In vivo mutations in human blood cells: Biomarkers for molecular epidemiology
- Univ. of Vermont, Burlington (United States)
- Environmental Health Research and Testing, Inc., Research Triangle Park, NC (United States)
- Univ. of North Carolina, Chapel Hill (United States)
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 [times] 10[sup [minus]8]) < hprt (5 [times] 10[sup [minus]6]) = GPA (10 [times] 10[sup [minus]6]) < HLA (30 [times] 10[sup [minus]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. Finally, fetal hprt mutations frequently have characteristic deletions of hprt exons 2 and 3, which appear to be mediated by the VDJ recombinase that rearranges the T-cell receptor genes during thymic ontogeny. 60 refs., 3 tabs.
- OSTI ID:
- 6058458
- Report Number(s):
- CONF-9110511--; CNN: 68-02-4456
- Journal Information:
- Environmental Health Perspectives; (United States), Journal Name: Environmental Health Perspectives; (United States) Vol. 99; ISSN EVHPAZ; ISSN 0091-6765
- Country of Publication:
- United States
- Language:
- English
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59 BASIC BIOLOGICAL SCIENCES
AMINES
ANIMAL CELLS
AROMATICS
AZAARENES
BIOLOGICAL INDICATORS
BIOLOGICAL MATERIALS
BLOOD
BLOOD CELLS
BODY FLUIDS
CARBOXYLIC ACIDS
CARCINOGENS
CONNECTIVE TISSUE CELLS
GENE RECOMBINATION
GLOBINS
GUANINE
HEMOGLOBIN
HETEROCYCLIC ACIDS
HETEROCYCLIC COMPOUNDS
HYDROXY COMPOUNDS
HYPOXANTHINE
IN VIVO
LEUKOCYTES
LYMPHOCYTES
MATERIALS
MUTAGEN SCREENING
MUTAGENS
MUTATIONS
ORGANIC ACIDS
ORGANIC COMPOUNDS
ORGANIC NITROGEN COMPOUNDS
PIGMENTS
PORPHYRINS
PROTEINS
PURINES
SCREENING
SOMATIC CELLS