Previously Unknown Form of Endometrial Cancer Linked to Genetic 'Hotspot'

Subtle differences, including facial expression, moles, voice tone and gait help parents and family members distinguish between twins. In a similarly way, physicians treating women with endometrial cancer distinguish between different versions of the disease form based on subtle differences. With nearly 50,000 cases of endometrial cancer in the United States in 2013 alone, it is the the most common gynecological cancer in the western world, ranked as the fourth most prevalent in the U.S.. Hence, distinguishing between disease forms can literally be a matter of life and death. In contrast to other cancers, mortality rates from this cancer have nearly tripled in the past 25 years. Researchers attribute this to the rising incidence of obesity. Another obstacle to individualized patient care is the heterogeneous clinical course of the disease.

Scientists at The University of Texas MD Anderson Cancer Center in Houston have identified genetic mutations in endometrioid endometrial carcinoma or EEC, the most common form of this cancer of the uterine lining. The mutations revealed a more lethal version of an EEC subtype previously thought to respond well to treatment. It's possible that by identifying these patients early on, oncologists can try more aggressive treatment approaches to increase the likelihood for a positive outcome.[1]

...the identification of this second cluster of patients with endometrial cancer helps to refute long-standing teachings that young, obese patients universally have endometrial cancers that are estrogen-driven and thus have a good prognosis...

Recurrence and treatment
"EEC is categorized into subtypes that help determine risk of recurrence and guide treatment," said Wei Zhang, Ph.D., professor of pathology at MD Anderson. "Most patients have Type I, which can be diagnosed early and generally has a good outcome with treatment."

Type I accounts for 70 to 80% of all EECs. Although this form of the disease is typically sex hormone sensitive, most women being diagnosed with Type I have already gone through menopause. Research confirms that the postmenopausal ovary is hormonally active, and estradiol production from the ovaries persists for as much as 10 years beyond menopause. Hence, the majority of women with endometrial cancer Type I are postmenopausal.

Type II is more troublesome and is usually diagnosed late in the cancer's progression resulting in a poor prognosis. The overal outcome of the disease varies with FIGO (International Federation of Gynecology and Obstetrics) - stage and tumor grade. 

Zhang and his team, identified a cluster of patients within Type I that appears to have a more virulent form of it previously not recognized. Zhang labeled this patient group as Cluster II. "The patients were mostly younger and obese that's typical for Type I. What's unusual is for patients in this disease category to have decreased survival rates," said Zhang. "Molecular subtyping of EEC may help oncologists with diagnosis and prognosis within this unique subset."

Identifying molecular attributes
Zhang believes that by being able to identify molecular "attributes," physicians can identify EEC patients at risk for this more lethal form of the disease. The findings of the study, funded by a Career Development Award from MD Anderson Gynecologic SPORE in Uterine Cancers, the Genome Data Analysis Centers from the National Institute of Health and the National Foundation for Cancer Research, were published in an article appearing in the September 3, 2014 edition of JNCI: the Journal of the National Cancer Institute.

His team discovered distinctive genetic mutations in 87% of Cluster II patients. The mutations occurred in the CTNNB1 gene, which is necessary for the creation and maintenance of tissue-producing epithelial cells. Within CTNNB1, genetic sequences known as exon 3 created a "hotspot," a cellular cauldron of biological blunders. This resulted in the normally passive Type I becoming deadly for some patients. 

In their study, the researchers conclude that these exon 3 mutations of CTNNB1 are likely a driver that characterizes an aggressive subset of ow-grade and low stage EEC occurring in younger women.[1]

With the identification of Cluster I, which includes young, obese patients who respond well to treatment and generally have a good prognosis, and the more lethal Cluster II, Zhang demonstrated that, like twins, the two cancers may appear similar, but they have distinct genetic differences that make them unique. In the case of Cluster II, the discovery of these chromosomal quirks could lead to earlier and more effective treatments.

"The identification of this second cluster of patients with endometrial cancer helps to refute long-standing teachings that young, obese patients universally have endometrial cancers that are estrogen-driven and thus have a good prognosis," explained Russell Broaddus, M.D.,Ph.D., professor of pathology at MD Anderson. "Endometrial cancer in this patient population is much more complex than we were previously led to believe. We hope that the study results can help pave the way for more individualized therapy of endometrial cancer patients who have tumors with CTNNB1 mutations."

For more information:
[1] Liu Y, Patel L, Mills GB, Lu KH, Sood AK, Ding L, Kucherlapati R, Mardis ER, Levine DA, Shmulevich I, Broaddus RR, Zhang W. CTNNB1 Mutation and Wnt Pathway Activation Define Aggressive Endometrioid Endometrial Carcinoma. Published Online First, September 3, 2014, JNCI: the Journal of the National Cancer Institute.

This article was last updated on September 8, 2014.

Photo: Wei Zhang, Ph.D. Photo Courtesy: MD Anderson Cancer Center, Houston.

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