Faculty Collaboration Database

CHD7 expression predicts survival outcomes in patients with resected pancreatic cancer. Cancer Res 2014 May 15;74(10):2677-87

Date

03/15/2014

Pubmed ID

24626090

Pubmed Central ID

PMC4025946

DOI

10.1158/0008-5472.CAN-13-1996

Scopus ID

2-s2.0-84901278176 (requires institutional sign-in at Scopus site)   31 Citations

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 early-stage 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.

Author List

Colbert LE, Petrova AV, Fisher SB, Pantazides BG, Madden MZ, Hardy CW, Warren MD, Pan Y, Nagaraju GP, Liu EA, Saka B, Hall WA, Shelton JW, Gandhi K, Pauly R, Kowalski J, Kooby DA, El-Rayes BF, Staley CA 3rd, Adsay NV, Curran WJ Jr, Landry JC, Maithel SK, Yu DS

Author

William Adrian Hall MD Professor in the Radiation Oncology department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Animals
Antimetabolites, Antineoplastic
Biomarkers, Tumor
Carcinoma, Pancreatic Ductal
Cell Line, Tumor
DNA Helicases
DNA-Binding Proteins
Deoxycytidine
Drug Screening Assays, Antitumor
Gene Expression Regulation, Enzymologic
Gene Expression Regulation, Neoplastic
Gene Knockdown Techniques
Humans
Male
Mice
Pancreatic Neoplasms
Proportional Hazards Models
Random Allocation
Survival Analysis
Xenograft Model Antitumor Assays