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Genetic Classification of Lung Adenocarcinoma Based on Array-Based Comparative Genomic Hybridization Analysis: Its Association with Clinicopathologic Features

Authors' Affiliations: ¹ Pathology Division, ² Cancer Genomics Project, ³ Center for Medical Genetics, ⁴ Cancer Proteomics Project, National Cancer Center Research Institute, Tokyo, Japan; ⁵ Clinical Laboratory and ⁶ Thoracic Surgery Divisions, National Cancer Center Hospital, Tokyo, Japan; ⁷ Department of Molecular Cytogenetics, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan; and ⁸ Core Research for Evolutional Science and Technology of Japan, Science and Technology Corporation, Saitama, Japan

Requests for reprints: Setsuo Hirohashi, Pathology Division, National Cancer Center Research Institute, 5-1-1, Tsukiji, Chuo-ku, 104-0045 Tokyo, Japan. Phone: 81-3-3547-5201, ext. 4101; Fax: 81-3-3248-2463; E-mail: shirohas{at}ncc.go.jp.

The array-based comparative genomic hybridization using microarrayed bacterial artificial chromosome clones allows high-resolution analysis of genome-wide copy number changes in tumors. To analyze the genetic alterations of primary lung adenocarcinoma in a high-throughput way, we used laser-capture microdissection of cancer cells and array comparative genomic hybridization focusing on 800 chromosomal loci containing cancer-related genes. We identified a large number of chromosomal numerical alterations, including frequent amplifications on 7p12, 11q13, 12q14-15, and 17q21, and two homozygous deletions on 9p21 and one on 8p23. Unsupervised hierarchical clustering analysis of multiple alterations revealed three subgroups of lung adenocarcinoma that were characterized by the accumulation of distinct genetic alterations and associated with smoking history and gender. The mutation status of the epidermal growth factor receptor (EGFR) gene was significantly associated with specific genetic alterations and supervised clustering analysis based on EGFR gene mutations elucidated a subgroup including all EGFR gene mutated tumors, which showed significantly shorter disease-free survival. Our results suggest that there exist multiple molecular carcinogenesis pathways in lung adenocarcinoma that may associate with smoking habits and gender, and that genetic cancer profiling will reveal previously uncharacterized genetic heterogeneity of cancer and be beneficial in estimating patient prognosis and discovering novel cancer-related genes including therapeutic targets.

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