title: In vivo mutations in human blood cells: biomarkers for molecular epidemiology.
abstract: Mutations arising in vivo in recorder genes of human blood cells provide biomarkers for molecular epidemiology by serving as surrogates for cancer-causing genetic changes. Current markers include mutations of the glycophorin-A (GPA) or hemoglobin (Hb) genes, measured in red blood cells, or mutations of the hypoxanthine-guanine phosphoribosyltransferase (hprt) or HLA genes, measured in T-lymphocytes. Mean mutant frequencies (variant frequencies) for normal young adults are approximately: Hb (4 x 10(-8)) < hprt (5 x 10(-6)) = GPA (10 x 10(-6)) < HLA (30 x 10(-6)). Mutagen-exposed individuals show decided elevations. Molecular mutational spectra are also being defined. For the hprt marker system, about 15% of background mutations are gross structural alterations of the hprt gene (e.g., deletions); the remainder are point mutations (e.g., base substitutions or frameshifts). Ionizing radiations result in dose-related increases in total gene deletions. Large deletions may encompass several megabases as shown by co-deletions of linked markers. Possible hprt spectra for defining radiation and chemical exposures are being sought. In addition to their responsiveness to environmental mutagens/carcinogens, three additional findings suggest that the in vivo recorder mutations are relevant in vivo surrogates for cancer mutations. First, a large fraction of GPA and HLA mutations show exchanges due to homologous recombination, an important mutational event in cancer. Second, hprt mutations arise preferentially in dividing T-cells, which can accumulate additional mutations in the same clone, reminiscent of the multiple hits required in the evolution of malignancy.(ABSTRACT TRUNCATED AT 250 WORDS)
authors.affiliation: VCC Genetics Laboratory, University of Vermont, Burlington 05401.
authors.forename: R J
authors.initials: RJ
authors.lastname: Albertini
authors.forename: J A
authors.initials: JA
authors.lastname: Nicklas
authors.forename: J C
authors.initials: JC
authors.lastname: Fuscoe
authors.forename: T R
authors.initials: TR
authors.lastname: Skopek
authors.forename: R F
authors.initials: RF
authors.lastname: Branda
authors.forename: J P
authors.initials: JP
authors.lastname: O'Neill
mesh_terms: D000970:Antineoplastic Agents / Q000009:adverse effects; D001773:Blood Cells / Q000378:metabolism*; D004781:Environmental Exposure; D004812:Epidemiologic Methods; D005796:Genes / Q000528:radiation effects; D005819:Genetic Markers; D006680:HLA Antigens / Q000235:genetics; D006801:Humans; D007041:Hypoxanthine Phosphoribosyltransferase / Q000235:genetics; D009154:Mutation; D009369:Neoplasms / Q000235:genetics; D012907:Smoking / Q000235:genetics
chemical_list: D000970:Antineoplastic Agents; D005819:Genetic Markers; D006680:HLA Antigens; D007041:Hypoxanthine Phosphoribosyltransferase