Gene amplification of CCNE1, CCND1, and CDK6 in gastric cancers detected by multiplex ligation-dependent probe amplification and fluorescence in situ hybridization.

Abstract	New and effective treatments for advanced gastric cancer are urgently needed. Cyclins E and D1 form a complex with cyclin-dependent kinase 2, 4, or 6 to regulate G1-S transition. The G1-S regulatory genes encoding cyclin E (CCNE1), cyclin D1 (CCND1), and CDK6 (CDK6) are frequently amplified in gastric cancer and may therefore influence molecularly targeted therapies against ERBB2 or EGFR when coamplified. A total of 179 formalin-fixed and paraffin-embedded gastric cancer specimens were examined for these gene amplifications by multiplex ligation-dependent probe amplification and fluorescence in situ hybridization. Amplification of at least 1 G1-S regulatory gene was found in 35 tumors (CCNE1 amplification, 15% of samples; CCND1, 6%; CDK6, 1%). In 13 of the 35 tumors, dual-color fluorescence in situ hybridization identified coamplification of the G1-S regulatory genes with ERBB2, EGFR, and/or KRAS in single cancer nuclei. The observation that cells with G1-S regulatory gene amplification contained clonal subpopulations with coamplification of ERBB2, EGFR, or KRAS in 5 early and 3 advanced cancers suggests that amplification of the G1-S regulatory genes represents an early event, which precedes ERBB2, EGFR, or KRAS amplification. Amplified CCNE1, CCND1, and CDK6 in advanced gastric cancer may be potentially useful as direct targets for molecular therapy or for combination therapy with ERBB2 or EGFR inhibitors. Multiplex ligation-dependent probe amplification could be a useful tool for identification of patients who would benefit from such therapies.
Authors	Akishi Ooi, Takeru Oyama, Ritsuko Nakamura, Ryousuke Tajiri, Hiroko Ikeda, Sachio Fushida, Yoh Dobashi
Journal	Human pathology (Hum Pathol) Vol. 61 Pg. 58-67 (03 2017) ISSN: 1532-8392 [Electronic] United States
PMID	27864121 (Publication Type: Journal Article)
Copyright	Copyright © 2017 Elsevier Inc. All rights reserved.
Chemical References	Biomarkers, Tumor CCND1 protein, human CCNE1 protein, human Cyclin E KRAS protein, human Oncogene Proteins Cyclin D1 EGFR protein, human ERBB2 protein, human ErbB Receptors Receptor, ErbB-2 CDK6 protein, human Cyclin-Dependent Kinase 6 Proto-Oncogene Proteins p21(ras)
Topics	Adenocarcinoma (enzymology, genetics, pathology, therapy) Biomarkers, Tumor (genetics) Biopsy Cell Cycle Checkpoints Cell Proliferation Cyclin D1 (genetics) Cyclin E (genetics) Cyclin-Dependent Kinase 6 (genetics) DNA Copy Number Variations DNA Mutational Analysis ErbB Receptors (genetics) Gene Amplification Gene Dosage Genetic Predisposition to Disease Humans Immunohistochemistry In Situ Hybridization, Fluorescence Multiplex Polymerase Chain Reaction Mutation Oncogene Proteins (genetics) Phenotype Predictive Value of Tests Proto-Oncogene Proteins p21(ras) (genetics) Receptor, ErbB-2 (genetics) Stomach Neoplasms (enzymology, genetics, pathology, therapy)

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