Surgery (Austin & Northern Health) - Theses

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    Identification of genetic changes in prostate tissue of men with prostate cancer from multiple breast cancer families
    Kavanagh, Liam ( 2013)
    Introduction: Male BRCA2 mutation carriers are at higher risk of developing aggressive prostate cancer. My research looks at DNA changes in prostate cancer specimens from men positive for a BRCA2 mutation. The first project involves DNA analysis of HG PIN tissue to look for loss of heterozygosity (LOH) in those carriers of a BRCA2 mutation. The purpose of looking for LOH in HG PIN of BRCA2 positive carriers is to ascertain if this tissue is a genomic predictor for tumorigenesis in this population. We also considered that whole exome copy-number analysis (CNA) of prostate cancer tissue, as well as HG PIN and normal prostate tissue from these BRCA2 men, may provide additional insight. Another inheritable mutation associated with prostate cancer is the HOXB13 mutation. We explored our cohort of prostate cancer men from breast cancer-rich families for the incidence of this mutation and impact on survival. We also investigated the incidence of the HOXB13 mutation in breast cancer women from breast cancer-rich families. Patients and Methods: Ten BRCA2 positive participants, from the kConFab cohort of high-risk breast cancer families, were identified , with access to archival prostate tissue specimens. Loss of heterozygosity (LOH) at the BRCA2 gene was examined using mutation specific PCR and sequencing of DNA from laser microdissected HG PIN. We also dispatched 15 DNA samples to Affymetrix for CNA: 9 prostate adenocarcinoma tissue DNA samples with 4 matched normal prostate tissue samples and 2 matched HG PIN samples. This data was analysed using specific software for microarray genetic analysis. For the HOXB13 study, the G84E variant was screened for using high resolution melting analysis in germ-line DNA in the index case or youngest affected member of 898 high-risk breast cancer families and in 1097 population controls. Results: Within this cohort of 10 pathogenic BRCA2 carriers, no patient displayed LOH at the mutation locus within HG PIN, irrespective of whether or not corresponding adenocarcinoma DNA displayed LOH. For the CNA project, our samples showed common sites of amplification at 8q, as well as deletions at 10q and 13q. Six out of 898 multi-case breast cancer families had carriers of the HOXB13 G84E variant: three families had either a single or multi-case family history of prostate cancer (3/99) and three had a personal and family history of breast cancer (3/799). Conclusion: Although HGPIN is considered a precursor to cancer, as no LOH was observed, this assay does not provide a genetic marker that may be considered a positive predictor of tumorigenesis in BRCA2 carriers. Regarding the CNA study, this is the first genomic analysis of this specific patient group, with our results have validated previous results of CNA in prostate cancer, as well as demonstrating the highly heterogenous nature of copy-number changes in this subset of patients. We confirm an association of the HOXB13 G84E variant with good prognosis prostate cancer in non BRCA1 or BRCA2 breast cancer families but we found no evidence for an increased risk of familial breast cancer.