title: Degeneration of human oncogenes and mitochondrial genes occurs in cells that exhibit age-related pathology.
abstract: The development of a new class of assays to determine in vivo mutation frequencies has provided new perspectives on the timing, location, and distribution of somatic mutagenesis in mitochondrial genes and in oncogenes of the aging human body. This descriptive information has led to the inference of new models for age-related pathophysiology and oncogenesis. Mutations of mitochondrial genes rise rapidly with age to frequencies a thousand-fold higher than those of nuclear genes. Genotypic selection analysis has revealed that mitochondrial mutations accumulate predominantly in nonmitotic cells whose age-dependent loss is associated with pathology. Random mitochondrial mutation is most likely to inactivate Complex I, deficiency of which induces mitochondrial superoxide formation and cell death. Genotypic selection of oncogenic mutations at the BCL2 and p53 loci has revealed that the cell specificity of oncogenic mutations in persons without cancer correlates well with sites of tumor origin, indicating that cells bearing such mutations are the likely precursors of future tumors. Quantitative variation in human BCL2 mutation frequency is extensive, and BCL2 mutation frequency rises with age, concordant with increased risk for lymphoma. The clonality and persistence of BCL2 mutations suggests two specific testable mechanisms of lymphomagenesis. BCL2 mutation frequency rises in persons exposed to cigarette smoke, and more p53 mutations occur in skin exposed to sunlight than in unexposed skin. Thus, in addition to their likely relevance to future cancer risk, the dose-response relationship between exposure and oncogenic mutations indicates promise for their future use as in vivo biodosimeters of human exposure to carcinogens.
authors.affiliation: Department of Molecular Biosciences, University of California, Davis 95616, USA.
authors.forename: G
authors.initials: G
authors.lastname: Cortopassi
authors.forename: Y
authors.initials: Y
authors.lastname: Liu
authors.forename: T
authors.initials: T
authors.lastname: Hutchin
mesh_terms: D000375:Aging / Q000473:pathology*; D004272:DNA, Mitochondrial / Q000235:genetics*; D005838:Genotype; D006801:Humans; D008954:Models, Biological; D009154:Mutation; D009857:Oncogenes; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D019253:Proto-Oncogene Proteins c-bcl-2
chemical_list: D004272:DNA, Mitochondrial; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2