Share Print

Gene Mutation in Some Uterine Tumors May Signal That Cancer Runs in Family

Darrell Ward

May 13, 2003 – Testing younger women with endometrial cancer for mutations in a certain gene might help identify families at risk for inherited cancers, according to a study led by Washington University School of Medicine in St. Louis.

"The findings suggest that more women than previously thought carry mutations that signal an inherited susceptibility to cancer," says study leader Paul J. Goodfellow, PhD, professor of surgery and of obstetrics and gynecology. "They also may help explain why cancer seems to run in some families that lack mutations in other cancer susceptibility genes."

Goodfellow's team found that mutations in a gene known as MSH6 occur in at least 1.6 percent of women with endometrial cancer, a frequency comparable to that for the most common form of inherited colon cancer. Continuing studies suggest that mutations in MSH6 increase the risk that a woman and members of her family may have a higher-than-average risk for developing certain cancers later in life.

Once verified, the research could lead to changes in screening recommendations for some younger women with endometrial cancer and their families. The study is published in the May 13 issue of the Proceedings of the National Academy of Sciences.

Endometrial cancer, or cancer of the uterus, is the most common gynecologic cancer and the fourth most common cancer in women. An estimated 39,300 women developed the disease last year, and 6,600 women died from it.

"Presently, women under age 50 with endometrial cancer are treated as isolated cases of cancer, with no recommendation for greater surveillance of family members for an inherited cancer susceptibility," says senior author David G. Mutch, M.D., the Ira C. and Judith Gall Professor in Obstetrics and Gynecology. "This study could help change that."

The investigators examined a consecutive series of tumors from 441 women with endometrial cancer. To determine which tumors were likely to have mutations in MSH6, they first tested all tumors for a genetic change known as microsatellite instability (MSI). The presence of MSI indicates that the cancer occurred because cells were unable to repair damaged DNA.

Normally, these repairs are carried out by so-called mismatch repair enzymes. Mutations in the genes for these enzymes lead to ineffective DNA repair and cancer. MSH6 is involved in mismatch repair, as are the genes known as MLH1 and MSH2.

An initial molecular analysis showed that 127 tumors had high levels of MSI. The investigators then tested these for changes in MLH1 and MSH2. Ninety-two showed a molecular change known as methylation in the MLH1 and five had mutations in MSH2.

Of the remaining 30 tumors with high MSI and normal MLH1 and MSH2 genes, 11 showed mutations in MSH6.

In addition, seven of these women showed MSH6 mutations in healthy body cells -- white blood cells -- indicating it was an inherited, or germline, mutation.

Furthermore, the average age of these women was about 57 years vs. an average age of 66 for women in the other groups; two of the seven women also developed multiple cancers. Younger age at cancer onset and development of multiple cancer are characteristics of an inherited cancer predisposition.

"Based on the evidence from this study," says Mutch, "we concluded that mutations in the MSH6 gene may increase the risk of developing certain malignancies. Molecular testing can determine which women with endometrial cancer have the mutation, and genetic testing can determine which family members also carry the mutation. These individuals can then seek regular checkups for the early detection and treatment of cancer, should it occur."

Both Goodfellow and Mutch are researchers in the Cancer Genetics and the Clinical and Translational Research Programs at the Alvin J. Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine.


Goodfellow PJ, Buttin BM, Herzog TJ, Rader JS, Gibb RK, Swisher E, Look K, Walls KC, Fan M-Y, Mutch DG. Prevalence of defective DNA mismatch repair and MSH6 mutation in an unselected series of endometrial cancers. Proceedings of the National Academy of Sciences, May 13, 2003.

Funding from the National Cancer Institute supported this research.

The full-time and volunteer faculty of Washington University School of Medicine are the physicians and surgeons of Barnes-Jewish and St. Louis Children's hospitals. The School of Medicine is one of the leading medical research, teaching and patient-care institutions in the nation. Through its affiliations with Barnes-Jewish and St. Louis Children's hospitals, the School of Medicine is linked to BJC HealthCare.
Washington University School of Medicine, Office of Medical Public Affairs, Washington University School of Medicine at Washington University Medical Center, Campus Box 8508, 4444 Forest Park Ave., St. Louis MO 63108-2259, (314) 286-0100 FAX: (314) 286-0199