exciting blood test to predict risk of bc in those BRCA- by current testing

[Lani]

their brca problem may be epigenetic (methylation of genes--sort of like chewing gum stuck onto the outside of the DNA stopping RNA from reading it correctly and making the right protein) rather than a problem in the DNA of the gene itself

If this holds out we might screen only the high risk people, alter their risk factors, prevent many cases and treat many fewer with more effective treatment(as they should be able to afford more genetic and epigenetic testing to individualize tumor treatment if they are treating fewer patients) . There are also drugs which affect methylation/demethylation of genes .... altogether very hopeful for minimizing the number of people getting invasive breast cancer and their ability to receive effective treatment if they do

New test predicts the risk of non-hereditary breast cancer
[Eureka News Service]

A simple blood test is currently in development that could help predict the likelihood of a woman developing breast cancer, even in the absence of a high-risk BRCA1 gene mutation, according to research published in the open access journal Genome Medicine.

Researchers from UCL (University College London) identified an epigenetic signature in the blood of women predisposed for breast cancer owing to an inherited genetic mutation of the BRCA1 gene. Epigenetic alterations are thought to be key molecular switches that are involved in the development of cancer. Strikingly, the same signature was discovered in the blood of women without a BRCA1 mutation but who went on to develop breast cancer, making it a potential early marker of women's cancer in the general population.

BRCA1 mutation is inherited from a parent, and is the cause of at least ten percent of breast cancers. The cause of the remaining 90% of sporadic breast cancers in non-mutation carriers remains to be explained. Scientists are beginning to understand that genetic mutations are not the sole contributors to disease development and that the way in which genes are arranged in our cells can affect whether they function appropriately - that is, whether they are turned on or off. The arrangement and expression of our genes is overseen by the process of epigenetics. One of the most studied epigenetic mechanisms is a process called DNA methylation, which was the focus of the current study.

In this study, researchers used blood samples collected several years before breast cancer development from two large UK cohorts of women - the MRC National Survey of Health and Development and the UK Collaborative Trial of Ovarian Cancer Screening. They looked at the DNA methylation signature from blood of those women with and without BRCA1 mutations. When this signature was applied to samples from both these groups, those women who developed non-hereditary cancers were found to have the same DNA methylation signature.

Professor Martin Widschwendter, the study's lead author and Head of University College London's Department of Women's Cancer says: "We identified an epigenetic signature in women with a mutated BRCA1 gene that was linked to increased cancer risk and lower survival rates. Surprisingly, we found the same signature in large cohorts of women without the BRCA1 mutation and it was able to predict breast cancer risk several years before diagnosis."

The researchers believe the epigenetic signature they found is consistent with the idea that changes in the epigenome of immune cells are key to cancer progression. The signature may be responsible for silencing genes in immune cells, which in turn could affect the ability of the immune system to prevent breast cancer development. Further research needs to be done to find out whether this epigenetic signature is just an indicator of breast cancer risk or is involved with the progression of breast cancer. Work is now proceeding on using these findings in the clinical setting.

Professor Widschwendter says: "The data is encouraging since it shows the potential of a blood based epigenetic test to identify breast cancer risk in women without known predisposing genetic mutations".

The work was jointly funded by The Eve Appeal and the National Institute for Health Research (NIHR) University College London Hospitals Biomedical Research Centre.

OPEN ACCESS: A BRCA1-mutation associated DNA methylation signature in blood cells predicts sporadic breast cancer incidence and survival
[Genome Medicine]

Background: BRCA1 mutation carriers have an 85% risk of developing breast cancer but the risk of developing non-hereditary breast cancer is difficult to assess. Our objective is to test whether a DNA methylation (DNAme) signature derived from BRCA1 mutation carriers is able to predict non-hereditary breast cancer.

Methods: In a case/control setting (72 BRCA1 mutation carriers and 72 BRCA1/2 wild type controls) blood cell DNA samples were profiled on the Illumina 27 k methylation array. Using the Elastic Net classification algorithm, a BRCA1-mutation DNAme signature was derived and tested in two cohorts: (i) The NSHD (19 breast cancers developed within 12 years after sample donation and 77 controls) and (ii) the UKCTOCS trial (119 estrogen receptor positive breast cancers developed within 5 years after sample donation and 122 controls).

Results: We found that our blood based BRCA1-mutation DNAme signature applied to blood cell DNA from women in the NSHD resulted in a Receiver Operating Characteristics (ROC) Area Under the Curve (AUC) of 0.65 (95% CI 0.51-0.78, P = 0.02) which did not validate in buccal cells from the same individuals. Applying the signature in blood DNA from UKCTOCS volunteers resulted in AUC of 0.57 (95% CI 0.50-0.64; P = 0.03) and is independent of family history or any other known risk factors. Importantly the BRCA1-mutation DNAme signature was able to predict breast cancer mortality (AUC = 0.67; 95% CI 0.51-0.83) P = 0.02). We also found that the 1074 CpGs which are hypermethylated in BRCA1 mutation carriers are massively enriched for stem cell polycomb group target genes (P < 10-20).

Conclusions: A DNAme signature derived from BRCA1 carriers is able to predict breast cancer risk and death years in advance of diagnosis. Future studies may need to focus on DNAme profiles in epithelial cells in order to reach the AUC thresholds required of preventative measures or early detection strategies.