LACK OF THE DNA-REPAIR PROTEIN O-6-METHYLGUANINE-DNA METHYLTRANSFERASE IN HISTOLOGICALLY NORMAL BRAIN ADJACENT TO PRIMARY HUMAN BRAIN-TUMORS

Exposure to exogenous alkylating agents, particularly N-nitroso compou nds, has been associated with increased incidence of primary human bra in tumors, while intrinsic risk factors are currently unknown. The DNA repair protein O-6-methylguanine-DNA methyltransferase (MGMT) is a ma jor defense against the carcinogenicity of N-nitroso compounds and oth er alkylators. We report here that in 55% (64/117) of cases, histologi cally normal brain tissue adjacent to primary human brain tumors lacke d detectable MGMT activity [methyl excision repair-defective (Mer(-)) status]. The incidence of Mer(-) status in normal brain tissue from br ain 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(-) sta tus was found in 12% (5/43) of normal brain specimens from patients op erated for conditions other than primary brain tumors and was not age- dependent. The 4.6-fold elevation in incidence of Mer(-) status in bra in tumor patients is highly significant (chi(2) = 24; p less than or e qual to 0.001). MGMT activity was independent of age in the lymphocyte s of brain tumor patients and was present in lymphocytes from six of n ine tumor patients whose normal brain specimen was Mer(-). DNA polymer ase beta, apurinic/apyrimidinic endonuclease, and lactate dehydrogenas e activities were present in all specimens tested, including Mer(-) sp ecimens from brain tumor patients. Our data are consistent with a mode l of carcinogenesis in human brain in which epigenetically regulated l ack of MGMT is a predisposing factor and alkylation-related mutagenesi s is a driving force.