- Title
- The contribution of genetic susceptibility to breast cancer
- Creator
- Wong-Brown, Michelle Wai Yin
- Relation
- University of Newcastle Research Higher Degree Thesis
- Resource Type
- thesis
- Date
- 2014
- Description
- Research Doctorate - Doctor of Philosophy (PhD)
- Description
- Breast cancer is the most common cancer in women worldwide, and although genetic predispositions to breast cancer have been intensively studied, there remain a considerable number of questions to be answered. Approximately 75% of all breast cancer cases have an unknown aetiology, whereas about 25% have an apparent inherited genetic component. Of these that have a family history, approximately 40% are due to mutations in BRCA1 and BRCA2, the two breast cancer susceptibility genes discovered over two decades ago. The remaining 60% of familial cases do not have any identifiable BRCA1 or BRCA2 mutations and await the discovery of their genetic origins. Conventional sequencing technologies are also limited in their capacity to sequence highly homologous sequences as identified in the introns of the BRCA genes. This raises the possibility that there may be mutations residing in regions that are difficult to interrogate in BRCA1 and BRCA2 or there exist other biologically relevant genes that contribute to genetic risk. Many have hypothesized that the genes involved in the BRCA DNA repair pathway are prime targets for analysis as they have a high likelihood of contributing to breast cancer risk. The paucity of information about their involvement in breast cancer risk is a result of the limitations of conventional mutation detection technologies (such as Sanger sequencing), such that insufficient groups around the world have focused on the other candidate genes in this pathway. Due to the lack of information about disease penetrance in genes apart from BRCA1 and BRCA2, little traction has been gained in applying knowledge about genes such as BRIP1, PALB2, and RAD51C in a clinical setting. In addition to the problems associated with genes that are not commonly associated with breast cancer risk there is also a major problem with the classification of variants in any gene (including BRCA1 and BRCA2) as pathogenicity is not always obvious. The specific aims of this PhD research project were to sequence the genes involved in this pathway including BRCA1 and BRCA2 using conventional and new mutation detection technologies and elucidate the contribution of the BRCA DNA repair pathway to breast cancer predisposition. In the studies to follow, we have assigned the BRCA1 c.5194-12 G>A unclassified variant of the BRCA1 transcript as pathogenic, by demonstrating that the intronic variant results in a truncated non-functional protein. We have also shown that there are many unclassified variants in the introns of the BRCA genes, and one or many of these variants may lead to the decreased expression of the BRCA1 transcript in breast cancer patients. This project has also shown that mutations in BRIP1 and PALB2 are present at relatively low frequencies (2.8%) in the familial breast cancer population, and that they do contribute to the genetic predisposition to familial breast cancer. It has been recognised for some time that there are phenotypic similarities between tumours arising on a background of BRCA1 (and to a lesser extent BRCA2) and triple negative breast tumours, suggesting that there may be a link between them. Pathogenic BRCA and PALB2 mutations were identified in 8.6% and 0.9% of individuals with triple-negative breast cancer, respectively. This shows that BRCA and BRCA-associated genes are also involved in the genetic predisposition to non-familial triple-negative breast cancer. Taken together, the results presented in this thesis show that there are more genes implicated in the genetic predisposition to familial breast cancer, such as BRIP1 and PALB2. However, these additional genes do not appear to account for more than a small proportion of all familial breast cancer cases compared to those attributed to BRCA1 and BRCA2. There are many other variants in BRCA1 and BRCA2 with unknown clinical significance that could lead to the altered gene expression, thereby influencing breast cancer risk. Our studies suggest that there are similarities between the mutation profiles of triple-negative and familial breast cancers, and that TNBC should be screened for mutations in the BRCA genes. This research project has added to our knowledge of the genetic predisposition to breast cancer and has clarified the genetic landscape of a small proportion of breast cancer cases that was previously unknown.
- Subject
- genetics; breast cancer
- Identifier
- http://hdl.handle.net/1959.13/1050561
- Identifier
- uon:15177
- Rights
- Copyright 2014 Michelle Wai Yin Wong-Brown
- Language
- eng
- Full Text
- Hits: 627
- Visitors: 955
- Downloads: 398
| Thumbnail | File | Description | Size | Format | |||
|---|---|---|---|---|---|---|---|
| View Details Download | ATTACHMENT01 | Abstract | 465 KB | Adobe Acrobat PDF | View Details Download | ||
| View Details Download | ATTACHMENT02 | Thesis | 12 MB | Adobe Acrobat PDF | View Details Download |