Assessing the prognostic role of ATR mutation in endometrioid endometrial cancer: An NRG Oncology/Gynecologic Oncology Group study

Israel Zighelboim, Shamshad Ali, Heather A. Lankes, Floor Backes, Kathleen Moore, David Mutch, Katina Robison, Kian Behbakht, Steven Waggoner, Rahel G. Ghebre, Michael Pearl, Nilsa C. Ramirez, Paul Goodfellow

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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.

Original languageEnglish
Pages (from-to)614-619
Number of pages6
JournalGynecologic oncology
Volume138
Issue number3
DOIs
StatePublished - Sep 1 2015

Keywords

  • ATR
  • Cancer
  • Endometrial
  • Mutation
  • Survival

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    Zighelboim, I., Ali, S., Lankes, H. A., Backes, F., Moore, K., Mutch, D., Robison, K., Behbakht, K., Waggoner, S., Ghebre, R. G., Pearl, M., Ramirez, N. C., & Goodfellow, P. (2015). Assessing the prognostic role of ATR mutation in endometrioid endometrial cancer: An NRG Oncology/Gynecologic Oncology Group study. Gynecologic oncology, 138(3), 614-619. https://doi.org/10.1016/j.ygyno.2015.06.038