Chest
Session 2Molecular Mechanisms of Lung Cancer: Interaction of Environmental and Genetic Factors: Giles F. Filley Lecture
Section snippets
Genetic Susceptibility for Lung Cancer
Epidemiologic and family studies provide evidence that there can be genetic predisposition for lung cancer4, 5 that appears to be inherited as a mendelian autosomal trait.6 Only 5 to 10% of lifetime smokers develop lung cancer, which may reflect differential genetic susceptibility. Polymorphisms in genes that encode enzymes responsible for activation and detoxification of environmental carcinogens may be important determinants of disease.3, 7 In addition, inherited polymorphisms in other genes,
K-ras Oncogenes in Lung Cancer
The ras family of proto-oncogenes occupies a critical point in the pathway of signal transduction from the cell membrane to the nucleus and appears to play a role in control of cell growth. The K-ras proto-oncogene, one of the first genes found to be altered in lung cancers, is activated by point mutation in about 30% of human lung adenocarcinomas and large cell carcinomas, but infrequently in squamous cell carcinomas and only rarely in small cell lung cancer (SCLC) (Table 1).17 The predominant
Role of the P53 Tumor Suppressor Gene in Lung Cancer
The p53 tumor suppressor gene is the most commonly mutated gene in human cancer. The highest incidence of p53 mutations in lung cancer is in SCLC in which 70% of tumors have mutations, followed by squamous cell, large cell, and adenocarcinoma with 65%, 60%, and 33%, respectively (Table 1).27 Recent studies have discovered that p53 functions in a pivotal role at the Gl/S cell cycle checkpoint, controlling genetic stability, growth arrest, and cell death.28, 29, 30 Loss of function of p53 or one
Loss of Heterozygosity in Lung Cancer
Loss of chromosomes or portions of chromosomes is a frequent event in cancer and may reflect the inactivation of tumor suppressor genes in those locations. Loss of chromosomes 3p, 9p, and 17p is common in lung cancer (Table 2),47, 48, 49, 50, 51 with the losses on 3p and 9p occurring relatively early in tumorigenesis.2, 52 Loss of heterozygosity (LOH) on chromosome 2q, 18q, and 22q is also a frequent but late event in lung cancer.53 Increased knowledge of the timing and frequency of different
Loci on Chromosome 3P Involved in Most Lung Cancers
Deletions of 3p are among the earliest lesions detected in lung cancer, appearing in about 75% of hyperplasias.52 Three distinct regions of loss of 3p have been identified: 3p25, 3p21.3, and 3pl4-cen.56, 57 The von Hippel-Lindau tumor suppressor gene maps to 3p25 but is mutated only rarely in lung cancer cell lines.58 The c-raf oncogene has been mapped to 3p25 and is deleted frequently in lung cancer 59 The DNA mismatch repair gene hMLHl, associated with hereditary nonpolyposis colon cancer,
Tumor Suppressor Gene on Chromosome 9P Altered in NSCLC
The region most frequently deleted on chromosome 9p in a variety of cancers, including lung, is 9p21,62, 63 thus providing evidence for the existence of at least one tumor suppressor gene in this region. Candidate genes p16 (MTS1/ p16-INK4) and p15 (MTS2/p15-INK4B), which map to this region, encode inhibitors of cyclin-dependent kinase CDK4 that is involved in cell cycle control at the G1 checkpoint.64, 65, 66 Loss of this function could cause the cell cycle to become unregulated, thereby
Genetic Instability in Lung Cancer
Progression of human cancer is characterized by an accumulation of genetic changes leading progressively to increased genetic instability. The molecular causes of these changes are not fully understood, but a mutator phenotype leading to genomic instability may be an early step in the development of some cancers. A mutator or replication error (RER) phenotype appears to be important in hereditary nonpolyposis colon cancer and is characterized by a high frequency of microsatellite instability
Conclusions
Our knowledge of the molecular events leading to lung cancer has increased greatly during the past decade. Although the dangers of smoking have been known for decades, and the disease would be largely preventable by cessation of smoking, this action has not taken place. Largely through epidemiology and family studies, we are beginning to identify susceptible subpopulations. As we discover more susceptibility factors and genetic alterations involved in lung cancer development, it might be
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