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Clin Cancer Res. 2011 Jul 1;17(13):4513-22. doi: 10.1158/1078-0432.CCR-11-0244. Epub 2011 May 18.

Early G₁ cyclin-dependent kinases as prognostic markers and potential therapeutic targets in esophageal adenocarcinoma.

Author information

1
Department of Surgery, University of Rochester Medical Center, Rochester, New York, USA. amin_ismail@urmc.rochester.edu

Abstract

PURPOSE:

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.

EXPERIMENTAL DESIGN:

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.

RESULTS:

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.

CONCLUSIONS:

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.

PMID:
21593195
PMCID:
PMC3390776
DOI:
10.1158/1078-0432.CCR-11-0244
[Indexed for MEDLINE]
Free PMC Article

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