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Will New Endometrial Cancer Mutations Spur Diagnostic Criteria for Patients and Families?


Researchers at Washington University School of Medicine in St. Louis claim that certain gene mutations present in uterine tumors may help physicians identify family members at risk for inherited cancers.

The team found that mutations in the MSH6 gene occur “in at least” 1.6 percent of women with endometrial cancer. The findings, published in the May 13 Proceedings of the National Academy of Sciences, show that mutations in the gene “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.”

The results may lead to molecular tests like BRCA1 and BRCA2 not only for women who are at an increased risk for endometrial cancer, but also for their families.

Today, women under age 50 with endometrial cancer are treated as “isolated cases” of cancer, and physicians, absent clinical evidence, have no reason to survey their families for susceptibility to an inherited cancer, said senior author David Mutch, a professor of obstetrics and gynecology at Washington University. “This study could help change that.”

Paul Goodfellow, professor of surgery and of obstetrics and gynecology at Washington University, added that “more women than previously thought carry mutations that signal an inherited susceptibility to cancer.” The findings “may also help explain why cancer seems to run in some families that lack mutations in other cancer susceptibility genes,” he said.

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 tested all tumors for microsatellite instabilities, or MSIs. The presence of an instability would indicate to researchers that the cancer occurred because cells were unable to repair damaged DNA, in this case cells in the uterus.

According to the authors, these repairs are traditionally performed by mismatch repair enzymes. However, mutations in the genes that regulate these enzymes lead to “ineffective DNA repair and cancer.” As it happens, MSH6 is involved in mismatch repair, as are the genes MLH1 and MSH2.

Until now, “it was unclear whether or not MHS6 really played a big role in endometrial cancer, and mutation carriers have really been identified because they have cancer and a strong family history,” Goodfellow told SNPtech Reporter. “Our molecular study shows that we can look at a patient with cancer without any of the information about relatives being affected or anything else and have a good chance of finding a mutation.”

Endometrial cancer is the most common gynecologic malignancy in the world, and is the fourth most common cancer among women in the United States, according to the National Cancer Institute. There are about 35,000 new cases of the disease every year in the United States and between 4,000-5,000 deaths.

There are currently no molecular diagnostics to test either for the presence of the disease or for a patient's risk of developing it — and certainly no test that might shed light on family members’ risk of developing cancer. To confirm endometrial cancer, oncologists rely on biopsies, dilations and curettages, computed tomographies, and intravenous pyelograms. Physicians may also study a patient’s blood for the presence of CA-125, an enzyme that some endometrial cancer cells secrete into the bloodstream.

For Goodfellow, his next step was to perform an initial molecular analysis that showed that 127 tumors had high levels of MSI. After testing for changes in MLH1 and MSH2, the researchers found 92 that showed methylation in the MLH1 and five had mutations in MSH2. Furthermore, of the remaining 30 tumors with high MSI and normal MLH1 and MSH2 genes, 11 showed mutations in MSH6. Seven of these women showed MSH6 mutations in leukocytes, which indicate that they were germline mutations.

Interestingly, the results showed that the average age of these women was about 57 years compared with an average age of 66 for women in the other groups. In addition, two of the seven women with MSH6 mutations in their leukocytes went on to develop multiple cancers.

“Based on the evidence from this study, we concluded that mutations in the MSH6 gene may increase the risk of developing certain malignancies,” said Mutch. “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.”

To be sure, the rate at which women have an MSH6 mutation — one in 50 — does not warrant screening, said Goodfellow. However, if the tumor has the mutation, “then of course [the patient and her family] warrant screening. What we’ve been able to do is demonstrate that if we look at tumors as they roll into the clinic, there are certain molecular features that say, ‘This tumor is likely to have arisen in a woman who has an inherited mutation, and we can focus our efforts on a group that’s going to benefit from a more intensive molecular and clinical analysis.’”

Garret Hampton, director of cancer biology at the Genomics Institute of the Novartis Research Foundation, called Goodfellow’s work “a good study overall” and said “the arguments over whether this knowledge would be helpful or not [for women or their families] are ongoing. However, knowing for sure that one has a mutation which increases the relative risk of cancer is useful to the extent that the individual may have choices as to what action to take,” he told SNPtech Reporter in an e-mail message.

“I expect that over time, the combination of mutation analysis in MSH6, MSH2, as well as other known ... genes ... may be developed into a diagnostic that can assess a women’s risk of endometrial carcinoma,” he said.

“However, it is not yet clear how many women will benefit, since the frequencies of these mutations in an unselected series … are generally low.”

— KL


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