Identification and Characterisation of Breast Cancer Susceptibility Genes

Genetic Susceptibility Team

Section: Section of Cancer Genetics

 

Ascertainment and collection of samples from Breast Cancer Families

We are collecting families with three or more cases of breast cancer. Thus far we have collected over 3,000 families for research (together with the Breast Cancer Susceptibility Collaboration (UK)) probably the largest collection the world. All the families are screened for mutations in BRCA1, BRCA2 and for the presence of CHEK2*1100delC. We are using several different strategies to try to identify breast cancer susceptibility genes utilising this extensive series of breast cancer families.

Genome-wide linkage analyses in familial breast cancer

In an effort to identify further high or moderate penetrance breast cancer predisposition genes, we have completed a genome-wide linkage search using 400 microsatellite markers at 10cM density in approximately 80 BRCA1/2-negative families with three or more cases of breast cancer diagnosed before 60 years. These data have been combined with a further 70 families contributed by collaborators from USA, Europe and Australia. Linkage analyses performed in collaboration with Professor Doug Easton (University of Cambridge) suggest that there is unlikely to be another high penetrance breast cancer gene that accounts for a large proportion of familial breast cancer.

Genome-wide non-synonymous coding polymorphism analyses in familial breast cancer cases vs controls

In order to identify further low penetrance breast cancer susceptibility alleles we are performing genome-wide single nucleotide polymorphism-based allelic association analyses in 1,000 familial breast cancer cases versus 1,000 matched controls as part of the Wellcome Trust Case-Control Consortium. In the first phase we are evaluating approximately 17,000 non-synonymous coding polymorphisms that have currently been identified. We aim to extend these analyses to cover as many genes and non-synonymous coding SNPs in the genome as possible over the next few years.

Mutational screening of candidate genes from DNA repair pathways

BRCA1 and BRCA2 are involved in DNA repair processes. Mutations in genes encoding other proteins in these pathways are candidates for conferring breast cancer susceptibility. We are screening the full coding sequence of 40 DNA repair genes in familial breast cancer cases not due to BRCA1 or BRCA2, to identify mutations in DNA repair genes that may contribute to breast cancer susceptibility.

Evaluation of ATM in breast cancer susceptibility

Ataxia-telangiectasia is a rare recessive condition characterised by uncoordinated motor control, immunodeficiency and predisposition to malignancy, particularly leukemias and lymphomas. The disorder is caused by mutations in the ATM gene. Epidemiological studies of AT families suggest that heterozygotes are at increased risk of cancer with women estimated to have a 2-5 fold relative risk of breast cancer. However, molecular studies of the ATM gene in breast cancer cases have proved inconclusive and contradictory. To clarify the role of ATM mutations in breast cancer susceptibility, we have screened 500 BRCA1/2 negative familial breast cancer cases and 500 controls through the full coding sequence of ATM to evaluate its role.

Large-scale high throughput sequencing in familial breast cancer cases

Over the next few years we plan to extend mutational screening of candidate genes in non-BRCA1/2 familial breast cancer cases with the ultimate aim of undertaking genome-wide sequencing of all genes.