Beyond the BRCA Genetic Test: Predicting Risk of Non-Hereditary Breast Cancer

A blood draw may soon be used to help predict a woman’s risk of developing breast cancer, even in the absence of a BRCA1 gene mutation. Researchers at the Elizabeth Garrett Anderson Institute for Women’s Health at the University College London (UCL) in the United Kingdom are developing a genetic test based on an epigenetic signature that may predict whether a woman is predisposed to develop breast cancer. The results are published in the journal Genome Medicine.

Women who carry a mutation in the BRCA1 gene have as much as an 85% chance of developing breast cancer over their lifetime. Yet BRCA1 and BRCA2 mutation carriers account for less than 10% of all breast cancer cases, making it likely that those other genetic signatures of breast cancer predisposition do exist.

Shahzia Anjum and Martin Widschwendter, both of the UCL, and colleagues, identified a DNA methylation signature which they call "DNAme" among BRCA1 mutation carriers that is also able to predict the predisposition for breast cancer of those women who are not BRCA1 mutation carriers. The authors suggest that this epigenetic signature may be an early biomarker of breast cancer risk among women.

In this study, researchers used blood samples collected several years before breast cancer development from two large UK cohorts of women: MRC National Survey of Health and Development (NSHD) and the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS). 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.

Widschwendter said in a statement:

"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 analyzed blood samples from two independent cohorts (NSHD and UKCTOCS) of BRCA1 mutation carriers and control samples that did not carry the BRCA1 mutation. A total of 152 women (75 who developed breast cancer and 77 controls who did not develop cancer during the 12-year follow up period) from the NSHD cohort who had blood draws at the age of 53 in 1999 and had previously not developed breast cancer were assessed. Samples from 119 women who developed breast cancer and 122 who were cancer-free during a 12-year follow-up from the UKCTOCS were also assessed.

The epigenetic signature could predict breast cancer risk independent of other known risk factors and family history of breast cancer (P=.03) among the UKCTOCS sample set. This DNAme signature could also predict breast cancer mortality (P=.02).

Certain epigenetic changes, such as aberrant DNA methylation changes, have been previously shown to be linked to cancer. According to the study authors, the epigenetic signature identified in the current study is consistent with this, but further studies are still required to understand whether these DNA methylation changes in the genome are directly linked to development and/or cancer progression, or are an indirect indicator of breast cancer risk. Other factors that may contribute to breast cancer risk and whether these factors can lead to the epigenetic signature identified by the current study is still unclear.