title: Assessing the prognostic role of ATR mutation in endometrioid endometrial cancer: An NRG Oncology/Gynecologic Oncology Group study.
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).
  
  
  CONCLUSIONS
  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.
authors.affiliation: 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.
authors.forename: Israel
authors.initials: I
authors.lastname: Zighelboim
authors.affiliation: NRG Oncology Statistics and Data Management Center, Roswell Park Cancer Institute, Buffalo, NY, United States.
authors.forename: Shamshad
authors.initials: S
authors.lastname: Ali
authors.affiliation: NRG Oncology Statistics and Data Management Center, Roswell Park Cancer Institute, Buffalo, NY, United States.
authors.forename: Heather A
authors.initials: HA
authors.lastname: Lankes
authors.affiliation: Division of Gynecologic Oncology (FB), Anatomic Pathology (NCR), Obstetrics and Gynecology (PG), Ohio State University, Columbus, OH, United States.
authors.forename: Floor
authors.initials: F
authors.lastname: Backes
authors.affiliation: Gynecologic Oncology, Stephenson Oklahoma Cancer Center, Oklahoma City, OK, United States.
authors.forename: Kathleen
authors.initials: K
authors.lastname: Moore
authors.affiliation: Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Washington University School of Medicine, Siteman Cancer Center, St. Louis, MO, United States.
authors.forename: David
authors.initials: D
authors.lastname: Mutch
authors.affiliation: Gynecologic Oncology, Women and Infants Hospital, Providence, RI, United States.
authors.forename: Katina
authors.initials: K
authors.lastname: Robison
authors.affiliation: Gynecologic Oncology, University of Colorado Cancer Center, Aurora, CO, United States.
authors.forename: Kian
authors.initials: K
authors.lastname: Behbakht
authors.affiliation: Gynecologic Oncology, University Hospital Case Medical Center, Cleveland, OH, United States.
authors.forename: Steven
authors.initials: S
authors.lastname: Waggoner
authors.affiliation: Gynecologic Oncology, University of Minnesota Medical School, Minneapolis, MN, United States.
authors.forename: Rahel G
authors.initials: RG
authors.lastname: Ghebre
authors.affiliation: Gynecologic Oncology, Stony Brook University Hospital, Stony Brook, NY, United States.
authors.forename: Michael
authors.initials: M
authors.lastname: Pearl
authors.affiliation: Division of Gynecologic Oncology (FB), Anatomic Pathology (NCR), Obstetrics and Gynecology (PG), Ohio State University, Columbus, OH, United States.
authors.forename: Nilsa C
authors.initials: NC
authors.lastname: Ramirez
authors.affiliation: Division of Gynecologic Oncology (FB), Anatomic Pathology (NCR), Obstetrics and Gynecology (PG), Ohio State University, Columbus, OH, United States.
authors.forename: Paul
authors.initials: P
authors.lastname: Goodfellow
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D064007:Ataxia Telangiectasia Mutated Proteins / Q000235:genetics; D014408:Biomarkers, Tumor / Q000235:genetics*; D018269:Carcinoma, Endometrioid / Q000235:genetics* / Q000473:pathology; D015331:Cohort Studies; D053843:DNA Mismatch Repair; D016889:Endometrial Neoplasms / Q000235:genetics* / Q000473:pathology; D005260:Female; D006801:Humans; D053842:Microsatellite Instability; D008875:Middle Aged; D009154:Mutation; D011379:Prognosis
chemical_list: D014408:Biomarkers, Tumor; C576597:ATR protein, human; D064007:Ataxia Telangiectasia Mutated Proteins
keywords: ATR; Cancer; Endometrial; Mutation; Survival