O(6)-Methylguanine-DNA methyltransferase expression and prognostic value in brain metastases of lung cancers.
O(6)-Methylguanine-DNA methyltransferase (MGMT) is critical for repairing pro-mutagenic DNA bases and is correlated with response to alkylating agents in cancers. Since there is great interest in pursuing the potential role of temozolomide, a novel alkylating agent, in the treatment of brain metastases, this study aimed to evaluate MGMT expression as well as its prognostic value in this devastating disease. We studied the expression and methylation status of MGMT in 86 brain metastases of lung cancers. Twenty of them had matched primary lung tumor tissues available for direct comparison. MGMT expression was assessed by immunohistochemistry (IHC); the methylation status of MGMT promoter was analyzed by nested methylation-specific PCR (MSP) and validated by quantitative real-time PCR analysis. Positive nuclear MGMT expression was detected more frequently in brain metastases as compared with primary lung cancers (83% versus 50%, P=0.004). The discordance in MGMT expression persisted in the 20 paired primary and metastatic tumors (P=0.031). MGMT promoter hypermethylation was highly correlated with loss of MGMT expression. Both univariate and multivariate analyses showed that median overall survival was significantly longer in patients with positive MGMT expression in brain metastases (16.5 versus 3.5 months, P<0.001). In conclusion, MGMT expression was enhanced in brain metastases as compared with the primary lung cancers. MGMT expression in brain metastases was significantly correlated with better survival.
Wu
Pei-Fang
PF
Graduate Institute of Clinical Medicine, National Taiwan University, College of Medicine, Taipei, Taiwan.
Kuo
Kuan-Ting
KT
Kuo
Lu-Ting
LT
Lin
Yi-Ting
YT
Lee
Wei-Chung
WC
Lu
Yen-Shen
YS
Yang
Chih-Hsin
CH
Wu
Ruey-Meei
RM
Tu
Yong-Kwang
YK
Tasi
Jui-Chang
JC
Tseng
Ham-Min
HM
Tseng
Sheng-Hong
SH
Cheng
Ann-Lii
AL
Lin
Ching-Hung
CH
D000230:Adenocarcinoma / Q000175:diagnosis* / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics / Q000401:mortality / Q000556:secondary; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage / Q000009:adverse effects; D001932:Brain Neoplasms / Q000175:diagnosis* / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics / Q000401:mortality / Q000556:secondary; D015254:DNA Modification Methylases / Q000235:genetics / Q000378:metabolism*; D045643:DNA Repair Enzymes / Q000235:genetics / Q000378:metabolism*; D003606:Dacarbazine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008175:Lung Neoplasms / Q000175:diagnosis* / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics / Q000401:mortality / Q000473:pathology; D008297:Male; D008745:Methylation; D008875:Middle Aged; D011237:Predictive Value of Tests; D011379:Prognosis; D011401:Promoter Regions, Genetic / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016019:Survival Analysis; D000077204:Temozolomide; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*
D018906:Antineoplastic Agents, Alkylating; D025521:Tumor Suppressor Proteins; D003606:Dacarbazine; D015254:DNA Modification Methylases; C515491:MGMT protein, human; D045643:DNA Repair Enzymes; D000077204:Temozolomide