Genomic Profiling of Familial Early-age of Onset Breast Cancer

Familial breast cancers make up a small proportion of all breast cancer cases. Mutations in known breast cancer susceptibility genes, such as BRCA1 and BRCA2, can explain a third of familial breast cancer risk. A woman's breast cancer risk increases two-folds if she has an affected first degree relative and the risk increases if the relative was diagnosed at a young age. Thus, it is important to understand the genetic architecture and the genes involved in breast cancer pathogenesis in individuals diagnosed at a young age with a family history of breast cancer. In this thesis I took advantage of archival and frozen specimens ascertained from the Familial Breast Cancer Registry and the Toronto Axillary Node Negative (ANN) Breast Cancer Study to investigate the copy number changes in fourteen non-BRCA1/2-mutated breast cancer cases with a family history and young age of onset to examine copy number analysis using genomic microarrays. The most recurrent alterations included losses of 8p and 17p, single copy gains of 1q and 8q, and high level amplification of ERBB2 and ZNF703. My work indicates there are some genomic regions that are more frequently aberrant in copy number among young familial breast cancer cases compared to independent datasets of young age of diagnosis cases. Next-generation sequencing was also used to study the exomes of 3 tumor-normal pairs and 20 unmatched ANN tumors. Genomic analysis of the tumor-normal pairs found one case with heterozygous variants in both the germline and tumor genome in three breast cancer susceptibility genes, BRCA1, BRCA2, and RAD50. It was observed that ten of the unmatched tumors contained significantly fewer variants than the other ten unmatched samples. The cases with fewer variants had between 866-3,459 variants and the cases with a high number of variants contained 6,452-77,870 variants. The samples with more variants also had significantly more C:G>A:T transversions, evidence for defective mismatch repair that warrants investigation in future studies.Ph.D