Faculty Collaboration Database

Low CHD5 expression activates the DNA damage response and predicts poor outcome in patients undergoing adjuvant therapy for resected pancreatic cancer. Oncogene 2014 Nov 20;33(47):5450-6

Date

11/28/2013

Pubmed ID

24276239

DOI

10.1038/onc.2013.488

Scopus ID

2-s2.0-84887905533 (requires institutional sign-in at Scopus site)   18 Citations

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.

Author List

Hall WA, Petrova AV, Colbert LE, Hardy CW, Fisher SB, Saka B, Shelton JW, Warren MD, Pantazides BG, Gandhi K, Kowalski J, Kooby DA, El-Rayes BF, Staley CA 3rd, Volkan Adsay N, Curran WJ, 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

Adenocarcinoma
Adult
Aged
Aged, 80 and over
Biomarkers, Tumor
Chemotherapy, Adjuvant
DNA Damage
DNA Helicases
Deoxycytidine
Disease-Free Survival
Female
Gene Expression Regulation, Neoplastic
Genes, Tumor Suppressor
Humans
Kaplan-Meier Estimate
Male
Middle Aged
Nerve Tissue Proteins
Pancreatic Neoplasms
Prognosis
Treatment Outcome
Tumor Cells, Cultured