(Chest. 2004;125:115S-116S.)
© 2004
American College of Chest Physicians
Non-small Cell Lung Cancer Molecular Profiles Are Associated With Lung Development*
Alain C. Borczuk, MD;
Adel M. Assaad, MD;
Liqun Q. Wang, MS;
Kristin L. Walter, MD and
Charles A. Powell, MD
* From the Columbia University College of Physicians & Surgeons, New York, NY.
Correspondence to: Charles Powell, Assistant Professor of Clinical Medicine, Columbia University College of Physicians & Surgeons, Department of Medicine, Division of Pulmonary, Allergy & Critical Care Medicine, 630 W 168th St, New York, NY 10032; e-mail: cap6{at}columbia.edu
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Introduction
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Current paradigms hold that lung carcinomas arise from a pleuripotent stem cell that is capable of differentiation into one or several histologic cell types. These paradigms suggest that lung tumor cell ontology is determined by the consequences of gene transcriptional activation and/or repression that recapitulates events that are important in embryonic lung development. We examined the relationship of non-small cell lung cancer (NSCLC) gene profiles with lung development.
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Materials and Methods
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Using a DNA array (model U95Av2; Affymetrix; Santa Clara, CA), we acquired gene profiles from 7 nonmalignant lung specimens and 32 microdissected NSCLC tumors. Because we were interested in the genes that distinguished lung cancer histology, we focused our analysis only on tumors, and we utilized microdissection to minimize the confounding of profiles by genes expressed by adjacent nonmalignant structures. Neoplastic cells examined microscopically at x40 magnification were microdissected with a 20-gauge needle, which enriched specimens for tumors and adjacent stroma.
Unsupervised clustering demonstrated the fact that tumors were segregated tightly by histology. We determined the top 100 marker genes for adenocarcinoma, squamous cell carcinoma, large cell cancer, and carcinoid tumors using nearest-neighbor permutation analysis. All class assignments were statistically significant after 500 random permutations. The results were validated by immunostaining for 11 selected proteins using a tissue microarray that contained cylinders from 24 of 32 tumor specimens in addition to 56 other NSCLCs. The data of gene expression during lung development were obtained from accessing a publicly available data set that had been generated with a Mu11k mouse genome microarray (AJRCMB 26:541). Murine orthologs of human NSCLC histology gene markers were identified using computer software (Resourcerer, version 4.0; The Institute for Genomic Research; Rockville, MD). Self-organized mapping showed murine orthologs segregated into two temporally distinct clusters.
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Results
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Large cell marker gene orthologs exclusively resided in a cluster expressed in pseudoglandular and canalicular stages, while adenocarcinoma orthologs were predominantly in the cluster expressed later in the terminal sac and alveolar stages of murine lung development. Representative large cell genes (eg, E2F3, MYBL2, HDAC2, CDK4, and PCNA) are expressed in the nucleus, and are associated with transcription regulation, cell cycle, and replication. Adenocarcinoma genes (eg, SFTPB, TTF-1, VEGFC, DOK1, and MUC1) are associated with lung-specific transcription, cell adhesion, and signal transduction.
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Conclusion
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Gene profiles of lung cancer histology subtypes are associated with lung development and clinical course. For example, large cell cancer genes are associated with proliferation, differentiation arrest, and poor prognosis, while adenocarcinoma genes are associated with glandular formation and improved outcomes relative to large cell carcinoma. In summary, NSCLC histology gene signatures recapitulate lung development pathways and provide insights into lung tumorigenesis.
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Footnotes
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Abbreviation: NSCLC = non-small cell lung cancer
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Introduction
Materials and Methods
