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.
Bibliographical noteFunding Information:
This study was supported by R21 CA155674 (I.Z. and P.J.G.) and Cancer Center Support Grant P30 CA91842 (The Siteman Cancer Center) as well as National Cancer Institute grants: NRG Oncology Operations U10 CA180868 as well as NRG SDMC U10 CA180822 , Gynecologic Oncology Group (GOG) Administrative Office and the GOG Tissue Bank ( CA27469 ) and the GOG Statistical and Data Center ( CA37517 ). The following Gynecologic Oncology Group member institutions participated in the primary treatment studies: Ohio State University Medical Center, University of Oklahoma Health Sciences Center, Washington University School of Medicine, Women and Infants Hospital, University of Colorado Cancer Center–Anschutz Cancer Pavilion, Case Western Reserve University, University of Minnesota Medical Center — Fairview, Stony Brook University Medical Center, Roswell Park Cancer Institute, University of North Carolina at Chapel Hill, Cooper Hospital University Medical Center, Yale University, Duke University Medical Center, University of Massachusetts Memorial Health Care Western Michigan (Butterworth), Women's Cancer Center of Nevada, University of Pittsburgh, University of Illinois, University of Iowa Hospitals and Clinics, University of Cincinnati, University of California Medical Center at Irvine — Orange Campus, University of Arkansas Medical Center, Penn State Milton S Hershey Medical Center, University of Virginia, Abington Memorial Hospital, University of Texas Southwestern Medical Center, University of Wisconsin Hospital and Clinics, Northwestern University, University of California at Los Angeles Health System, Indiana University Hospital/Melvin and Bren Simon Cancer Center, University of Chicago, Mayo Clinic, Moffitt Cancer Center and Research Institute, St. Vincent Hospital, Walter Reed National Military Medical Center, Fred Hutchinson Cancer Research Center, University of New Mexico, Fox Chase Cancer Center, The Hospital of Central Conn at New Britain General, Cleveland Clinic Foundation, North Shore University Hospital, Gynecologic Oncology of West Michigan PLLC, University of Alabama at Birmingham, Wake Forest University Health Sciences, and Tufts-New England Medical Center.
© 2015 Elsevier Inc.