 SNPs across 30 candidate genes in 1001 patients. Association was performed
using Cochran-Armitage trend test and 2-by-3 tables of disease by genotype.

We replicated observations from previous studies such as the association of SNPs in FGFR2,
TNRC9 and ATM with oestrogen receptor status and identified novel associations of SNPs in the
oestrogen receptor gene and matrix metalloproteinase-9 gene (MMP-9) with grade and presence
of distant metastasis respectively.

The function of two promoter SNPs in MMP-9 were further investigated using luciferase reporter
gene assays. The C allele of rs3918242 had a 1.5 fold increase in MMP-9 expression in MDA-MB-
231 cells and the A allele of rs3918241 showed a slight increase in MMP-9 expression in MCF-7
and NIH-3T3 cell lines although not significant.

The novel results identified need to be replicated for validation but this study provides evidence
that common genetic variants play a role in predisposing to certain tumour types.

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Identifiers

ORCID for Diana Eccles: orcid.org/0000-0002-9935-3169

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