Israel Zighelboim1, Shamshad Ali2, Heather A Lankes2, Floor Backes3, Kathleen Moore4, David Mutch5, Katina Robison6, Kian Behbakht7, Steven Waggoner8, Rahel G Ghebre9, Michael Pearl10, Nilsa C Ramirez3, Paul Goodfellow3. 1. Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Washington University School of Medicine, Siteman Cancer Center, St. Louis, MO, United States. Electronic address: israel.zighelboim@sluhn.org. 2. NRG Oncology Statistics and Data Management Center, Roswell Park Cancer Institute, Buffalo, NY, United States. 3. Division of Gynecologic Oncology (FB), Anatomic Pathology (NCR), Obstetrics and Gynecology (PG), Ohio State University, Columbus, OH, United States. 4. Gynecologic Oncology, Stephenson Oklahoma Cancer Center, Oklahoma City, OK, United States. 5. Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Washington University School of Medicine, Siteman Cancer Center, St. Louis, MO, United States. 6. Gynecologic Oncology, Women and Infants Hospital, Providence, RI, United States. 7. Gynecologic Oncology, University of Colorado Cancer Center, Aurora, CO, United States. 8. Gynecologic Oncology, University Hospital Case Medical Center, Cleveland, OH, United States. 9. Gynecologic Oncology, University of Minnesota Medical School, Minneapolis, MN, United States. 10. Gynecologic Oncology, Stony Brook University Hospital, Stony Brook, NY, United States.
Abstract
OBJECTIVE: We sought to validate the clinicopathologic implications and prognostic significance of ATR (ataxia telangiectasia mutated and Rad3-related) mutation in patients with endometrioid endometrial cancer and defective DNA mismatch repair enrolled in a cooperative group molecular staging study of endometrial cancer. METHODS: After pathology review, only endometrioid tumors with high neoplastic cellularity (≥70%) and high quality DNA for molecular analyses were included. MSI (microsatellite instability) typing was performed and the target sequence in exon 10 of ATR was evaluated by direct sequencing in all MSI-high tumors. Associations between ATR mutations and clinicopathologic variables were assessed using contingency table tests. Differences in overall survival (OS) and disease-free survival (DFS) were evaluated by univariate analyses and multivariable Cox proportional hazard models. RESULTS: A total of 475 eligible cases were identified. Of 368 MSI+ cases, the sequence of interest could be successfully genotyped in 357 cases. ATR mutations were exclusively identified in 46 tumors with high level microsatellite instability (MSI+) (12.9%, p<0.001) and were associated with higher tumor grade (p=0.001). ATR mutations were not associated with OS (HR 1.16; 95% CI, 0.58-2.32; p=0.68) or DFS (HR 0.61; 95% CI, 0.25-1.50; p=0.28). CONCLUSION: Truncating mutations in exon 10 of ATR occur exclusively in tumors with evidence of defective DNA mismatch repair. We were not able to confirm the prognostic value of these mutations in patients with endometrioid endometrial cancer.
OBJECTIVE: We sought to validate the clinicopathologic implications and prognostic significance of ATR (ataxia telangiectasia mutated and Rad3-related) mutation in patients with endometrioid endometrial cancer and defective DNA mismatch repair enrolled in a cooperative group molecular staging study of endometrial cancer. METHODS: After pathology review, only endometrioid tumors with high neoplastic cellularity (≥70%) and high quality DNA for molecular analyses were included. MSI (microsatellite instability) typing was performed and the target sequence in exon 10 of ATR was evaluated by direct sequencing in all MSI-high tumors. Associations between ATR mutations and clinicopathologic variables were assessed using contingency table tests. Differences in overall survival (OS) and disease-free survival (DFS) were evaluated by univariate analyses and multivariable Cox proportional hazard models. RESULTS: A total of 475 eligible cases were identified. Of 368 MSI+ cases, the sequence of interest could be successfully genotyped in 357 cases. ATR mutations were exclusively identified in 46 tumors with high level microsatellite instability (MSI+) (12.9%, p<0.001) and were associated with higher tumor grade (p=0.001). ATR mutations were not associated with OS (HR 1.16; 95% CI, 0.58-2.32; p=0.68) or DFS (HR 0.61; 95% CI, 0.25-1.50; p=0.28). CONCLUSION: Truncating mutations in exon 10 of ATR occur exclusively in tumors with evidence of defective DNA mismatch repair. We were not able to confirm the prognostic value of these mutations in patients with endometrioid endometrial cancer.
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