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Early Involvement of the Phosphatidylinositol 3-Kinase/Akt Pathway in Lung Cancer Progression

Division of Allergy, Pulmonary and Critical Care Medicine; Department of Medicine, Biostatistics Shared Resource; Tissue Informatics Shared Resource; Department of Pathology; and Department of Surgery, The Vanderbilt Ingram Comprehensive Cancer Center, Vanderbilt University School of Medicine; and VA Medical Center, Nashville, Tennessee

Correspondence and requests for reprints should be addressed to Pierre P. Massion, M.D., Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University Medical Center, the Vanderbilt-Ingram Comprehensive Cancer Center, 2220 Pierce Avenue, PRB 640, Nashville, TN 37232-6838. E-mail: pierre.massion{at}vanderbilt.edu

Signaling through the phosphatidylinositol 3-kinase (PI3-kinase) pathway has been associated with lung tumorigenesis. We examined the association between gene copy number of the PI3-kinase catalytic subunit (PIK3CA) and phosphorylated Akt expression in invasive and preinvasive lung cancers. We sought to determine at what stage of tumor development gene copy number increase or phosphorylated Akt overexpression might affect tumor development. We assessed PIK3CA gene copy number by fluorescence in situ hybridization and expression of phosphorylated Akt by immunohistochemistry in 242 invasive and 43 preinvasive lung cancers and correlated our findings with clinical outcome. The PIK3CA was amplified in 70% of squamous carcinomas, 38% of large cell carcinomas, 19% of adenocarcinomas, and 67% of small cell lung cancers. Phosphorylated Akt overexpression was frequently observed, and strongly so in 12 to 17% of lung cancers depending on nuclear or cytoplasmic localization. Neither PIK3CA gene copy number nor phosphorylated Akt protein expression had prognostic significance. In preinvasive lesions, amplification of the PIK3CA and overexpression of phosphorylated Akt were associated with severe dysplasia and each other. These observations suggest frequent and early involvement of the PI3-kinase pathway in lung cancer.

Key Words: amplification • PKB • preinvasive • tissue microarray • tumorigenesis

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