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Genetic alterations of multiple tumor suppressors and oncogenes in the carcinogenesis and progression of lung cancer

Abstract

Lung cancer has become the leading cause of cancer death in many economically well-developed countries. Recent molecular biological studies have revealed that overt lung cancers frequently develop through sequential morphological steps, with the accumulation of multiple genetic and epigenetic alterations affecting both tumor suppressor genes and dominant oncogenes. Cell cycle progression needs to be properly regulated, while cells have built-in complex and minute mechanisms such as cell cycle checkpoints to maintain genomic integrity. Genes in the p16INK4A-RB and p14ARF-p53 pathways appear to be a major target for genetic alterations involved in the pathogenesis of lung cancer. Several oncogenes are also known to be altered in lung cancer, leading to the stimulation of autocrine/paracrine loops and activation of multiple signaling pathways. It is widely acknowledged that carcinogens in cigarette smoke are deeply involved in these multiple genetic alterations, mainly through the formation of DNA adducts. A current understanding of the molecular mechanisms of lung cancer pathogenesis and progression is presented in relation to cigarette smoking, an absolute major risk factor for lung cancer development, by reviewing genetic alterations of various tumor suppressor genes and oncogenes thus far identified in lung cancer, with brief summaries of their functions and regulation.

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Acknowledgements

We thank members of our laboratory for their contributions including helpful discussions and critical reading. We apologize in advance for the incompleteness of the referencing due to space constraints. Studies in our laboratory have been supported in part by grants from the Ministry of Education, Science, Sports and Culture, Japan, and from the Ministry of Health, Labour, and Welfare, Japan.

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Correspondence to Takashi Takahashi.

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Osada, H., Takahashi, T. Genetic alterations of multiple tumor suppressors and oncogenes in the carcinogenesis and progression of lung cancer. Oncogene 21, 7421–7434 (2002). https://doi.org/10.1038/sj.onc.1205802

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