Tumor Suppressor and Immediate Early Transcription Factor Genes in Non-small Cell Lung Cancer* Wendy J. Levin; Graham Casey, PhD; Juan C. Ramos; M. Jane Arboleda; Peter T. Reissmann, MD; Dennis J. Slamon, MD, PhD Non-small lung cancer (NSCLC) is a disease that exhib- its multiple genetic lesions. Lung Cancer Study Group (LCSG) 871 was designed to analyze this group of malignancies for alterations in growth factors and/or their receptors, oncogenes, tumor suppressor genes, and immediate early transcription factor genes. Immuno- histochemical analysis showed that 32% of evaluable cases studied contained absent or abnormal Rb expres- sion. Sequence analysis of the p53 gene revealed that 58% of these cancers contained structural alterations of this gene, whereas only 45% of these cases overex- pressed p53 by immunohistochemical analysis. Finally, both Northern blot and immunohistochemical analysis showed that these tumors exhibited changes in the mRNA and protein expression levels respectively of the immediate early transcription factor genes c-fos, c-jun, and EGR, in that less expression of these genes was ev- ident in the tumors compared with adjacent normal tissue. Understanding both the biologic and molecular significance of these findings may allow us to explore novel modalities for treatment of this disease. Lung cancer will remain the leading cause of cancer death for both sexes in the United States this year. It is estimated that there will be 100,000 new cases of lung cancer in men and 72,000 new cases in women in 1994.1 Non-small cell lung cancer (NSCLC) comprises approxi- mately 75% of all lung cancers, and includes adenocarci- nomas, squamous cell carcinomas, bronchioalvelolar car- cinomas, large cell carcinomas, with the remaining con- sisting of combined histologic features and the uncommon pulmonary carcinoids.2 Several etiologic factors have been implicated in the development of lung cancer. These include smoking, which accounts for 75 to 80% of the deaths per year, exposure to hydrocarbons, radon, and as- bestos.3 While exposure to these factors can often be con- trolled by changing one's life-style, once a tumor has ini- tiated, the prognosis is often poor because the disease usu- ally presents at an advanced stage. The Lung Cancer Study Group (LSCG), through a cooperative effort, has been able to test different combinations of current acceptable mo- dalities of treatment such as chemotherapy, radiation, and surgery, yet it has become increasingly clear that these treatments do not impact significantly on an increase in *From the Department of Medicine, UCLA School of Medicine, Los Angeles (Ms. Levin, Mr. Ramos, Ms. Arboleda, and Drs. Reissmann and Slamon); and the Cleveland (Ohio) Clinic Foundation, Department of Cancer Biology, Research Institute NN1 (Dr. Casey). Supported by grant ROICA36829 from the National Institutes of Health, Bethesda, Md. long-term survival of these patients. In fact, only 13% of individuals with lung cancer will be alive 5 years after di- agnosis.3 Thus, we must begin to examine novel therapeu- tic approaches toward treatment of this disease. One area that has begun to be explored is the molecular biology of lung cancer and how genetic alterations impact on the pathophysiology of the disease. How are these tumors initiated and what molecular al- terations allow their progression? Although lung cancer has a pathophysiology distinct from other major cancers such as prostate, colorectal, and breast, all of these diseases ap- pear to have common genetic alterations in both dominant oncogenes (HER-2/neu, H-ras, c-myc) and recessive or antioncogenes (p53, Rb).4 Thus, despite the biologic het- erogeneity of these tumors, there appears to be a common denominator in terms of some of these alterations. This is encouraging because by studying one type of malignancy that contains an alteration in these genes, we may gain valuable insight into the role this mutation may play in many unrelated malignancies. Moreover, the pathway from the normal to the transformed phenotype is a mul- tistep process, with perhaps as many as 10 or 20 of these shared genetic mutations occurring by the time lung can- cer becomes clinically evident.5 7 Thus, by identifying cells that contain early lesions, it may be possible to interfere with tumor progression using very early treatment strate- gies. The goal of these types of studies is to understand gene alterations that occur in tumor development, and ulti- mately to provide more specific and effective treatments in the form of novel therapeutics. ALTERATIONS OF TUMOR SUPPRESSOR GENES IN NSCLC Oncogenes, identified some years ago as positively act- ing or dominant transforming genes, may cause cellular transformation through a variety of mechanisms. When overexpressed or functionally altered, they lead to uncon- trolled cell proliferation and provide a growth advantage for cells. Although many dominant oncogenes have been shown to be altered in NSCLC, a growing body of evidence indicates that tumor suppressor or antioncogenes are altered as well. In contrast to dominantly transforming oncogenes, tumor suppressor genes contribute to the transformed phenotype through loss of function muta- tions, which result in the absence of a functional gene product. Cells that contain such mutations have a growth advantage over cells that continue to express normal gene products. Thus, it is thought that normal versions of these proteins act to confine or restrain cell growth and/or pro- liferation. The prototypic tumor suppressor gene is the Rb or retinoblastoma gene, which was identified through its role in the development of childhood retinoblastoma. Inacti- vation of the Rb locus can be acquired in both a heritable and nonheritable fashion, and is recessive to the normal allele. As such, loss of function of both copies of the gene is necessary for cellular transformation and subsequent tumor development. Thus, if one inherits a single mutated Rb allele, progression may occur following the loss or in- activation of the remaining normal allele in growing ret- ina cells through spontaneous somatic mutations. Tumor Suppressor (Levin et al) 372S Downloaded From: http://journal.publications.chestnet.org/pdfaccess.ashx?url=/data/journals/chest/21705/ on 06/21/2017