Tobacco and cancer: epidemiology and the laboratory

Area of Science:

• Toxicology
• Molecular Epidemiology
• Cancer Research

Background:

• Tobacco smoke contains numerous mutagenic and carcinogenic chemicals.
• Animal studies and carcinogen-macromolecule adducts demonstrate the link between specific chemicals and tumor development.
• Molecular epidemiology suggests gene mutations in oncogenes and tumor-suppressor genes correlate with environmental exposures like smoking.

Purpose of the Study:

• To investigate the molecular mechanisms linking tobacco smoke exposure to cancer.
• To identify specific DNA adducts and gene mutations associated with smoking-related cancers.
• To evaluate the role of genetic susceptibility in tobacco carcinogen action.

Main Methods:

• Analysis of carcinogen-macromolecule adducts in animal models and human tissues.
• Molecular epidemiology studies examining oncogene and tumor-suppressor gene mutations (e.g., p53, K-ras) in smokers' tumors.
• Measurement of DNA and hemoglobin adducts formed by aromatic amines in exfoliated bladder cells and blood.

Main Results:

• Lungs of smokers contain benzo[a]pyrene diol-epoxide-guanine DNA adducts, consistent with G to T transversions in K-ras and p53 genes.
• Aromatic amine derivatives were identified as major DNA adducts in bladder cells, correlating with smoking habits.
• Evidence suggests genetically based metabolic polymorphisms influence individual susceptibility to tobacco carcinogens.

Conclusions:

• The evidence strongly supports a causal relationship between smoking and cancer.
• Specific chemical exposures in tobacco smoke lead to characteristic DNA adducts and mutations.
• Genetic factors modulate susceptibility, but do not solely explain the smoking-cancer association, refuting alternative hypotheses.