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	NHGRI	CANCER-22

Authors

• 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

Abstract

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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