Genetic Connection Between Endometriosis And Ovarian Cancer Found

A new cancer gene mutation – ARID1A – has been found which links endometriosis to two types of ovarian cancer, researchers report in an article published in the New England Journal of Medicine (NEJM). After examining 600 ovarian cancer samples, scientists from the Ovarian Cancer Research Program of British Columbia (OvCaRe) concluded that the genetic mutation, ARID1A and loss of function is thought to be an early event in the development of clear-cell and endometrioid cancers in endometriosis.

Endometriosis is a condition in which cells that normally exist inside the uterus (endometrial cells) are found growing outside of the uterus. That is, the lining of the inside of the uterus is found outside of it. Endometrial cells are the cells that shed every month during menstruation, and so endometriosis is most likely to affect women during their childbearing years. The cellular growth is not cancerous, but benign. Though there are not always symptoms, it can be painful and lead to other problems. The lining of the uterus consists of a type of tissue called endometrium – composed of endometrial cells – that thickens each month to prepare for an egg. It is here where an egg cell implants and grows if it is fertilized. If an egg is not fertilized, the endometrium breaks down and exits the body during the menstrual period.

Endometrial cells that grow outside of the uterus – usually on the ovaries, fallopian tubes, outer wall of the uterus, or intestines – are called implants. However, these implants follow the same pattern as the endometrium lining the uterus of getting thicker, breaking down, and bleeding. Problems occur because these growths are outside of the uterus, and the blood cannot flow out of the body. This can lead to the formation of scar tissue and cysts as well as difficulties getting pregnant.

In this study, researchers detected ARID1A mutations in 46% of ovarian clear-cell carcinomas and in 30% of endometrioid carcinomas. They then joined up with Canadian and international collaborators to determine the frequency and relevance of these genetic mutations.

Clear-cell and endometrioid carcinomas account for about 25% of all ovarian cases in North America; they are the second and third most common forms of ovarian cancer, the authors inform.

Dr. David Huntsman, director of OvCaRe, a partnership program between the BC Cancer Agency and Vancouver Coastal Health Research Institute and professor, University of British Columbia, Faculty of Medicine, said:

Our discovery of the dominant mutation in clear-cell ovarian cancer raises hope for much needed treatments for this little understood cancer type. Connecting ARID1A gene mutations to endometriotic lesions accelerates us toward the development of tools to determine which women with endometriosis are at increased risk for ovarian cancer.

The authors inform that the discovery was the result of a collaboration with Dr. Marco Marra and team from British Columbia’s Cancer Agency’s Genome Sciences Centre – they decoded the RNA from 18 clear-cell carcinomas. With the use of the latest bioinformatics tools, the geneticists took the billions of letters of genetic code and extracted a list of likely mutations.

Main author, Kim Wiegand, a UBC Faculty of Medicine graduate student in Dr. Huntsman’s lab, first observed multiple mutations targeting the ARID1A gene:

When we first saw these mutations we very excited because ARID1A has several functions that made it a potential cancer gene yet mutations in this gene have never been identified before in ovarian cancer

Dr. Andrew Berchuck, director, Division of Gynecologic Oncology, Duke University Medical Center, said:

The finding that ARID1A is the most frequently mutated gene described thus far in endometrioid and clear cell ovarian cancers represents a major scientific breakthrough. This discovery also sheds light on how endometriosis predisposes to the development of these cancers. The novel insights provided by this work have the exciting potential to facilitate advances in early diagnosis, treatment and prevention of endometrioid and clear cell cancers, which account for over 20 per cent of ovarian cancer cases.

Huntsman said:

Ten years ago, ovarian cancer appeared to be an unsolvable problem – the liberating moment came when we established that ovarian cancer is actually a number of distinct diseases. We tailor our research approach to each subtype with the hope of developing effective treatments specific to each disease.