© 1999 by Oxford University Press
Journal of the National Cancer Institute, Vol. 91, No. 21, 1863-1868,
November 3, 1999
© 1999 Oxford University Press
REPORTS |
Multiple Clonal Abnormalities in the Bronchial Epithelium of Patients With Lung Cancer
Affiliations of authors: I.-W. Park, Hamon Center for Therapeutic Oncology and Research, University of Texas Southwestern Medical Center, Dallas, and Department of Internal Medicine, Chung-Ang University Medical School, Seoul, Korea; I. I. Wistuba, A. K. Virmani, Hamon Center for Therapeutic Oncology and Research, University of Texas Southwestern Medical Center; A. Maitra, A. F. Gazdar, Hamon Center for Therapeutic Oncology and Research and Department of Pathology, University of Texas Southwestern Medical Center; S. Milchgrub, Department of Pathology, University of Texas Southwestern Medical Center; J. D. Minna, Hamon Center for Therapeutic Oncology and Research and Departments of Medicine and Pharmacology, University of Texas Southwestern Medical Center.
Correspondence to: Adi F. Gazdar, M.D., Hamon Center for Therapeutic Oncology and Research, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX (e-mail: gazdar{at}simmons.swmed.edu).
BACKGROUND: Several molecular changes, including loss of heterozygosity (i.e., deletion of one copy of allelic DNA sequences) and alterations in microsatellite DNA, have been detected early in the pathogenesis of lung cancer, even in histologically normal epithelium. In the bronchial epithelium of patients with lung cancer, we have determined the frequency, size, and patterns of molecularly abnormal clonal patches. METHODS: We studied formalin-fixed, paraffin-embedded samples from 16 surgically resected lung carcinomas (five squamous cell carcinomas, four small-cell carcinomas, six adenocarcinomas, and one large-cell carcinoma). From each carcinoma, we microdissected foci (each containing about 200 cells) of tumor tissue and equivalent samples of histologically normal and abnormal epithelium. Furthermore, multiple discontinuous foci of bronchial epithelium were analyzed from methanol-fixed samples from three additional patients with lung cancer (two with squamous cell carcinoma and one with adenocarcinoma). We used two-step polymerase chain reaction-based assays involving 12 microsatellite markers at seven chromosomal regions frequently deleted in lung cancer. RESULTS: Two hundred eighteen foci of nonmalignant bronchial epithelium (195 of histologically normal or slightly abnormal epithelium and 23 of dysplastic epithelium) were studied from the 19 surgically resected lobectomy specimens. Thirteen (68%) of the 19 specimens had at least one focus of bronchial epithelium with molecular changes. At least one molecular abnormality was detected in 32% of the 195 histologically normal or slightly abnormal foci and in 52% of the 23 dysplastic foci. Extrapolating from our two-dimensional analyses, we estimate that most clonal patches contain approximately 90 000 cells. Although, in a given individual, tumors appeared homogeneous with respect to molecular changes, the clonally altered patches of mildly abnormal epithelium were heterogeneous. CONCLUSIONS: Our findings indicate that multiple small clonal or subclonal patches containing molecular abnormalities are present in normal or slightly abnormal bronchial epithelium of patients with lung cancer.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  C. Rhiner and E. Moreno Super competition as a possible mechanism to pioneer precancerous fields Carcinogenesis, May 1, 2009; 30(5): 723 - 728. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 X. Wang, M. Wang, G. T. MacLennan, F. W. Abdul-Karim, J. N. Eble, T. D. Jones, F. Olobatuyi, R. Eisenberg, O. W. Cummings, S. Zhang, et al. Evidence for Common Clonal Origin of Multifocal Lung Cancers J Natl Cancer Inst, April 15, 2009; 101(8): 560 - 570. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Walser, X. Cui, J. Yanagawa, J. M. Lee, E. Heinrich, G. Lee, S. Sharma, and S. M. Dubinett Smoking and Lung Cancer: The Role of Inflammation Proceedings of the ATS, December 1, 2008; 5(8): 811 - 815. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. S. Herbst, J. V. Heymach, and S. M. Lippman Lung Cancer N. Engl. J. Med., September 25, 2008; 359(13): 1367 - 1380. [Full Text] [PDF]
|
|
|
|
 |
|
 S. Lam, B. Standish, C. Baldwin, A. McWilliams, J. leRiche, A. Gazdar, A. I. Vitkin, V. Yang, N. Ikeda, and C. MacAulay In vivo Optical Coherence Tomography Imaging of Preinvasive Bronchial Lesions Clin. Cancer Res., April 1, 2008; 14(7): 2006 - 2011. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Gray, J. T. Mao, E. Szabo, M. Kelley, J. Kurie, and G. Bepler Lung Cancer Chemoprevention: ACCP Evidence-Based Clinical Practice Guidelines (2nd Edition) Chest, September 1, 2007; 132(3_suppl): 56S - 68S. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. M. Lippman and J. V. Heymach The Convergent Development of Molecular-Targeted Drugs for Cancer Treatment and Prevention Clin. Cancer Res., July 15, 2007; 13(14): 4035 - 4041. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Angeloni Molecular analysis of deletions in human chromosome 3p21 and the role of resident cancer genes in disease Brief Funct Genomic Proteomic, May 24, 2007; (2007) elm007v1. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Li, N. W. Todd, Q. Qiu, T. Fan, R. Y. Zhao, W. H. Rodgers, H.-B. Fang, R. L. Katz, S. A. Stass, and F. Jiang Genetic Deletions in Sputum as Diagnostic Markers for Early Detection of Stage I Non-Small Cell Lung Cancer Clin. Cancer Res., January 15, 2007; 13(2): 482 - 487. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Vineis and K. Husgafvel-Pursiainen Air pollution and cancer: biomarker studies in human populations Carcinogenesis, November 1, 2005; 26(11): 1846 - 1855. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. E. Miller Pathogenesis of Lung Cancer: 100 Year Report Am. J. Respir. Cell Mol. Biol., September 1, 2005; 33(3): 216 - 223. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. M. Safar, H. Spencer III, X. Su, M. Coffey, C. A. Cooney, L. D. Ratnasinghe, L. F. Hutchins, and C.-Y. Fan Methylation Profiling of Archived Non-Small Cell Lung Cancer: A Promising Prognostic System Clin. Cancer Res., June 15, 2005; 11(12): 4400 - 4405. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Meuwissen and A. Berns Mouse models for human lung cancer Genes & Dev., March 15, 2005; 19(6): 643 - 664. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I. I. Wistuba Histologic Evaluation of Bronchial Squamous Lesions: Any Role in Lung Cancer Risk Assessment? Clin. Cancer Res., February 15, 2005; 11(4): 1358 - 1360. [Full Text] [PDF]
|
|
|
|
 |
|
 D. Moro-Sibilot, F. Fievet, M. Jeanmart, S. Lantuejoul, F. Arbib, M.H. Laverriere, E. Brambilla, and C. Brambilla Clinical prognostic indicators of high-grade pre-invasive bronchial lesions Eur. Respir. J., July 1, 2004; 24(1): 24 - 29. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Kaminski and M. Krupsky Gene Expression Patterns, Prognostic and Diagnostic Markers, and Lung Cancer Biology Chest, May 1, 2004; 125(5_suppl): 111S - 115S. [Full Text] [PDF]
|
|
|
|
|
|
H. Kim, G.-L. Xu, A. C. Borczuk, S. Busch, J. Filmus, M. Capurro, J. S. Brody, J. Lange, J. M. D'Armiento, P. B. Rothman, et al. The Heparan Sulfate Proteoglycan GPC3 Is a Potential Lung Tumor Suppressor Am. J. Respir. Cell Mol. Biol., December 1, 2003; 29(6): 694 - 701. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K M Fong, Y Sekido, A F Gazdar, and J D Minna Lung cancer * 9: Molecular biology of lung cancer: clinical implications Thorax, October 1, 2003; 58(10): 892 - 900. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. J. M. Braakhuis, M. P. Tabor, J. A. Kummer, C. R. Leemans, and R. H. Brakenhoff A Genetic Explanation of Slaughter's Concept of Field Cancerization: Evidence and Clinical Implications Cancer Res., April 15, 2003; 63(8): 1727 - 1730. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Sutedja New techniques for early detection of lung cancer Eur. Respir. J., January 1, 2003; 21(39_suppl): 57S - 66s. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. H. Dragnev, D. Stover, and E. Dmitrovsky Lung Cancer Prevention: The Guidelines Chest, January 1, 2003; 123 (2009): 60S - 71S. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. J. C. Slebos, D. S. Oh, D. M. Umbach, and J. A. Taylor Mutations in Tetranucleotide Repeats following DNA Damage Depend on Repeat Sequence and Carcinogenic Agent Cancer Res., November 1, 2002; 62(21): 6052 - 6060. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Cave-Riant, B. Cuillerier, M. Beau-Faller, N. Martinet, F. Alla, C. Bronner, A. Schneider, P. Oudet, and M. P. Gaub Association of Genetic Defects in Primary Resected Lung Adenocarcinoma Revealed by Targeted Allelic Imbalance Analysis Am. J. Respir. Cell Mol. Biol., October 1, 2002; 27(4): 495 - 502. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Ji, M. Nishizaki, B. Gao, D. Burbee, M. Kondo, C. Kamibayashi, K. Xu, N. Yen, E. N. Atkinson, B. Fang, et al. Expression of Several Genes in the Human Chromosome 3p21.3 Homozygous Deletion Region by an Adenovirus Vector Results in Tumor Suppressor Activities in Vitro and in Vivo Cancer Res., May 1, 2002; 62(9): 2715 - 2720. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. A. Belinsky, W. A. Palmisano, F. D. Gilliland, L. A. Crooks, K. K. Divine, S. A. Winters, M. J. Grimes, H. J. Harms, C. S. Tellez, T. M. Smith, et al. Aberrant Promoter Methylation in Bronchial Epithelium and Sputum from Current and Former Smokers Cancer Res., April 1, 2002; 62(8): 2370 - 2377. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. A. O'Shaughnessy, G. J. Kelloff, G. B. Gordon, A. J. Dannenberg, W. K. Hong, C. J. Fabian, C. C. Sigman, M. M. Bertagnolli, S. P. Stratton, S. Lam, et al. Treatment and Prevention of Intraepithelial Neoplasia: An Important Target for Accelerated New Agent Development : Recommendations of the American Association for Cancer Research Task Force on the Treatment and Prevention of Intraepithelial Neoplasia Clin. Cancer Res., February 1, 2002; 8(2): 314 - 346. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Uematsu, A. Yoshimura, A. Gemma, H. Mochimaru, Y. Hosoya, S. Kunugi, K. Matsuda, M. Seike, F. Kurimoto, K. Takenaka, et al. Aberrations in the Fragile Histidine Triad (FHIT) Gene in Idiopathic Pulmonary Fibrosis Cancer Res., December 1, 2001; 61(23): 8527 - 8533. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Aoyagi, T. Yokose, Y. Minami, A. Ochiai, T. Iijima, Y. Morishita, T. Oda, K. Fukao, and M. Noguchi Accumulation of Losses of Heterozygosity and Multistep Carcinogenesis in Pulmonary Adenocarcinoma Cancer Res., November 1, 2001; 61(21): 7950 - 7954. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Vilkki, J.-L. Tsao, A. Loukola, M. Poyhonen, O. Vierimaa, R. Herva, L. A. Aaltonen, and D. Shibata Extensive Somatic Microsatellite Mutations in Normal Human Tissue Cancer Res., June 1, 2001; 61(11): 4541 - 4544. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. G. Burbee, E. Forgacs, S. Zochbauer-Muller, L. Shivakumar, K. Fong, B. Gao, D. Randle, M. Kondo, A. Virmani, S. Bader, et al. Epigenetic Inactivation of RASSF1A in Lung and Breast Cancers and Malignant Phenotype Suppression J Natl Cancer Inst, May 2, 2001; 93(9): 691 - 699. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. J. Roth, N. Hu, M. R. Emmert-Buck, Q.-H. Wang, S. M. Dawsey, G. Li, W.-J. Guo, Y.-Z. Zhang, and P. R. Taylor Genetic Progression and Heterogeneity Associated with the Development of Esophageal Squamous Cell Carcinoma Cancer Res., May 1, 2001; 61(10): 4098 - 4104. [Abstract] [Full Text]
|
|
|
|
|
|
J. O. Boyle, F. Lonardo, J. H. Chang, D. Klimstra, V. Rusch, and E. Dmitrovsky Multiple High-Grade Bronchial Dysplasia and Squamous Cell Carcinoma: Concordant and Discordant Mutations Clin. Cancer Res., February 1, 2001; 7(2): 259 - 266. [Abstract] [Full Text]
|
|
|
|
|
|
M. I. Lerman and J. D. Minna The 630-kb Lung Cancer Homozygous Deletion Region on Human Chromosome 3p21.3: Identification and Evaluation of the Resident Candidate Tumor Suppressor Genes Cancer Res., November 1, 2000; 60(21): 6116 - 6133. [Abstract] [Full Text]
|
|
|
|
 |
|
 K. H. Dragnev, J. R. Rigas, and E. Dmitrovsky The Retinoids and Cancer Prevention Mechanisms Oncologist, October 1, 2000; 5(5): 361 - 368. [Abstract] [Full Text]
|
|
|
|
 |
|
 Y. Yatabe, H. Konishi, T. Mitsudomi, S. Nakamura, and T. Takahashi Topographical Distributions of Allelic Loss in Individual Non-Small-Cell Lung Cancers Am. J. Pathol., September 1, 2000; 157(3): 985 - 993. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I. I. Wistuba, J. Berry, C. Behrens, A. Maitra, N. Shivapurkar, S. Milchgrub, B. Mackay, J. D. Minna, and A. F. Gazdar Molecular Changes in the Bronchial Epithelium of Patients with Small Cell Lung Cancer Clin. Cancer Res., July 1, 2000; 6(7): 2604 - 2610. [Abstract] [Full Text]
|
|
|
|
|
|
X. Matias-Guiu, E. Bussaglia, L. Catasus, H. Lagarda, E. Gras, P. Machin, J. Prat, W. M. Lin, and C. Y. Muller Correspondence re: W. M. Lin et al., Loss of Heterozygosity and Mutational Analysis of the PTEN/MMAC1 Gene in Synchronous Endometrial and Ovarian Carcinomas. Clin. Cancer Res., 4: 2577-2583, 1998. Clin. Cancer Res., April 1, 2000; 6(4): 1598 - 1600. [Full Text]
|
|
|
|
|
|
W. N. Hittelman Clones and Subclones in the Lung Cancer Field J Natl Cancer Inst, November 3, 1999; 91(21): 1796 - 1799. [Full Text] [PDF]
|
|