CHD7 Expression Predicts Survival Outcomes in Patients with Resected Pancreatic Cancer

• Type of Material: Article
• Authors: Lauren E. Colbert, Emory University; Aleksandra V. Petrova, Emory University; Sarah B. Fisher, Emory University; Brooke G. Pantazides, Emory University; Matthew Z. Madden, Emory University; Claire W. Hardy, Emory University; Matthew D. Warren, Emory University; Yunfeng Pan, Emory University; P Nagaraju Ganji, Emory University; Elaine A. Liu, Emory University; Burcu Saka, Emory University; WA Hall, Emory University; Joseph W Shelton, Emory University; Khanjan Gandhi, Emory University; Rini Pauly, Emory University; Jeanne Kowalski, Emory University; David A Kooby, Emory University; Bassel El-Rayes, Emory University; Charles Staley, Emory University; Nazmi Adsay, Emory University; Walter Curran Jr, Emory University; Jerome C Landry, Emory University; Shishir Kumar Maithel, Emory University; David Yu, Emory University
• Language: English
• Date: 2014-05-15
• Publisher: American Association for Cancer Research
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2014 American Association for Cancer Research.
• Final Published Version (URL): http://dx.doi.org/10.1158/0008-5472.CAN-13-1996
• Title of Journal or Parent Work: Cancer Research
• ISSN: 0008-5472
• Volume: 74
• Issue: 10
• Start Page: 2677
• End Page: 2687
• Grant/Funding Information: 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: DNA-DAMAGE RESPONSE; Life Sciences & Biomedicine; Oncology; CHECKPOINT; ADENOCARCINOMA; PROTEIN; GEMCITABINE; ADJUVANT CHEMOTHERAPY; THERAPY; Science & Technology; FLUOROURACIL; MUTATIONS
• Research Categories: Health Sciences, Oncology; Health Sciences, Pathology

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.