Copy number variants and their role in hereditary breast cancer and hereditary colorectal cancers

Hereditary breast cancer and hereditary colorectal cancers are associated with an earlier age of diagnosis and a higher frequency of disease among family members. In recent decades cancer susceptibility genes have been associated with hereditary forms of breast cancer and colorectal cancers however these genes only account for a minority of families seeking diagnostic testing. Genetic variation explains a significant proportion to susceptibility of disease. Copy number variants (CNVs) are a form of structural genetic variation yet to be fully explored for their contribution to hereditary breast cancer or hereditary colorectal cancers. CNV analysis can be used to identify new genes and loci which may be associated with disease risk. The Affymetrix Cytogenetic Whole Genome 2.7M (Cyto2.7M) array was used to detect regions of genomic gain and loss in a cohort of 350 samples (encompassing 129 BRCA1/BRCA2 mutation negative hereditary breast cancer patients, 56 Familial adenomatous polyposis (FAP) APC mutation negative and 125 Hereditary non-polyposis colorectal cancer (HNPCC) mismatch repair (MMR) mutation negative colorectal cancer patients and each were compared to 40 healthy control genomes). CNV analysis revealed the presence of 614 genes unique to the combined patient cohort which represent candidates for involvement in hereditary breast cancer and hereditary colorectal cancers. Several CNVs were found that were associated with previously reported cancer susceptibility genes. These included CNVs associated with APC, DCC, MLH1 and CTNNB1 in four polyposis patients and RPA3, NBN (NBS1), MRE11A and CYP19A1 in five breast cancer patients and suggests their role in disease development in the affected individuals. Of special interest was the identification of WWOX and FHIT rearrangements in three breast cancer patients, and a recurrent deletion that was observed on chromosome 18 at position 18p11.32 in 9% of the polyposis patients screened. These variants could further account for disease in the affected patients. Bioinformatic analysis of the uniquely identified gene sets provided further insight into the roles of these genes in disease. This thesis provides evidence supporting the hypothesis that CNVs are likely contributors to disease development in a small but significant proportion of hereditary breast cancer and hereditary colorectal cancer patients.