Cell Changes in Fallopian Tubes of BRCA Mutation Carriers May Lead to Strategies for Preventing Ovarian Cancer

Recognition of early changes in the Fallopian tube cells of BRCA gene mutation carriers may be key to new strategies for preventing ovarian cancer that could also reduce the need for invasive surgery.1

This research project sought to understand why women with BRCA1/2 mutations develop ovarian cancer and what happens in the cells where the cancer originates to trigger its development. The project was funded by The Eve Appeal, a charity in the United Kingdom that funds world-class research into women's cancers.

The researchers examined postsurgical reproductive tubal tissue from 115 women, including 56 with BRCA1/2 mutation and a control group of 59 women without the mutation. Their analysis looked at the epigenetics of the cells, which affects how DNA is read. Crucially, they compared both ends of the Fallopian tubes—the fimbrial (closest to the ovary) and the uterine (closest to the womb)—from the same woman.

Radically altered subcellular activity was discovered in the fimbrial tubal cells in approximately 60% of the women carrying the BRCA1 or BRCA2 gene mutation. These subcellular changes were similar to those seen in cells from ovarian cancer specimens. The changes were not seen in the women without BRCA mutations. In addition, the researchers identified activation-induced cytosine deaminase (AID), an enzyme that appears to trigger this reprogramming.

"These new findings take us a step closer to understanding how ovarian cancers develop in BRCA1/2 gene mutation carriers, opening up new opportunities for ovarian cancer prevention,” said senior author Martin Widschwendter, MD, of the Department of Women's Cancer at University College London, London, United Kingdom.

“This is vital as at present the most effective method of prevention is drastic risk-reducing surgery which deprives women of their hormones and their ability to give birth prior to the menopause. The next steps will be to investigate the merit of drugs that affect epigenetic reprogramming and to look for biomarkers which allow safe monitoring of the effect of such drugs."

Widschwendter and his team are now further investigating their findings including whether these findings could benefit women who do not have a predisposing genetic mutation by facilitating the development of a noninvasive test that could potentially predict these cellular events in the tubal cells.

Athena Lamnisos, chief executive of The Eve Appeal said, "Stopping women's cancers before they start is the ultimate ambition of our research program. To do this we need to track cancer development right back to its earliest development and understand how it begins. This research is an important step in achieving this ambition. It provides hope for women of the future who might not need to undergo such drastic, invasive surgery to aid the prevention of ovarian cancer."

Reference

1. Bartlett TE, Chindera K, McDermott J, et al. Epigenetic reprogramming of fallopian tube fimbriae in BRCA mutation carriers defines early ovarian cancer evolution [published online May 24, 2016]. Nat Commun. doi:10.1038/ncomms11620.

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