title: CHD7 expression predicts survival outcomes in patients with resected pancreatic cancer.
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.
authors.affiliation: Authors' Affiliations: Departments of Radiation Oncology, Medical Oncology, and Pathology; Division of Surgical Oncology, Department of Surgery; Biostatistics and Bioinformatics Shared Resource, Winship Cancer Institute, Emory University; and Atlanta Veterans Affairs Medical Center, Atlanta, Georgia.
authors.forename: Lauren E
authors.initials: LE
authors.lastname: Colbert
authors.affiliation: Authors' Affiliations: Departments of Radiation Oncology, Medical Oncology, and Pathology; Division of Surgical Oncology, Department of Surgery; Biostatistics and Bioinformatics Shared Resource, Winship Cancer Institute, Emory University; and Atlanta Veterans Affairs Medical Center, Atlanta, Georgia.
authors.forename: Aleksandra V
authors.initials: AV
authors.lastname: Petrova
authors.affiliation: Authors' Affiliations: Departments of Radiation Oncology, Medical Oncology, and Pathology; Division of Surgical Oncology, Department of Surgery; Biostatistics and Bioinformatics Shared Resource, Winship Cancer Institute, Emory University; and Atlanta Veterans Affairs Medical Center, Atlanta, Georgia.
authors.forename: Sarah B
authors.initials: SB
authors.lastname: Fisher
authors.affiliation: Authors' Affiliations: Departments of Radiation Oncology, Medical Oncology, and Pathology; Division of Surgical Oncology, Department of Surgery; Biostatistics and Bioinformatics Shared Resource, Winship Cancer Institute, Emory University; and Atlanta Veterans Affairs Medical Center, Atlanta, Georgia.
authors.forename: Brooke G
authors.initials: BG
authors.lastname: Pantazides
authors.affiliation: Authors' Affiliations: Departments of Radiation Oncology, Medical Oncology, and Pathology; Division of Surgical Oncology, Department of Surgery; Biostatistics and Bioinformatics Shared Resource, Winship Cancer Institute, Emory University; and Atlanta Veterans Affairs Medical Center, Atlanta, Georgia.
authors.forename: Matthew Z
authors.initials: MZ
authors.lastname: Madden
authors.affiliation: Authors' Affiliations: Departments of Radiation Oncology, Medical Oncology, and Pathology; Division of Surgical Oncology, Department of Surgery; Biostatistics and Bioinformatics Shared Resource, Winship Cancer Institute, Emory University; and Atlanta Veterans Affairs Medical Center, Atlanta, Georgia.
authors.forename: Claire W
authors.initials: CW
authors.lastname: Hardy
authors.affiliation: Authors' Affiliations: Departments of Radiation Oncology, Medical Oncology, and Pathology; Division of Surgical Oncology, Department of Surgery; Biostatistics and Bioinformatics Shared Resource, Winship Cancer Institute, Emory University; and Atlanta Veterans Affairs Medical Center, Atlanta, Georgia.
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Warren
authors.affiliation: Authors' Affiliations: Departments of Radiation Oncology, Medical Oncology, and Pathology; Division of Surgical Oncology, Department of Surgery; Biostatistics and Bioinformatics Shared Resource, Winship Cancer Institute, Emory University; and Atlanta Veterans Affairs Medical Center, Atlanta, Georgia.
authors.forename: Yunfeng
authors.initials: Y
authors.lastname: Pan
authors.affiliation: Authors' Affiliations: Departments of Radiation Oncology, Medical Oncology, and Pathology; Division of Surgical Oncology, Department of Surgery; Biostatistics and Bioinformatics Shared Resource, Winship Cancer Institute, Emory University; and Atlanta Veterans Affairs Medical Center, Atlanta, Georgia.
authors.forename: Ganji P
authors.initials: GP
authors.lastname: Nagaraju
authors.affiliation: Authors' Affiliations: Departments of Radiation Oncology, Medical Oncology, and Pathology; Division of Surgical Oncology, Department of Surgery; Biostatistics and Bioinformatics Shared Resource, Winship Cancer Institute, Emory University; and Atlanta Veterans Affairs Medical Center, Atlanta, Georgia.
authors.forename: Elaine A
authors.initials: EA
authors.lastname: Liu
authors.affiliation: Authors' Affiliations: Departments of Radiation Oncology, Medical Oncology, and Pathology; Division of Surgical Oncology, Department of Surgery; Biostatistics and Bioinformatics Shared Resource, Winship Cancer Institute, Emory University; and Atlanta Veterans Affairs Medical Center, Atlanta, Georgia.
authors.forename: Burcu
authors.initials: B
authors.lastname: Saka
authors.affiliation: Authors' Affiliations: Departments of Radiation Oncology, Medical Oncology, and Pathology; Division of Surgical Oncology, Department of Surgery; Biostatistics and Bioinformatics Shared Resource, Winship Cancer Institute, Emory University; and Atlanta Veterans Affairs Medical Center, Atlanta, Georgia.
authors.forename: William A
authors.initials: WA
authors.lastname: Hall
authors.affiliation: Authors' Affiliations: Departments of Radiation Oncology, Medical Oncology, and Pathology; Division of Surgical Oncology, Department of Surgery; Biostatistics and Bioinformatics Shared Resource, Winship Cancer Institute, Emory University; and Atlanta Veterans Affairs Medical Center, Atlanta, Georgia.
authors.forename: Joseph W
authors.initials: JW
authors.lastname: Shelton
authors.affiliation: Authors' Affiliations: Departments of Radiation Oncology, Medical Oncology, and Pathology; Division of Surgical Oncology, Department of Surgery; Biostatistics and Bioinformatics Shared Resource, Winship Cancer Institute, Emory University; and Atlanta Veterans Affairs Medical Center, Atlanta, Georgia.
authors.forename: Khanjan
authors.initials: K
authors.lastname: Gandhi
authors.affiliation: Authors' Affiliations: Departments of Radiation Oncology, Medical Oncology, and Pathology; Division of Surgical Oncology, Department of Surgery; Biostatistics and Bioinformatics Shared Resource, Winship Cancer Institute, Emory University; and Atlanta Veterans Affairs Medical Center, Atlanta, Georgia.
authors.forename: Rini
authors.initials: R
authors.lastname: Pauly
authors.affiliation: Authors' Affiliations: Departments of Radiation Oncology, Medical Oncology, and Pathology; Division of Surgical Oncology, Department of Surgery; Biostatistics and Bioinformatics Shared Resource, Winship Cancer Institute, Emory University; and Atlanta Veterans Affairs Medical Center, Atlanta, Georgia.
authors.forename: Jeanne
authors.initials: J
authors.lastname: Kowalski
authors.affiliation: Authors' Affiliations: Departments of Radiation Oncology, Medical Oncology, and Pathology; Division of Surgical Oncology, Department of Surgery; Biostatistics and Bioinformatics Shared Resource, Winship Cancer Institute, Emory University; and Atlanta Veterans Affairs Medical Center, Atlanta, GeorgiaAuthors' Affiliations: Departments of Radiation Oncology, Medical Oncology, and Pathology; Division of Surgical Oncology, Department of Surgery; Biostatistics and Bioinformatics Shared Resource, Winship Cancer Institute, Emory University; and Atlanta Veterans Affairs Medical Center, Atlanta, Georgia.
authors.forename: David A
authors.initials: DA
authors.lastname: Kooby
authors.affiliation: Authors' Affiliations: Departments of Radiation Oncology, Medical Oncology, and Pathology; Division of Surgical Oncology, Department of Surgery; Biostatistics and Bioinformatics Shared Resource, Winship Cancer Institute, Emory University; and Atlanta Veterans Affairs Medical Center, Atlanta, Georgia.
authors.forename: Bassel F
authors.initials: BF
authors.lastname: El-Rayes
authors.affiliation: Authors' Affiliations: Departments of Radiation Oncology, Medical Oncology, and Pathology; Division of Surgical Oncology, Department of Surgery; Biostatistics and Bioinformatics Shared Resource, Winship Cancer Institute, Emory University; and Atlanta Veterans Affairs Medical Center, Atlanta, Georgia.
authors.forename: Charles A
authors.initials: CA
authors.lastname: Staley
authors.affiliation: Authors' Affiliations: Departments of Radiation Oncology, Medical Oncology, and Pathology; Division of Surgical Oncology, Department of Surgery; Biostatistics and Bioinformatics Shared Resource, Winship Cancer Institute, Emory University; and Atlanta Veterans Affairs Medical Center, Atlanta, Georgia.
authors.forename: N Volkan
authors.initials: NV
authors.lastname: Adsay
authors.affiliation: Authors' Affiliations: Departments of Radiation Oncology, Medical Oncology, and Pathology; Division of Surgical Oncology, Department of Surgery; Biostatistics and Bioinformatics Shared Resource, Winship Cancer Institute, Emory University; and Atlanta Veterans Affairs Medical Center, Atlanta, Georgia.
authors.forename: Walter J
authors.initials: WJ
authors.lastname: Curran
authors.affiliation: Authors' Affiliations: Departments of Radiation Oncology, Medical Oncology, and Pathology; Division of Surgical Oncology, Department of Surgery; Biostatistics and Bioinformatics Shared Resource, Winship Cancer Institute, Emory University; and Atlanta Veterans Affairs Medical Center, Atlanta, Georgia.
authors.forename: Jerome C
authors.initials: JC
authors.lastname: Landry
authors.affiliation: Authors' Affiliations: Departments of Radiation Oncology, Medical Oncology, and Pathology; Division of Surgical Oncology, Department of Surgery; Biostatistics and Bioinformatics Shared Resource, Winship Cancer Institute, Emory University; and Atlanta Veterans Affairs Medical Center, Atlanta, Georgia.
authors.forename: Shishir K
authors.initials: SK
authors.lastname: Maithel
authors.affiliation: Authors' Affiliations: Departments of Radiation Oncology, Medical Oncology, and Pathology; Division of Surgical Oncology, Department of Surgery; Biostatistics and Bioinformatics Shared Resource, Winship Cancer Institute, Emory University; and Atlanta Veterans Affairs Medical Center, Atlanta, Georgia dsyu@emory.edu.
authors.forename: David S
authors.initials: DS
authors.lastname: Yu
mesh_terms: D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology* / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000096:biosynthesis / Q000235:genetics; D021441:Carcinoma, Pancreatic Ductal / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics / Q000601:surgery; D045744:Cell Line, Tumor; D004265:DNA Helicases / Q000096:biosynthesis* / Q000235:genetics; D004268:DNA-Binding Proteins / Q000096:biosynthesis* / Q000235:genetics; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D004354:Drug Screening Assays, Antitumor; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D006801:Humans; D008297:Male; D051379:Mice; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000201:enzymology* / Q000235:genetics / Q000601:surgery; D016016:Proportional Hazards Models; D011897:Random Allocation; D016019:Survival Analysis; D023041:Xenograft Model Antitumor Assays; D000093542:Gemcitabine
chemical_list: D000964:Antimetabolites, Antineoplastic; D014408:Biomarkers, Tumor; D004268:DNA-Binding Proteins; D003841:Deoxycytidine; D004265:DNA Helicases; C491434:CHD7 protein, human; D000093542:Gemcitabine