Fetal-juvenile origins of point mutations in the adult human tracheal-bronchial epithelium: Absence of detectable effects of age, gender or smoking status

Hiroko Sudo, Xiao Cheng Li-Sucholeiki, Luisa A. Marcelino, Amanda N. Gruhl, Pablo Herrero-Jimenez, Helmut Zarbl, James C. Willey, Emma E. Furth, Stephan Morgenthaler, Hilary A. Coller, Per O. Ekstrom, Ray Kurzweil, Elena V. Gostjeva, William G. Thilly*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

17 Scopus citations


Allele-specific mismatch amplification mutation assays (MAMA) of anatomically distinct sectors of the upper bronchial tracts of nine nonsmokers revealed many numerically dispersed clusters of the point mutations C742T, G746T, G747T of the TP53 gene, G35T of the KRAS gene and G508A of the HPRT1 gene. Assays of these five mutations in six smokers have yielded quantitatively similar results. One hundred and eighty four micro-anatomical sectors of 0.5-6 × 106 tracheal-bronchial epithelial cells represented en toto the equivalent of approximately 1.7 human smokers' bronchial trees to the fifth bifurcation. Statistically significant mutant copy numbers above the 95% upper confidence limits of historical background controls were found in 198 of 425 sector assays. No significant differences (P = 0.1) for negative sector fractions, mutant fractions, distributions of mutant cluster size or anatomical positions were observed for smoking status, gender or age (38-76 year). Based on the modal cluster size of mitochondrial point mutants, the size of the adult bronchial epithelial maintenance turnover unit was estimated to be about 32 cells. When data from all 15 lungs were combined the log 2 of nuclear mutant cluster size plotted against log 2 of the number of clusters of a given cluster size displayed a slope of ∼1.1 over a range of cluster sizes from ∼26 to 215 mutant copies. A parsimonious interpretation of these nuclear and previously reported data for lung epithelial mitochondrial point mutant clusters is that they arose from mutations in stem cells at a high but constant rate per stem cell doubling during at least ten stem cell doublings of the later fetal-juvenile period. The upper and lower decile range of summed point mutant fractions among lungs was about 7.5-fold, suggesting an important source of stratification in the population with regard to risk of tumor initiation.

Original languageEnglish (US)
Pages (from-to)25-40
Number of pages16
JournalMutation Research - Fundamental and Molecular Mechanisms of Mutagenesis
Issue number1-2
StatePublished - Nov 10 2008


  • Age
  • Fetal-juvenile
  • Gender
  • Lung
  • Mutation
  • Smoking

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Health, Toxicology and Mutagenesis


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