Low CHD5 expression activates the DNA damage response and predicts poor outcome in patients undergoing adjuvant therapy for resected pancreatic cancer

• Published in: Oncogene Vol. 33; no. 47; pp. 5450 - 5456
• Main Authors: Hall, W A, Petrova, A V, Colbert, L E, Hardy, C W, Fisher, S B, Saka, B, Shelton, J W, Warren, M D, Pantazides, B G, Gandhi, K, Kowalski, J, Kooby, D A, El-Rayes, B F, Staley, C A, Volkan Adsay, N, Curran, W J, Landry, J C, Maithel, S K, Yu, D S
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 20-11-2014; Nature Publishing Group
• Subjects: 692/699/67/1059/99; 692/699/67/1504/1713; 692/700/1750; Adenocarcinoma; Adenocarcinoma - metabolism; Adenocarcinoma - mortality; Adenocarcinoma - surgery; Adenocarcinoma - therapy; Adjuvant therapy; Adult; Aged; Aged, 80 and over; Apoptosis; Biomarkers; Biomarkers, Tumor - metabolism; Cancer; Cell Biology; Chemotherapy; Chemotherapy, Adjuvant; Deoxycytidine - analogs & derivatives; Deoxycytidine - therapeutic use; Deoxyribonucleic acid; Disease-Free Survival; DNA; DNA damage; DNA Damage - drug effects; DNA Helicases - genetics; DNA Helicases - metabolism; Female; Gene Expression Regulation, Neoplastic - drug effects; Genes, Tumor Suppressor - drug effects; Genetic aspects; Genetic research; Genetic screening; Genomes; Human Genetics; Humans; Internal Medicine; Kaplan-Meier Estimate; Male; Medicine; Medicine & Public Health; Middle Aged; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - metabolism; Oncology; Oncology, Experimental; original-article; Pancreatic cancer; Pancreatic Neoplasms - metabolism; Pancreatic Neoplasms - mortality; Pancreatic Neoplasms - surgery; Pancreatic Neoplasms - therapy; Patients; Phosphorylation; Prognosis; Properties; siRNA; Survival analysis; Transcription activation; Treatment Outcome; Tumor Cells, Cultured; Tumor suppressor genes; Tumors; CHD5; tumor suppressor; pancreatic cancer; biomarker; DNA damage response
• DOI: 10.1038/onc.2013.488
• EISSN: 1476-5594
• ISSN: 0950-9232

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.