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Methylated CpG islands as biomarkers for familial breast cancer
Detection, Diagnosis and Prognosis
Background: The age of onset of breast cancer is variable in BRCA1 and BRCA2 carriers. Surveillance modalities are limited in sensitivity. It is therefore important to develop new biomarkers for breast cancer risk. Methylation markers are potentially useful biomarkers but little is currently known about the methylation profile of familial breast tumors. Hypotheses: 1. Breast tumors from BRCA1, BRCA2 and BRCAx carriers show distinct patterns of cancer-related methylation at CpG Islands (CGIs) ; 2. CGIs, frequently methylated in breast tumors from BRCA1 /2 carriers, can be used in risk assessment using ductal lavage (DL) specimens Aim 1 : Methylation Array analysis in familial breast tumors will be used to identify CGIs methylated in tumors vs normal breast cells. Aim 2 : Selection of CGIs in which methylation is associated with reduced transcription of the nearby gene, and validation by bisulphite SNaPshot analysis. Aim 3 : Bisulphite SNaPshot analysis of validated, methylated CGIs in normal breast (from women of different ages) to identify cancer-related, as opposed to age-related, methylation events as novel biomarkers for breast cancer. Aim 4 : DL can be used to obtain cells to enable the prospective analysis of CGIs, frequently methylated in breast tumors from BRCA1/2 carriers, as a means of risk assessment. Study Design We will use DNA from familial breast tumors, with DNA from normal breasts as a reference, in order to identify frequently methylated CGIs. We will use pattern recognition tools to determine which CGIs are specifically methylated BRCA1, BRCA2 and BRCAx tumors. We will chose the 20 CGIs that are most frequently methylated in BRCA1, BRCA2 and BRCAx tumors, and associated with down-regulation, for validation by bisulphite SNaPshot analysis. Validated, methylated CGIs will then be evaluated in normal breast samples from women of different ages to identify cancer-related methylation. W e will then use these potential biomarkers in our serially-collected DL samples to determine whether there is a relationship between a pattern of CpG methylation and the development of breast cancer and/or cytological atypia . Potential outcomes and benefits If we develop new biomarkers for breast cancer risk in carriers of BRCA1 and BRCA2 mutations, we will be able to add these to the current surveillance approaches used in order to identify small, and potentially treatable, tumors.
Background: Not all BRCA1 and BRCA2 carriers develop cancer and the age of onset is variable. Current screening methods are limited in sensitivity. It is therefore important to develop new ways of finding out which high-risk women are most likely to develop breast cancer. A potentially useful way of doing this would be to find methylation ‘signals’ in breast tumour DNA that might be present in breast cells collected from the ducts before any tumor can be detected by other means. Hypothesis: Breast tumors from carriers show distinct patterns of methylation that can be used in risk assessment using ductal lavage specimens collected from the breast of unaffected, but high-risk women. Aim: To identify novel methylation markers for women with familial breast cancer, and test them on ductal lavage samples to see whether their presence predicts the development of breast cancer. Study Design: We will identify methylation ‘signals’ in frozen tumors from carrier women and then use these potential biomarkers in our serially-collected ductal lavage samples from unaffected, high-risk women. Results will be analyzed to determine whether there is a relationship between a pattern of methylation signals and the development of breast cancer and/or abnormal cells from the breast. Potential outcomes and benefits If we develop new biomarkers for breast cancer risk in carriers of BRCA1 and BRCA2 mutations, we will be able to add these to the current approaches used in order to identify small, and potentially treatable, tumors.