What if a doctor could alert a woman a year or more in advance that she is likely to develop endometrial cancer? Researchers at Mayo Clinic Center for Individualized Medicine have found evidence linking functional modification of certain genes to the emergence of the disease, providing a novel opportunity for intervention and prevention.
The new finding, reported in the journal Gynecologic Oncology, is far-reaching, both to the basic understanding of endometrial cancer — affecting more than 600,000 women in the U.S. — and for the search for preventative measures. Endometrial cancer is the fourth most common cancer in women, with nearly 62,000 new cases and 12,000 deaths estimated in 2019. Incidence rates are expected to rise significantly over the next decade, driven by environmental factors, obesity and diabetes.
“We found that some of the epigenetic markers that are known to be associated with endometrial cancer are altered months to years before the development of the disease,” says Marina Walther-Antonio, Ph.D. “Patients who have increased methylation in particular genes in benign endometrial biopsies are more likely to develop endometrial cancer in the future.”
Flipping the switch: finding genes that have been “turned off”
Dr. Walther-Antonio says “epigenetic markers” are changes in gene activity that control the functional gene level and can effectively turn the gene “on” or “off.”
“In this sense, the gene can be free of mutations, yet be in practice, non-functional — equivalent to a perfectly functional car that will not respond to the accelerator pedal because the key is not turned on in the ignition,” she describes.
“We found that some of the epigenetic markers that are known to be associated with endometrial cancer are altered months to years before the development of the disease." - Dr. Walther-Antonio
Methylation, she explains, is in this analogy, controlling the position of the key in the ignition. This disruption of gene functioning through epigenetic processes such as methylation can be a hallmark of cancer.
The research team studied samples of women over nine years whose endometrial biopsies were benign, but subsequently developed endometrial cancer an average of one year later. To demonstrate their hypothesis, the team studied the promoters of four particular genes that are reported as hypermethylated in endometrial cancer. Which, in this case, is turning the key in the ignition to an “off” position, and in effect, shutting the gene function down.
“We could see that the women who developed cancer in the future were already different at the time of the biopsy,” Dr. Walther-Antonio explains. “They already presented a hypermethylated state in these genes back then.”
Discovering a missed opportunity for prevention
Co-author of the study, Andrea Mariani, M.D. M.S., a gynecology oncologist surgeon who has conducted extensive research on endometrial cancer over two decades, says he developed the study in hopes of discovering this “missed opportunity for prevention.”
“Post-menopausal women would go to the doctor because of bleeding, and they would get a biopsy of their uterus and the biopsy was benign, and then sometime down the road they developed endometrial cancer,” he says. “We call this a missed opportunity.”
Dr. Mariani previously demonstrated that as many as 28% of endometrial cancer patients had a previous non-malignant endometrial biopsy during their lifetime.
"This means that approximately one quarter of endometrial cancers can be potentially prevented if we target this population," he explains.
In his search for answers, Dr. Mariani, who also serves on Mayo Clinic Robotics Subcommittee and collaborates on the use of robotic surgery for the treatment of endometrial cancer, pulled together a team of scientists to combine their expertise.
“I am a physician, I am a surgeon, and I can help define where we need to go, but then we need people like Dr. Walther-Antonio and the other scientists who co-authored this paper, to lead the studies in the lab, and working on identifying and characterizing those genes,” he explains.
“Post-menopausal women would go to the doctor because of bleeding, and they would get a biopsy of their uterus and the biopsy was benign, and then sometime down the road they developed endometrial cancer." - Dr. Mariani.
Dr. Mariani says fortunately, most women are diagnosed with an early stage of endometrial cancer.
“Why? Because many are post-menopausal patients who start to bleed, and so they seek the attention of the doctor. They get scared,” Dr. Mariani says.
But not all outcomes are favorable, he adds. Nearly 20 percent of patients are diagnosed with an aggressive form of the cancer.
“Studying this group of patients is the most important in studying endometrial cancer,” he says. “We are focusing on treating these patients, but also, we are studying how to prevent this cancer,” he says.
Two biomarkers may help identify endometrial cancer risk
The study comes on the heels of a previously published endometrial cancer study by Dr. Walther-Antonio and Dr. Mariani, which identifies a reproductive tract microbiome signature promoted in part by post menopause.
“With results from these two studies, we will look at the two biomarkers — the microbiome and epigenetic — to see if these are connected or just happen to both be biomarkers in cancer,” she says. “We think the microbiome is probably the driver, but it could very well be the other way around too. We just don’t know.”
Dr. Mariani says obesity is another known factor.
“This may represent an opportunity to prevent the development of endometrial cancer altogether.” - Dr. Walther-Antonio
“The reason for that is obesity creates in women a very high estrogen environment, and this stimulates the uterine lining, and so this is a very high risk factor for endometrial cancer,” Dr. Mariani says.
Dr. Mariani and Dr. Walther-Antonio plan to expand their studies on microbiome and methylation, in a larger group of patients with aggressive endometrial cancer.
By identifying molecular markers of the disease, an effective tool could be developed to predict which patients are at high risk of developing endometrial cancer, Dr. Walther-Antonio says.
“More importantly, these markers could also be targeted for primary prevention during the window of time between a benign biopsy that contains altered markers and the development of the disease,” she says. “This may represent an opportunity to prevent the development of endometrial cancer altogether.”
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