title: O⁶-methylguanine-DNA methyltransferase promoter methylation in 45 primary central nervous system lymphomas: quantitative assessment of methylation and response to temozolomide treatment.
abstract: Favorable responses to temozolomide chemotherapy have recently been reported in primary central nervous system lymphoma (PCNSL) patients who are refractory to high-dose methotrexate therapy. The gene encoding the DNA repair enzyme O (6)-methylguanine-DNA methyltransferase (MGMT) is transcriptionally silenced by promoter methylation in several human tumors, including gliomas and systemic lymphomas. MGMT promoter methylation is also a prognostic marker in glioblastoma patients treated with temozolomide. To validate temozolomide treatment in PCNSL, we applied methylation-sensitive high resolution melting (MS-HRM) analysis to quantitate MGMT methylation in PCNSL. MGMT promoter methylation was detected in tumors from 23 (51%) of 45 PCNSL patients, 11 of which were considered to have high (more than 70.0%) methylation status. Of the five recurrent PCNSLs treated with temozolomide, four cases responded, with three achieving complete response and one, a partial response. All four responsive PCNSLs had methylated MGMT promoters, whereas the non-responsive recurrent PCNSL did not. Thus, the use of quantitative MS-HRM analysis for the detection of MGMT promoter methylation has been suggested in PCNSL for the first time. The assay allows rapid and high-throughput evaluation of the MGMT methylation status, and seems to be promising in clinical settings. MGMT promoter methylation may become a useful marker for predicting the response of PCNSLs to temozolomide.
authors.affiliation: Department of Neuro-Oncology/Neurosurgery, Comprehensive Cancer Center, Saitama Medical University International Medical Center, 1397-1 Yamane, Hidaka-shi, Saitama 350-1298, Japan. jadachi@saitama-med.ac.jp
authors.forename: Jun-Ichi
authors.initials: J
authors.lastname: Adachi
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Mishima
authors.forename: Kenji
authors.initials: K
authors.lastname: Wakiya
authors.forename: Tomonari
authors.initials: T
authors.lastname: Suzuki
authors.forename: Kohei
authors.initials: K
authors.lastname: Fukuoka
authors.forename: Takaaki
authors.initials: T
authors.lastname: Yanagisawa
authors.forename: Masao
authors.initials: M
authors.lastname: Matsutani
authors.forename: Atsushi
authors.initials: A
authors.lastname: Sasaki
authors.forename: Ryo
authors.initials: R
authors.lastname: Nishikawa
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D018906:Antineoplastic Agents, Alkylating / Q000627:therapeutic use; D016543:Central Nervous System Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D019175:DNA Methylation; D004273:DNA, Neoplasm / Q000235:genetics; D003606:Dacarbazine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D016393:Lymphoma, B-Cell / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D016403:Lymphoma, Large B-Cell, Diffuse / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D019853:O(6)-Methylguanine-DNA Methyltransferase / Q000235:genetics*; D016133:Polymerase Chain Reaction; D011401:Promoter Regions, Genetic / Q000235:genetics*; D016879:Salvage Therapy; D000077204:Temozolomide; D016896:Treatment Outcome
chemical_list: D018906:Antineoplastic Agents, Alkylating; D004273:DNA, Neoplasm; D003606:Dacarbazine; D019853:O(6)-Methylguanine-DNA Methyltransferase; D000077204:Temozolomide