COLUMBUS, Ohio – Undesirable changes in our genes cause most cancers, including endometrial cancer, which affects cells lining the uterus. In about 20-40% of endometrial cancer patients, the mutated genes are the ones that check and correct errors in the DNA, called mismatch repair genes. Since these changes can make the cancer hereditary, doctors test for them by either looking for specific proteins in the cell, or by scanning for unrepaired errors accumulated in the DNA strands. In an ideal world, both test results must match. But with endometrial cancer, sometimes, they don’t—puzzling oncologists for a long time. In a new study, researchers at The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (OSUCCC – James) have found that the two test results differ because there are underlying subtle differences in the cells that make up an endometrial cancerous tumor. The study is published in the journal Cancer. “Tumors that have mismatch repair deficiency are good candidates for immunotherapy treatments,” said principal investigator and corresponding author Casey M Cosgrove, MD, at OSUCCC – James. “Finding such tumors can help us provide the most precise medical advice for patients with endometrial cancer.” Between 2014 and 2017, the researchers conducted the two tests to identify mutations in the mismatch repair genes on over 600 hysterectomy samples. While the results agreed with each other for most of the cases, about 25 of them did not. The researchers then analyzed the cells in the contradicting samples to understand what led to differences in the test result.  They found that some endometrial cancer tumors with mismatch repair defects had abnormal cells that did not look like other tumor cells. These cells either clumped together and stood out from other tumor cells or intermixed with them showing a blotchy pattern under a microscope. When compared with other tumor cells, these cells had changes to over 70 genes, including those that promote tumor growth and tumor metastasis. “Our study is the first to report that these atypical staining patterns in the tumor cells actually have a higher risk of recurrence,” said Cosgrove, a gynecologic oncologist and member of the OSUCCC – James Translational Therapeutics Research Program. He notes that when compared with other endometrial cancers, those with atypical pathology mismatch repair defects were more likely to recur, and more likely to aggressively spread to other organs. Under current guidelines, when a pathologist views a tissue sample under the microscope to diagnose cancer, they don’t have to report these small differences in the make-up of a tumor. But, as the study shows, these differences are key to understanding how cancer develops. “Knowing that information has direct implications for us, as oncologists, about what treatment options we offer, and what genetic testing we recommend,” said study author Courtney J. Riedinger, MD, a gynecologic oncology fellow at OSUCCC – James. “If we don't have that information, we can't make an informed judgment.” Today, endometrial cancer is the most common gynecologic cancer in the United States. The American Cancer Society estimates that in 2023, 66,200 new patients will be diagnosed with this cancer and over 13,000 women will die from it. Oncologists expect these numbers to increase in the coming years, especially among women belonging to racial and ethnic minorities. Although detecting it early on can save lives, less than one in five patients with advanced stage endometrial cancer survive longer than five years.  As endometrial cancer tumors with mismatch repair defects and atypical cells are likely to respond better to immunotherapy—a cancer therapy where drugs stimulate our immune system to fight cancer cells—pinpointing them during biopsies may help treat patients with drugs that work better and have fewer side effects. The Food and Drug Administration (FDA) recently approved dostarlimab, an immunotherapeutic drug in combination with chemotherapy to treat endometrial cancers with mismatch repair defects, making such treatments possible. The study emphasizes treatments for endometrial cancers should not take a one-size-fits-all approach. “With endometrial cancer, there are a lot of small details now that dictate how we counsel our patients,” Cosgrove said. “Differences within a primary tumor are going to become increasingly important for us to recognize in the future.” This study was supported by grants from The Ohio State University Comprehensive Cancer Center and the National Institutes of Health (P30CA016058), Kay Yow Cancer Fund and the Perlman Family CCARE Lynch Syndrome Research Prize. Other researchers involved in this study were Ashwini Esnakula, Paulina J. Haight, Adrian A. Suarez, Wei Chen, Jessica Gillespie, Alyssa Villacres, Alexis Chassen, David E. Cohn and Paul J. Goodfellow. ### MEDIA CONTACT Amanda Harper, Associate Director 614-685-5420 | Amanda.Harper2@osumc.edu ** News release written by Spoorthy Raman