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Genetic and functional defects in ATAD5, a chromosome instability gene, in primary endometrial cancers

Monday, October 24, 2011 — Poster Session I

Noon – 2:00 p.m.

Natcher Conference Center




  • ML Rudd
  • J Price
  • LM Pollock
  • K Lee
  • SK Fogoros
  • C Hanigan
  • S Zhang
  • T Wolfsberg
  • KJ McManus
  • A Young
  • R Blakesley
  • AK Godwin
  • MJ Merino
  • P Hieter
  • K Myung
  • DW Bell


Endometrial cancer (EC) is the most frequently diagnosed gynecological malignancy and the eighth leading cause of cancer-related death among women in the United States. Aneuploidy, a form of chromosomal instability (CIN), is significantly more frequent among non-endometrioid ECs (NEECs), the most clinically aggressive subtype of EC, than among endometrioid ECs (EECs). Here, in a discovery screen, we used Sanger sequencing to screen 22 candidate CIN genes for somatic mutations within a series of 24 primary NEECs. Any gene that was somatically mutated was then resequenced from 42 additional NEECs and 42 EECs, in a validation screen. We identified somatic mutations in ATAD5, ESCO1, MRE11, and CHTF18. ATAD5 had the highest mutation frequency (6.0%, 4 of 66 NEECs; 2.3%, 1 of 42 EECs) and exhibited both nonsense and missense mutations. In vitro functional characterization of a subset of ATAD5 mutants showed that the ATAD5-R1414X truncation mutant was unstable, whereas the ATAD5-E723X truncation mutant had an impaired ability to bind to RFC4, an ATAD5-interacting protein. Taken together, our findings provide the first evidence for the mutational disruption of ATAD5 in human cancer, and suggest that somatic loss-of-function mutations within ATAD5 may contribute to endometrial tumorigenesis.

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