Genetic variation and allelic imbalance in a selection of genes in breast cancer patients

Abstract

Genetic variation, such as Single Nucleotide Polymorphisms (SNPs), are naturally occurring characteristics of the genome that differs between individuals of a species, and in some cases affect the risk of developing a disease. When the phenotype is affected by the genotype it happens through expression, and the level of expression itself can be considered a phenotype. When two alleles have different expression levels it is known as Allelic Imbalance (AI). Breast cancer (BC) is a complex disease which is influenced by genetic variation and level of expression of certain genes, along with other risk factors, e.g. Mendelian inherited gene variants (like BRCA1 and BRCA2) and hormone replacement therapy (HRT). This thesis examines the variation in germline DNA and tumour expression level in BC patients. SNPs in 9 haplotypes associated with Reactive Oxygen Species (ROS) pathways, and previously shown to have significantly different genotype frequencies in BC cases and controls, were genotyped with MassArray in a larger number of BC cases and healthy controls, and the frequency distribution of the two groups was compared. This validation showed that all 9 haplotypes was significantly associated with BC risk. In addition, 20 SNPs in 19 genes were genotyped in tumour RNA with the TaqMan SNP Genotyping assays to measure the level of expression of each allele relative to each other, and 50 % was shown to have significant AI.