Lack of the DNA repair protein O6-methylguanine-DNA methyltransferase in histologically normal brain adjacent to primary human brain tumors.
Exposure to exogenous alkylating agents, particularly N-nitroso compounds, has been associated with increased incidence of primary human brain tumors, while intrinsic risk factors are currently unknown. The DNA repair protein O6-methylguanine-DNA methyltransferase (MGMT) is a major defense against the carcinogenicity of N-nitroso compounds and other alkylators. We report here that in 55% (64/117) of cases, histologically normal brain tissue adjacent to primary human brain tumors lacked detectable MGMT activity [methyl excision repair-defective (Mer-) status]. The incidence of Mer- status in normal brain tissue from brain tumor patients was age-dependent, increasing from 21% in children 0.25-19 years of age to 75% in adults over 50. In contrast, Mer- status was found in 12% (5/43) of normal brain specimens from patients operated for conditions other than primary brain tumors and was not age-dependent. The 4.6-fold elevation in incidence of Mer- status in brain tumor patients is highly significant (chi2 = 24; p < or = 0.001). MGMT activity was independent of age in the lymphocytes of brain tumor patients and was present in lymphocytes from six of nine tumor patients whose normal brain specimen was Mer-. DNA polymerase beta, apurinic/apyrimidinic endonuclease, and lactate dehydrogenase activities were present in all specimens tested, including Mer- specimens from brain tumor patients. Our data are consistent with a model of carcinogenesis in human brain in which epigenetically regulated lack of MGMT is a predisposing factor and alkylation-related mutagenesis is a driving force.
Silber
J R
JR
Department of Neurological Surgery, University of Washington, Seattle, WA 98195, USA.
Blank
A
A
Bobola
M S
MS
Mueller
B A
BA
Kolstoe
D D
DD
Ojemann
G A
GA
Berger
M S
MS
D000293:Adolescent; D000328:Adult; D000368:Aged; D000375:Aging / Q000378:metabolism*; D001921:Brain / Q000201:enzymology* / Q000254:growth & development / Q000473:pathology; D001932:Brain Neoplasms / Q000201:enzymology* / Q000473:pathology / Q000601:surgery; D002648:Child; D002675:Child, Preschool; D004256:DNA Polymerase I / Q000378:metabolism; D004260:DNA Repair; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase; D043223:Deoxyribonuclease IV (Phage T4-Induced); D006801:Humans; D007223:Infant; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008190:Lyases / Q000378:metabolism; D008214:Lymphocytes / Q000201:enzymology; D008780:Methyltransferases / Q000378:metabolism*; D008875:Middle Aged; D019853:O(6)-Methylguanine-DNA Methyltransferase
D007770:L-Lactate Dehydrogenase; D008780:Methyltransferases; D019853:O(6)-Methylguanine-DNA Methyltransferase; D004256:DNA Polymerase I; D043223:Deoxyribonuclease IV (Phage T4-Induced); D008190:Lyases; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase