Endometrial Cancer: Genetics and Cancer Disparities

Endometrial cancer is the most common gynecological malignancy in the United States. It is the fourth most common cancer in females, and the seventh leading cause of cancer-related deaths among females. The American Cancer Society estimates that 36,000 cases will occur in 2000 and approximately 6,500 women will die from this disease. There is a significant racial disparity in survival among women in the United States with endometrial adenocarcinoma. Five-year survival in the 1989-94  reviews by the National Cancer Institute was 86 percent in whites compared to only 54 percent in African Americans. Likewise, among patients treated at Duke University Medical Center from 1990-93, survival of African Americans was 20 percent worse.

The etiology of the racial disparity in endometrial cancer incidence and survival has been elucidated to some extent. First, it has been shown that differences in hormone use contribute to the racial disparity in endometrial cancer survival. Unopposed estrogen replacement therapy increases the risk of endometrial cancer and is more often prescribed to white women; but because estrogen-induced cancers usually are well-differentiated, hormone replacement contributes to more favorable survival in whites. A racial disparity in survival persists after correcting for hormone use.

The poor outcome in African Americans with endometrial cancer also may be attributed in part to the higher frequency of unfavorable prognostic features. Their cancers are more often poorly differentiated, deeply invasive, non-endometrioid and advanced stage at diagnosis. Although it has been suggested that delayed diagnosis in African Americans might explain their more frequent presentation at an advanced stage, one group of investigators has reported the absence of a racial disparity in the interval from onset of abnormal uterine bleeding to hysterectomy for endometrial cancer. In addition, there did not appear to be a difference in the intensity of treatment received by African Americans and Caucasians. This suggests that the worse prognosis of African Americans might be due to differences in the underlying molecular pathogenesis of the disease. This group of investigators tackles the disparities as well as the molecular mechanisms responsible for differences in gynecologic cancer development and progression.
 
Graham A. Colditz, MD, DrPH, is the Niess-Gain Professor of Surgery, associate director of prevention and control at the Alvin J. Siteman Cancer Center, and deputy director of the Institute of Public Health at Washington University in St. Louis. Colditz has a longstanding interest in the causes and prevention of chronic disease, particularly among women. He has evaluated numerous lifestyle factors including exogenous hormones and breast cancer risk and the development of statistical models to predict cancer risk for individuals. Additional areas of his expertise include tobacco and obesity in relation to cancer and other chronic diseases. His long-term goals are to implement prevention strategies that engage clinicians, the community and individuals. Siteman Cancer Center has enormous strength in basic science research and understanding disease processes. The cancer center’s Prevention and Control Program creates a complement between discoveries in biological science and effective interventions. The challenge is to add ways to identify cancer risks for both individuals and within whole communities and to change behavior to lower risk and improve people’s lives.

Jeffrey D. Milbrandt, MD, PhD, is professor and head of the Department of Genetics, the David Clayson Professor of Neurology, professor of pathology and immunology and professor of medicine.

Milbrandt’s lab is studying the biological roles of Egr transcription factors. Through analysis of knockout mice, it is clear that these transcription factors regulate a variety of processes including female reproduction (Egr1/NGFI-A), male reproduction (Egr4/NGFI-C), muscle spindle formation (Egr3) and peripheral nerve myelination (Egr2/Krox20). He also has identified two corepressors, Nab1 and Nab2, that modulate activity of Egr proteins and hence the expression of Egr-regulated target genes. In addition, the Milbrandt lab is focusing on the development of prostate and endometrial cancer. He is investigating the role of several genes, including Egr1, Nab2 and a homeodomain protein, Nkx3.1, that have been implicated in the development and progression of cancer. Milbrandt is highly experienced at using a variety of functional genomics techniques to identify additional gene products that may play a role in diseases, in particular prostate cancer. Combining the endometrial cancer biology focus with Milbrandt’s skills in computational human genomics creates a strong emphasis on translational cancer genetic and genomics. Trainees will have the unique opportunity to combine molecular and genetic mechanisms with translational studies to address new hypotheses using human normal and cancerous tissue.

David G. Mutch, MD, is the Ira C. and Judith Gall Professor of Obstetrics and Gynecology at Washington University School of Medicine. Mutch’s contributions to breakthrough clinical research and superb basic science are many. He was a key participant with Perry W. Grigsby, MD, professor of radiation oncology at the School of Medicine’s Mallinckrodt Institute of Radiology, in a landmark study published in the New England Journal of Medicine. In studies of women with inoperable cervical cancer, Grigsby and Mutch, with other physicians in the division, found that the addition of two chemotherapy drugs to radiation treatment very significantly increased patients’ chances of survival. Mutch was the senior author of another study that he conducted with lead investigator Paul J. Goodfellow, PhD, of genetics and of obstetrics and gynecology. The research involving 441 women showed that mutations in the MSH6 gene occur in at least 1.6 percent of younger women with endometrial cancer — a frequency similar to that of the most prevalent form of inherited colon cancer. Of the 11 women who had MSH6 mutations, seven had the genetic changes in healthy body cells. Of those women, whose average age was 57 — versus 66 in the other groups — two developed multiple cancers. Cancer onset at a younger age and multiple cancer development are characteristics of an inherited predisposition to cancer. Currently, when women are diagnosed with endometrial cancer, no recommendations are made to watch family members for inherited susceptibility. But this research and subsequent findings could lead to testing women with endometrial cancer for MSH6 mutations — a feature that could help identify families at risk for certain inherited cancers.

SUMMARY

This group of investigators and their work bring together basic and clinical scientists to conduct innovative and diverse translational investigations aimed at preventing, diagnosing and treating endometrial cancer. The combination of these mentors provides fertile ground for a young investigator interested in cancer disparities among gynecologic cancers as well as the basic mechanism of these cancers. These junior faculty would have outstanding resources and opportunities under the mentorship of these faculty and with the presence of the Alvin J. Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine.