title: Low CHD5 expression activates the DNA damage response and predicts poor outcome in patients undergoing adjuvant therapy for resected pancreatic cancer.
abstract: The DNA damage response (DDR) promotes genome integrity and serves as a cancer barrier in precancerous lesions but paradoxically may promote cancer survival. Genes that activate the DDR when dysregulated could function as useful biomarkers for outcome in cancer patients. Using a siRNA screen in human pancreatic cancer cells, we identified the CHD5 tumor suppressor as a gene, which, when silenced, activates the DDR. We evaluated the relationship of CHD5 expression with DDR activation in human pancreatic cancer cells and the association of CHD5 expression in 80 patients with resected pancreatic adenocarcinoma (PAC) by immunohistochemical analysis with clinical outcome. CHD5 depletion and low CHD5 expression in human pancreatic cancer cells lead to increased H2AX-Ser139 and CHK2-Thr68 phosphorylation and accumulation into nuclear foci. On Kaplan-Meier log-rank survival analysis, patients with low CHD5 expression had a median recurrence-free survival (RFS) of 5.3 vs 15.4 months for patients with high CHD5 expression (P=0.03). In 59 patients receiving adjuvant chemotherapy, low CHD5 expression was associated with decreased RFS (4.5 vs 16.3 months; P=0.001) and overall survival (OS) (7.2 vs 21.6 months; P=0.003). On multivariate Cox regression analysis, low CHD5 expression remained associated with worse OS (HR: 3.187 (95% CI: 1.49-6.81); P=0.003) in patients undergoing adjuvant chemotherapy. Thus, low CHD5 expression activates the DDR and predicts for worse OS in patients with resected PAC receiving adjuvant chemotherapy. Our findings support a model in which dysregulated expression of tumor suppressor genes that induce DDR activation can be utilized as biomarkers for poor outcome.
authors.affiliation: Department of Radiation Oncology, Winship Cancer Institute, Emory University, Atlanta, GA, USA.
authors.forename: W A
authors.initials: WA
authors.lastname: Hall
authors.affiliation: Department of Radiation Oncology, Winship Cancer Institute, Emory University, Atlanta, GA, USA.
authors.forename: A V
authors.initials: AV
authors.lastname: Petrova
authors.affiliation: Department of Radiation Oncology, Winship Cancer Institute, Emory University, Atlanta, GA, USA.
authors.forename: L E
authors.initials: LE
authors.lastname: Colbert
authors.affiliation: Department of Radiation Oncology, Winship Cancer Institute, Emory University, Atlanta, GA, USA.
authors.forename: C W
authors.initials: CW
authors.lastname: Hardy
authors.affiliation: Division of Surgical Oncology, Department of Surgery, Winship Cancer Institute, Emory University, Atlanta, GA, USA.
authors.forename: S B
authors.initials: SB
authors.lastname: Fisher
authors.affiliation: Department of Pathology, Winship Cancer Institute, Emory University, Atlanta, GA, USA.
authors.forename: B
authors.initials: B
authors.lastname: Saka
authors.affiliation: Department of Radiation Oncology, Winship Cancer Institute, Emory University, Atlanta, GA, USA.
authors.forename: J W
authors.initials: JW
authors.lastname: Shelton
authors.affiliation: Department of Radiation Oncology, Winship Cancer Institute, Emory University, Atlanta, GA, USA.
authors.forename: M D
authors.initials: MD
authors.lastname: Warren
authors.affiliation: Department of Radiation Oncology, Winship Cancer Institute, Emory University, Atlanta, GA, USA.
authors.forename: B G
authors.initials: BG
authors.lastname: Pantazides
authors.affiliation: Biostatistics and Bioinformatics Shared Resource, Winship Cancer Institute, Atlanta, GA, USA.
authors.forename: K
authors.initials: K
authors.lastname: Gandhi
authors.affiliation: Biostatistics and Bioinformatics Shared Resource, Winship Cancer Institute, Atlanta, GA, USA.
authors.forename: J
authors.initials: J
authors.lastname: Kowalski
authors.affiliation: 1] Division of Surgical Oncology, Department of Surgery, Winship Cancer Institute, Emory University, Atlanta, GA, USA [2] Atlanta Veterans Affairs Medical Center, Atlanta, GA, USA.
authors.forename: D A
authors.initials: DA
authors.lastname: Kooby
authors.affiliation: Department of Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, GA, USA.
authors.forename: B F
authors.initials: BF
authors.lastname: El-Rayes
authors.affiliation: Division of Surgical Oncology, Department of Surgery, Winship Cancer Institute, Emory University, Atlanta, GA, USA.
authors.forename: C A
authors.initials: CA
authors.lastname: Staley
authors.affiliation: Department of Pathology, Winship Cancer Institute, Emory University, Atlanta, GA, USA.
authors.forename: N
authors.initials: N
authors.lastname: Volkan Adsay
authors.affiliation: Department of Radiation Oncology, Winship Cancer Institute, Emory University, Atlanta, GA, USA.
authors.forename: W J
authors.initials: WJ
authors.lastname: Curran
authors.affiliation: Department of Radiation Oncology, Winship Cancer Institute, Emory University, Atlanta, GA, USA.
authors.forename: J C
authors.initials: JC
authors.lastname: Landry
authors.affiliation: Division of Surgical Oncology, Department of Surgery, Winship Cancer Institute, Emory University, Atlanta, GA, USA.
authors.forename: S K
authors.initials: SK
authors.lastname: Maithel
authors.affiliation: Department of Radiation Oncology, Winship Cancer Institute, Emory University, Atlanta, GA, USA.
authors.forename: D S
authors.initials: DS
authors.lastname: Yu
mesh_terms: D000230:Adenocarcinoma / Q000378:metabolism* / Q000401:mortality / Q000601:surgery / Q000628:therapy; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000378:metabolism; D017024:Chemotherapy, Adjuvant; D004249:DNA Damage / Q000187:drug effects; D004265:DNA Helicases / Q000235:genetics / Q000378:metabolism*; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000627:therapeutic use; D018572:Disease-Free Survival; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D016147:Genes, Tumor Suppressor / Q000187:drug effects; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D010190:Pancreatic Neoplasms / Q000378:metabolism* / Q000401:mortality / Q000601:surgery / Q000628:therapy; D011379:Prognosis; D016896:Treatment Outcome; D014407:Tumor Cells, Cultured; D000093542:Gemcitabine
chemical_list: D014408:Biomarkers, Tumor; D009419:Nerve Tissue Proteins; D003841:Deoxycytidine; D004265:DNA Helicases; C471926:CHD5 protein, human; D000093542:Gemcitabine