Early G1 Cyclin-Dependent Kinases as Prognostic Markers and Potential Therapeutic Targets in Esophageal Adenocarcinoma

• Published in: Clinical cancer research Vol. 17; no. 13; pp. 4513 - 4522
• Main Authors: ISMAIL, Amin, BANDLA, Santhoshi, PETERS, Jeffrey H, PENNATHUR, Arjun, LUKETICH, James D, GODFREY, Tony E, REVEILLER, Marie, TOIA, Liana, ZHONGREN ZHOU, GOODING, William E, KALATSKAYA, Irina, STEIN, Lincoln, D'SOUZA, Mary, LITLE, Virginia R
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 01.07.2011
• Subjects: Adenocarcinoma; Adenocarcinoma - diagnosis; Adenocarcinoma - enzymology; Adenocarcinoma - mortality; Adult; Aged; Aged, 80 and over; Antineoplastic agents; Biological and medical sciences; Biomarkers, Tumor - genetics; Cell Line, Tumor; Cell proliferation; Cell Proliferation - drug effects; chromosome 7; Chromosomes, Human, Pair 7 - genetics; Cyclin-dependent kinase 4; Cyclin-Dependent Kinase 4 - antagonists & inhibitors; Cyclin-Dependent Kinase 4 - genetics; Cyclin-dependent kinase 6; Cyclin-Dependent Kinase 6 - antagonists & inhibitors; Cyclin-Dependent Kinase 6 - genetics; DNA Copy Number Variations - genetics; DNA microarrays; Esophageal Neoplasms - diagnosis; Esophageal Neoplasms - enzymology; Esophageal Neoplasms - mortality; Esophagus; Female; Gastroenterology. Liver. Pancreas. Abdomen; Gene Amplification - genetics; Gene expression; Gene Expression Regulation, Neoplastic; Gene Knockdown Techniques; Humans; Male; Medical sciences; Middle Aged; Oncogenes; Pharmacology. Drug treatments; Piperazines - pharmacology; Prognosis; Protein Kinase Inhibitors - pharmacology; Pyridines - pharmacology; Single-nucleotide polymorphism; siRNA; Survival; Survival Analysis; Tumors; Prognosis; Targeting; Enzyme; Targeted therapy; Transferases; Esophageal disease; Biological marker; Malignant tumor; Esophagus cancer; G1 Phase; Treatment; Cell cycle; Digestive diseases; Esophagus adenocarcinoma; Early; Cyclin dependent kinase; Cancer
• ISSN: 1078-0432; 1557-3265; 1078-0432
• DOI: 10.1158/1078-0432.ccr-11-0244

Chromosomal gain at 7q21 is a frequent event in esophageal adenocarcinoma (EAC). However, this event has not been mapped with fine resolution in a large EAC cohort, and its association with clinical endpoints and functional relevance are unclear. We used a cohort of 116 patients to fine map the 7q21 amplification using SNP microarrays. Prognostic significance and functional role of 7q21 amplification and its gene expression were explored. Amplification of the 7q21 region was observed in 35% of tumors with a focal, minimal amplicon containing six genes. 7q21 amplification was associated with poor survival and analysis of gene expression identified cyclin-dependent kinase 6 (CDK6) as the only gene in the minimal amplicon whose expression was also associated with poor survival. A low-level amplification (10%) was observed at the 12q13 region containing the CDK6 homologue cyclin-dependent kinase 4 (CDK4). Both amplification and expression of CDK4 correlated with poor survival. A combined model of both CDK6 and CDK4 expressions is a superior predictor of survival than either alone. Specific knockdown of CDK4 and/or CDK6 by siRNAs shows that they are required for proliferation of EAC cells and that their function is additive. PD-0332991 targets the kinase activity of both molecules and suppresses proliferation and anchorage independence of EAC cells through activation of the pRB pathway. We suggest that CDK6 is the driver of 7q21 amplification and that both CDK4 and CDK6 are prognostic markers and bona fide oncogenes in EAC. Targeting these molecules may constitute a viable new therapy for this disease.