Frequency of Loss of Heterozygosity at 3 p, 9 p, 13 q, and 17 p is Related to Proliferative Activity in Smokers with Stage I Non-Small Cell Lung Cancer

Abstract

Background: Tumor cells of lung cancer exhibit genetic abnormalities as well as high proliferative activity. The purpose of this study was to evaluate the relationship of genetic abnormalities and smoking status, histological type, and tumor proliferative activity in resected samples of stage I non-small cell lung cancer (NSCLC). Methods: We evaluated 126 samples of stage I NSCLC from patients who underwent complete resection between 1988 and 1993. Loss of heterozygosity (LOH) was assessed using primers that amplified polymorphic microsatellite markers at D3S1300, D3S643, D3S1317, D9S171, IFNA, D13S153, and TP53. Expression of Ki-67 nuclear antigen was examined using immunohistochemical methods to assess tumor proliferative activity. Results: The Fractional Regional Loss index (FRL) was significantly higher in squamous cell carcinoma samples than in adenocarcinoma samples (p < 0.0001). In smokers, Ki-67 labeling index (LI) in high-FRL cases was significantly higher than in low-FRL cases (p < 0.0001). Conclusion: The frequency of LOH at 3 p, 9 p, 13 q, and 17 p was related to proliferative activity in smokers with stage I non-small cell lung cancer.

Key words

Loss of heterozygosity - smoking - Ki-67 antigen - non-small cell lung cancer

References

• 1 Fujisawa T, Iizasa T, Saitoh Y. et al . Smoking before surgery predicts poor long-term survival in patients with stage I non-small cell lung carcinomas.  J Clin Oncol. 1999;  17 2086-2091
• 2 Haga Y, Hiroshima K, Iyoda A. et al . Ki-67 expression and prognosis for smokers with resected stage I non-small cell lung cancer.  Ann Thorac Surg. 2003;  75 1727-1733
• 3 Gerdes J, Li L, Schlueter C. et al . Immunobiochemical and molecular biologic characterization of the cell proliferation-associated nuclear antigen that is defined by monoclonal antibody Ki-67.  Am J Pathol. 1991;  138 867-873
• 4 Kamb A, Gruis N A, Weaver-Feldhaus J. et al . A cell cycle regulator potentially involved in genesis of many tumor types.  Science. 1994;  264 436-440
• 5 Fishel R. Genomic instability, mutators, and the development of cancer: is there a role for p53?.  J Natl Cancer Inst. 1996;  88 1608-1609
• 6 Sato S, Nakamura Y, Tsuchiya E. Difference of allelotype between squamous cell carcinoma and adenocarcinoma of the lung.  Cancer Res. 1994;  54 5652-5655
• 7 Shiseki M, Kohno T, Nishikawa R, Sameshima Y, Mizoguchi H, Yokota J. Frequent allelic losses on chromosomes 2 q, 18 q, and 22 q in advanced non-small cell lung carcinoma.  Cancer Res. 1994;  54 5643-5648
• 8 Sundaresan V, Ganly P, Hasleton P. et al . p53 and chromosome 3 abnormalities, characteristic of malignant lung tumours, are detectable in preinvasive lesions of the bronchus.  Oncogene. 1992;  7 1989-1997
• 9 Kohno H, Hiroshima K, Toyozaki T, Fujisawa T, Ohwada H. p53 mutation and allelic loss of chromosome 3 p, 9 p of preneoplastic lesions in patients with nonsmall cell lung carcinoma.  Cancer. 1999;  85 341-347
• 10 Hall M, Peters G. Genetic alterations of cyclins, cyclin-dependent kinases, and Cdk inhibitors in human cancer.  Adv Cancer Res. 1996;  68 67-108
• 11 Greenblatt M S, Bennett W P, Hollstein M, Harris C C. Mutations in the p53 tumor suppressor gene: clues to cancer etiology and molecular pathogenesis.  Cancer Res. 1994;  54 4855-4878
• 12 Sozzi G, Sard L, De Gregorio L. et al . Association between cigarette smoking and FHIT gene alterations in lung cancer.  Cancer Res. 1997;  57 2121-2123
• 13 Mountain C F. Revisions in the international system for staging lung cancer.  Chest. 1997;  111 1710-1717
• 14 Wistuba I I, Behrens C, Milchgrub S. et al . Sequential molecular abnormalities are involved in the multistage development of squamous cell lung carcinoma.  Oncogene. 1999;  18 643-650
• 15 Hirao T, Nelson H H, Ashok T DS. et al . Tobacco smoke-induced DNA damage and an early age of smoking initiation induce chromosome loss at 3 p21 in lung cancer.  Cancer Res. 2001;  61 612-615
• 16 Tsuchiya E, Nakamura Y, Weng S Y. et al . Allelotype of non-small cell lung carcinoma - comparison between loss of heterozygosity in squamous cell carcinoma and adenocarcinoma.  Cancer Res. 1992;  52 2478-2481
• 17 Ishikawa Y, Furuta R, Miyoshi T. et al . Loss of heterozygosity and the smoking index increase with decrease in differentiation of lung adenocarcinomas: etiologic implications.  Cancer Lett. 2002;  187 47-51
• 18 Zienolddiny S, Ryberg D, Arab M O. et al . Loss of heterozygosity is related to p53 mutations and smoking in lung cancer.  British J Cancer. 2001;  84 226-231
• 19 Burke L, Khan M A, Freedman A N. et al . Allelic deletion analysis of the FHIT gene predicts poor survival in non-small cell lung cancer.  Cancer Res. 1998;  58 2533-2536
• 20 Geradts J, Fong K M, Zimmerman P V, Maynard R, Minna J D. Correlation of abnormal RB, p16^ink4a, and p53 expression with 3 p loss of heterozygosity, other genetic abnormalities, and clinical features in 103 primary non-small cell lung cancers.  Clin Cancer Res. 1999;  5 791-800