Cancer risk

Overview of our most important scientific findings associated with cancer risk.

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Epimutations in the BRCA1 gene results in increased risk of developing triple negative breast cancer and ovarian cancer

Germline mutations in one of the two so-called breast cancer genes (BRCA1 and BRCA2) is the most frequent cause of inherited breast (and ovarian) cancers. While other genes have been shown associated with breast cancer risk, their contribution is small.

Most genes contains one or more “on-off switches” regulating their activity. Such switching, on and off, is a normal procedure during life, and plays a pivotal role at the prenatal stage (before birth). Aberrant silencing or activation of genes by errors in this “button function” is well known, and may act like gene mutations. Such aberrant silencing is termed “epimutations”, or “hyper-methylation”, and may play serious effects in many diseases, including cancer.

An important question is whether such epimutations, affecting normal cells, may actually be cancer-triggering events. In a recent study now in the well-known medical journal JAMA Oncology we actually show this to happen. In collaboration with US investigators in the famous Women Health Initiative (WHI), we found such epimutations affecting the BRCA1 gene in the blood of about 5% of healthy women. As for those carrying such epimutations, the risk to develop a so-called triple negative breast cancer (TNBC), was nearly 2.5 times higher than for women not carrying such methylations. TNBC accounts for about 15% of all breast cancers and is characterized by the lack of receptors for estrogen, progesterone and HER2 in the cancer cells. TNBC is often affecting younger women, and in general carries a more serious prognosis compared to other breast cancer subtypes. Moreover, women carrying these BRCA1 epimutations had an 80% increased risk also of malignant ovarian cancer.

Currently, we do not know the cause of these epimutations, but based on previous data, we know they happen before birth. In a study recently published in the prestigious medical journal Genome Medicine, researchers at the Medical Department, in collaboration with other national cancer centres, have now shown that in around 20% of the women developing triple-negative breast cancer, the foundation for this disease is established in early embryonic life. This happens when the most important cancer gene, BRCA1, is aberrantly switched off in a small group of cells. No concordance in epimutations was observed between newborns and their parents, thus arguing against direct inheritance and pointing to other regulatory mechanisms during pregnancy. These findings have raised great scientific interest internationally, and researchers are now working to determine the cause of these epimutations, hopefully being able to reduce this cancer risk.