Widely dispersed p53 mutation in respiratory epithelium. A novel mechanism for field carcinogenesis.

Abstract

Individuals with one aerodigestive tract malignancy have a high incidence of second primary aerodigestive tumors. The mechanism for this field effect has not been determined. We studied an individual with widespread dysplastic changes in the respiratory epithelium but no overt carcinoma. The entire tracheobronchial tree obtained at autopsy was embedded in paraffin, and bronchial epithelial cells were isolated by microdissection. DNA extracted from the microdissected cells was analyzed for point mutations in the p53 tumor suppressor gene. A single, identical point mutation consisting of a G:C to T:A transversion in codon 245 was identified in bronchial epithelium from 7 of 10 sites in both lungs. Epithelium at sites containing the p53 mutation was morphologically abnormal, exhibiting squamous metaplasia and mild to moderate atypia. No invasive tumor was found in the tracheobronchial tree or any other location. Cells from peripheral blood, kidney, liver, and lymph node exhibited no abnormality in the p53 gene. The widespread presence of a single somatic p53 point mutation in the bronchi of a smoker suggests that a single progenitor bronchial epithelial clone may expand to populate broad areas of the bronchial mucosa-a novel mechanism for field carcinogenesis in the respiratory epithelium that may be of importance in assessing individuals for risk of a second primary tumor as well as in devising effective strategies for chemoprevention of lung cancer. ( J. Clin. Invest. 1997. 100:2133-2137.)

Sequential molecular abnormalities are involved in the multistage development of squamous cell lung carcinoma

“…We have proposed two possibilities for ASM (Hung et al, 1995): (a) a single cell or small clone of cells develops loss at a speci®c parental allele of one or more polymorphic loci, migrates widely throughout the respiratory epithelium of lung and gives rise to multiple foci of abnormal epithelium; or (b) in individuals, one of any pair of alleles has a greater tendency to be lost, perhaps as a result of some form of genomic imprinting or the presence of fragile sites. The ®nding of a single point mutation in the TP53 gene widely dispersed in the respiratory epithelium of a smoker (Franklin et al, 1997) would favor the clonal theory. However, ASMs were noted even in non neoplastic lesions that appeared to be of independent clonal origin, suggesting that ASMs occur via an alternative mechanism.…”

Homozygous deletions at 3p12 in breast and lung cancer

“…This is consistent with the observation that genetic loss on chromosome 3 is an early event in the aetiology of lung and other tumours, detectable in epithelial dysplasias (Chung et al, 1995;Hung et al, 1995). If inactivation or reduced expression of DUTT1 results in a loss of cell to cell adhesion and this is a very early event in the development of lung cancer, it may allow cells in hyperplastic/metaplastic bronchial lesions to dissociate from the epithelial sheet and migrate to other parts of the lung explaining the unexpected observation that bronchial lesions, with the same genotype, and therefore apparently clonally related, can be detected in dierent lobes of the lung (Hung et al, 1995;Franklin et al, 1997).…”

DNA adduct burden and tobacco carcinogenesis

“…Although animal models have been used to address these questions (Helleberg et al, 2001;Izzotti et al, 1999) they do not take into account the protracted exposures typical in humans, nor the cellular and physiologic changes induced in tissues undergoing chronic exposure, which may modify adduct induction and repair. As indicated below, widespread accumulations of genetically altered clones of cells is known to occur in smokers chronically exposed to tobacco carcinogens (Franklin et al, 1997).…”