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Author Notes:

David S. Yu, M.D., Ph.D., Department of Radiation Oncology, Emory University School of Medicine, 1365 Clifton Rd NE, C3008, Phone: 404-778-1758, Fax: 404-778-5520, dsyu@emory.edu.

We thank members of the Yu lab and Chris Crane for helpful comments during article preparation.

The authors declare no conflicts of interest.

Subjects:

Research Funding:

Supported by the National Center for Advancing Translational Sciences of the National Institutes of Health under Award Numbers ULl TR000454 to LEC and SBF; and TLlTR000456 to LEC; PanCAN/AACR 16982 to DSY; DOD/PRCRP CA110535 to DSY; and Georgia Cancer Coalition 11072 to DSY.

Keywords:

  • Science & Technology
  • Life Sciences & Biomedicine
  • Oncology
  • DNA-DAMAGE RESPONSE
  • ADJUVANT CHEMOTHERAPY
  • GEMCITABINE
  • PROTEIN
  • MUTATIONS
  • ADENOCARCINOMA
  • FLUOROURACIL
  • CHECKPOINT
  • THERAPY

CHD7 Expression Predicts Survival Outcomes in Patients with Resected Pancreatic Cancer

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Journal Title:

Cancer Research

Volume:

Volume 74, Number 10

Publisher:

, Pages 2677-2687

Type of Work:

Article | Post-print: After Peer Review

Abstract:

Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease with poor outcomes with current therapies. Gemcitabine is the primary adjuvant drug used clinically, but its effectiveness is limited. In this study, our objective was to use a rationale-driven approach to identify novel biomarkers for outcome in patients with earlystage resected PDAC treated with adjuvant gemcitabine. Using a synthetic lethal screen in human PDAC cells, we identified 93 genes, including 55 genes linked to DNA damage responses (DDR), that demonstrated gemcitabine sensitization when silenced, including CHD7, which functions in chromatin remodeling. CHD7 depletion sensitized PDAC cells to gemcitabine and delayed their growth in tumor xenografts. Moreover, CHD7 silencing impaired ATR-dependent phosphorylation of CHK1 and increased DNA damage induced by gemcitabine. CHD7 was dysregulated, ranking above the 90th percentile in differential expression in a panel of PDAC clinical specimens, highlighting its potential as a biomarker. Immunohistochemical analysis of specimens from 59 patients with resected PDAC receiving adjuvant gemcitabine revealed that low CHD7 expression was associated with increased recurrence-free survival (RFS) and overall survival (OS), in univariate and multivariate analyses. Notably, CHD7 expression was not associated with RFS or OS for patients not receiving gemcitabine. Thus, low CHD7 expression was correlated selectively with gemcitabine sensitivity in this patient population. These results supported our rationale-driven strategy to exploit dysregulated DDR pathways in PDAC to identify genetic determinants of gemcitabine sensitivity, identifying CHD7 as a novel biomarker candidate to evaluate further for individualizing PDAC treatment.

Copyright information:

© 2014 American Association for Cancer Research.

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