Abstract

1. Lung cancer is the leading cause of cancer-related death for both men and women in the United States and the solid tumor with the most defined relationship to a known environmental cause, cigarette smoking. The clinical and biologic aspects of this disease are complex in that four major histologic cancer types, all related to smoking, can arise from the bronchial epithelium, including large cell undifferentiated, squamous cell, adeno-, and small cell lung carcinomas. The first three types, collectively known as non-small cell lung cancer (NSCLC), metastasize later than the small cell tumors (SCLC) and can be cured by early surgery. SCLC is one of the most highly metastatic tumors in humans and has less than a 5 percent 5-year survival rate.

   
   

2. Hereditary aspects of lung cancer are probably less well understood than for any of the other common forms of solid tumors. There are no well-defined syndromes for inherited lung cancer. However, a growing body of evidence suggests that a complex Mendelian dominant inheritance pattern for genetic predisposition may play a significant role in determining which smokers eventually will get lung tumors. Animal models for carcinogen-induced lung cancers, particularly in mice, suggest a major locus for genetic predisposition to lung adenocarcinoma and may prove useful for defining a gene(s) important to the human disease. The specific gene(s) involved have not been defined, nor have the genetic loci involved been delineated.

   
   

3. In part because of the poorly defined hereditary aspects of lung cancer, little is known about the precise gene alterations that underly the earliest steps for lung carcinogenesis. However, multiple genetic alterations, in candidate gene regions (loss of heterozygosity at chromosomes 3p, 9p, 13q, and 17p) or in specific candidate genes (p16, p53, K-ras, cyclin D1 genes), have been elucidated for established lung cancers. The most frequent of these changes, and those which occur earliest in disease progression, provide clues for genes involved in both the initial steps and the hereditary aspects of lung neoplasia.

   
   

4. Further definition of the genes mediating the evolution of lung cancers is essential to establish critically needed markers to facilitate risk assessment for and design of novel tests for early diagnosis of these neoplasms.

   
   

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