- Title
- The role of short tandem repeats in genetic susceptibility to breast and endometrial cancers
- Creator
- Bolton, Katherine Anne
- Relation
- University of Newcastle Research Higher Degree Thesis
- Resource Type
- thesis
- Date
- 2016
- Description
- Research Doctorate - Doctor of Philosophy (PhD)
- Description
- Breast cancer is an estrogen-responsive malignancy and the most common cancer that develops in women worldwide, with one in eight Australian women being diagnosed with disease by age 85. Endometrial cancer is another estrogen-responsive cancer and is the most common gynaecological malignancy in women from developed countries. It is estimated that genetic predispositions account for between 5% and 10% of all breast cancer cases; however, approximately 25% of breast cancer patients have a family history of the disease. Therefore, a significant proportion of breast cancer patients are likely to have genetic causes that have not yet been identified. At present most of the genetic risk for endometrial cancer also remains unexplained. Genome-wide association studies (GWAS) into either breast or endometrial cancer have revealed some of the heritability associated with these diseases but there remains a significant proportion of disease that has not been explained genetically. This genetic susceptibility for disease that is yet to be identified is referred to as “missing heritability”. High-throughput investigations, including next-generation sequencing and GWAS have been used in efforts to identify genetic factors responsible for this missing heritability. However these studies have revealed the intricacy of genetic inheritance in complex diseases, with new variants identified, such as single-nucleotide polymorphisms that account for a fraction of disease risk. For this reason, alternative sources of genetic variability should be considered that may not be amenable to current high-throughput experiments. Tandem repeats (TRs) are a source of variation in the human genome that have been found to be responsible for various neurological conditions and have been associated with other complex diseases, but have largely been over-looked due to difficulties analysing them on a large scale. The role of TRs in cancer is not well understood, with only a small number of genes that contain TRs having been analysed in relation to cancer risk. Many associations uncovered between TRs and cancer risk have been contradictory, possibly due to different ethnic origins in cohorts or small sample sizes. It has become increasingly apparent that introns and regulatory regions outside of genetic coding regions can play a large role in affecting gene expression. Hence, this project has focused on the role that TRs in regulatory regions may play in the risk of developing the hormone-driven malignancies, breast and endometrial cancer. We hypothesise that variable short tandem repeats (STRs) in the regulatory regions of certain genes will be associated with breast and/or endometrial cancer. These polymorphisms are likely to alter chromatin structure and/or transcription factor binding and hence gene expression, changing the activity of the protein and resulting in altered risk of developing cancer. In order to investigate the role of STRs in cancer risk, specific genes with STRs in upstream regulatory regions needed to be singled out for analysis. This was done by two separate approaches: firstly, with a literature search to identify candidate genes previously known to be associated with cancer risk; and secondly, through a gene set enrichment analysis (GSEA) approach to identify novel genes containing these upstream regulatory STRs that may be involved in cancer processes. In order to perform GSEA we firstly developed a resource, called STaRRRT (for Short Tandem Repeats in Regulatory Regions Table), that outlines the location and characteristics of STRs found throughout the human genome in an upstream regulatory region. This genome-wide search revealed that 5,264 STRs are present in the upstream regulatory regions of 4,441 human genes, with this resource being made freely available on the internet for future use. The genes and pathways identified through GSEA were then prioritised for further analysis. A novel STR in the upstream region of the estrogen-induced gene, EIG121, which had previously been associated with endometrial cancer, was analysed in a case-control study. It was found that this STR is highly variable but not associated with the risk of developing either breast or endometrial cancer. Another STR, located in the promoter of the insulin-like growth factor 1 gene, IGF1, was also analysed in the same breast cancer, endometrial cancer and healthy control cohorts. The results were consistent with previous studies in finding no association with the risk of developing breast cancer; however a novel association with the age at diagnosis for endometrial cancer was found. The results presented in this thesis show that there are many STRs present in regulatory regions of the human genome that have the potential to affect the risk of developing cancer (or other complex diseases). Improving high-throughput techniques will make the study of such repetitive regions quicker, more thorough and efficient, and hence more appealing to investigate. The full potential of these important regions on gene expression, evolution and diseases may then be revealed. Such repetitive regions could be utilised to improve the understanding of disease processes and may provide more effective biomarkers for screening individuals at an increased risk of developing these cancers.
- Subject
- genetics; breast cancer; endometrial cancer; short tandem repeat; thesis by publication
- Identifier
- http://hdl.handle.net/1959.13/1316830
- Identifier
- uon:23272
- Rights
- Copyright 2016 Katherine Anne Bolton
- Language
- eng
- Full Text
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| Thumbnail | File | Description | Size | Format | |||
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| View Details Download | ATTACHMENT01 | Abstract | 1 MB | Adobe Acrobat PDF | View Details Download | ||
| View Details Download | ATTACHMENT02 | Thesis | 6 MB | Adobe Acrobat PDF | View Details Download |