Use this URL to cite or link to this record in EThOS: https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.778428
Title: DNA signatures as a predictor of breast cancer risk
Author: Koron, Roshan
ISNI:       0000 0004 7964 1627
Awarding Body: University of Liverpool
Current Institution: University of Liverpool
Date of Award: 2018
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Abstract:
Introduction: Breast cancer is the most common cancer in the UK with around 54,900 new cases diagnosed each year and 11,400 breast cancer deaths reported in 2016. Early diagnosis of breast cancer and personalised treatment strategies lead to a more favourable outcome. Biomarkers are essential for disease management in terms of risk calculation, response to treatment and disease outcome. The aim of this study has been to assess whether two variable number tandem repeats (VNTRs) may help to modify prediction of breast cancer risk in patients with pathogenic germline variants in the BRCA1 and BRCA2 tumour suppressor genes. I therefore explored the polymorphism of the AAAG VNTR in the 5' untranslated region (UTR) of the oestrogen related receptor ? (ESRRG) gene and a 15 bp VNTR located in the internal promoter region of the MIR137 gene as both genes are implicated in breast cancer. Reporter gene analysis was performed on the ESRRG AAAG VNTR to observe the effects of varying repeat lengths on differential expression of the gene under basal conditions and following exposure to oestrogen in a luciferase reporter gene assay. VNTRs are often regulatory in nature therefore they may show insight into pathways underlying cancer. Method: The ESRRG AAAG and MIR137 VNTRs were explored by genotyping analysis on germline DNA in a female breast cancer cohort containing BRCA1/2 positive, BRCA1/2 negative breast cancer patients, and a group of healthy controls. The variance of ESRRG AAAG VNTR copy number and its effect on gene transcription with oestrogen stimulation was assessed in a reporter gene assay in a breast cancer cell line (MCF7). Results: MIR137: MIR137 VNTR analysis revealed a significant difference in repeat distribution between BRCA positive and BRCA negative patients and was significantly different between BRACA1 and BRACA2 germline mutation carriers using clump statistical analysis. ESRRG AAAG VNTR: nine different allele variants of the AAAG repeats were observed. The longer copy numbers were more prevalent in the cancer free control group whereas the shorter copy numbers were associated with BRCA1/2 positive cases. Nine copies of the AAAG VNTR showed significantly enhanced reporter gene activity with oestrogen exposure in MCF-7 breast cancer cells. Conclusion: Significant differences in MIR137 VNTR length were found between BRACA1 and BRACA2 germline mutation carriers and wild type controls. The ESRRG AAAG VNTR showed significant distribution differences between the BRCA1/2 positive and control groups. An increase in ESRRG transcription on exposure to oestrogen in the presence of 9 copies of the VNTR may relate to an increased cancer risk. This may be influenced by environmental factors which contribute to GxE interactions in cancer. Our findings support the role of the ESRRG AAAG VNTRs as a potential biomarker in the prediction of breast cancer risk in BRCA1/2 pathogenic germline variant carriers and may also add information to genetic risk scores which can further stratify treatment and surveillance in high risk individuals. Although significant differences were found between groups in MIR137 VNTR the sample sizes were small therefore these results should be interpreted with caution. This data should be extended and validated in a larger cohort.
Supervisor: Quinn, John ; Bubb, Vivien Sponsor: Not available
Qualification Name: Thesis (M.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.778428  DOI:
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