Efficacy of temozolomide is correlated with 1p loss and methylation of the deoxyribonucleic acid repair gene MGMT in malignant gliomas.
Promoter methylation of the deoxyribonucleic acid (DNA) repair gene, O(6)-methylguanine-DNA methyltransferase (MGMT), is associated with improved outcome of patients with glioblastoma multiforme and anaplastic astrocytoma treated with temozolomide (TMZ). Molecular genetic analysis of loss of heterozygosity (LOH) of 1p, 19q, or 10q, p53 mutation, and MGMT promoter methylation was performed in 44 assessable tumor specimens obtained from 46 patients with recurrent malignant gliomas, including 21 with glioblastoma multiforme, 17 with anaplastic astrocytoma, and eight with anaplastic oligoastrocytoma, which have heterogeneous features and variable histological diagnosis, to assess the correlation with the response to TMZ. LOHs of 1p and 19q, and MGMT promoter methylation showed positive correlations with the clinical response to TMZ therapy (p < 0.005, 0.05, and 0.05, respectively; Fisher's exact test). In addition, LOH of 1p and MGMT promoter methylation were associated with longer progression-free survival (p < 0.05 and 0.05, respectively; Cox regression analysis). LOH of 1p in the heterogeneous population of malignant gliomas may be one of the important factors besides MGMT methylation that predict better outcome in patients treated with TMZ.
Ishii
Dai
D
Department of Neurosurgery, Nagoya University School of Medicine, Tsurumai-cho, Showa-ku, Nagoya, Aichi, Japan.
Natsume
Atsushi
A
Wakabayashi
Toshihiko
T
Hatano
Hisashi
H
Asano
Yoshio
Y
Takeuchi
Hiroki
H
Shimato
Shinji
S
Ito
Motokazu
M
Fujii
Masazumi
M
Yoshida
Jun
J
D000293:Adolescent; D000328:Adult; D000368:Aged; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000032:analysis / Q000378:metabolism; D001932:Brain Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D002878:Chromosomes, Human, Pair 1 / Q000235:genetics; D002888:Chromosomes, Human, Pair 19 / Q000235:genetics; D019175:DNA Methylation; D015254:DNA Modification Methylases / Q000235:genetics*; D004252:DNA Mutational Analysis; D004260:DNA Repair / Q000235:genetics; D045643:DNA Repair Enzymes / Q000235:genetics*; D003606:Dacarbazine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D005819:Genetic Markers / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics; D005820:Genetic Testing; D005910:Glioma / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D019656:Loss of Heterozygosity / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000235:genetics; D015996:Survival Rate; D000077204:Temozolomide; D025521:Tumor Suppressor Proteins / Q000235:genetics*
D018906:Antineoplastic Agents, Alkylating; D014408:Biomarkers, Tumor; D005819:Genetic Markers; D025521:Tumor Suppressor Proteins; D003606:Dacarbazine; D015254:DNA Modification Methylases; C515491:MGMT protein, human; D045643:DNA Repair Enzymes; D000077204:Temozolomide