{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T10:54:19Z","timestamp":1789988059709,"version":"4.0.1"},"reference-count":0,"publisher":"National Academy of Sciences","issue":"14","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[1996,7,9]]},"abstract":"<jats:p>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 &lt; 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.<\/jats:p>","DOI":"10.1073\/pnas.93.14.6941","type":"journal-article","created":{"date-parts":[[2002,7,26]],"date-time":"2002-07-26T10:31:39Z","timestamp":1027679499000},"page":"6941-6946","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":60,"title":["Lack of the DNA repair protein O6-methylguanine-DNA methyltransferase in histologically normal brain adjacent to primary human brain tumors."],"prefix":"10.1073","volume":"93","author":[{"given":"J R","family":"Silber","sequence":"first","affiliation":[{"name":"Department of Neurological Surgery, University of Washington, Seattle, WA 98195, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"A","family":"Blank","sequence":"additional","affiliation":[{"name":"Department of Neurological Surgery, University of Washington, Seattle, WA 98195, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M S","family":"Bobola","sequence":"additional","affiliation":[{"name":"Department of Neurological Surgery, University of Washington, Seattle, WA 98195, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"B A","family":"Mueller","sequence":"additional","affiliation":[{"name":"Department of Neurological Surgery, University of Washington, Seattle, WA 98195, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"D D","family":"Kolstoe","sequence":"additional","affiliation":[{"name":"Department of Neurological Surgery, University of Washington, Seattle, WA 98195, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"G A","family":"Ojemann","sequence":"additional","affiliation":[{"name":"Department of Neurological Surgery, University of Washington, Seattle, WA 98195, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M S","family":"Berger","sequence":"additional","affiliation":[{"name":"Department of Neurological Surgery, University of Washington, Seattle, WA 98195, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[1996,7,9]]},"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.93.14.6941","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,4,13]],"date-time":"2022-04-13T14:38:42Z","timestamp":1649860722000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/full\/10.1073\/pnas.93.14.6941"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[1996,7,9]]},"references-count":0,"journal-issue":{"issue":"14","published-print":{"date-parts":[[1996,7,9]]}},"alternative-id":["10.1073\/pnas.93.14.6941"],"URL":"https:\/\/doi.org\/10.1073\/pnas.93.14.6941","relation":{},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[1996,7,9]]},"assertion":[{"value":"1996-07-09","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}