Abstract
Evaluation of O-methylguanine-DNA methyltransferase (MGMT) expression is important for antiglioma therapy as many clinical trials have demonstrated that promoter hypermethylation and low level expression of MGMT are associated with an enhanced response to alkylating agents. However, here we report that the current strategies used to evaluate MGMT status in gliomas are unreliable. We observed discordance in the MGMT expression status when immunohistochemical evaluation and polymerase chain reaction-based methylation assessments were used: 73% of gliomas with methylated MGMT promoter had substantial numbers of MGMT-immunopositive tumor cells. Furthermore, when MGMT expression was tested in tumor homogenates using reverse transcription-polymerase chain reaction, 43% of tumors were found positive, in comparison to only 24%, when histologic samples were assayed immunohistochemically. To explain these inconsistencies we undertook a detailed immunohistochemical evaluation of tumor samples and found that some gliomas demonstrated remarkably high expression of MGMT in the entire tumor whereas others contained only a small immunopositive area. Additionally, we found that gliomas contained various types of non-neoplastic cells expressing MGMT, including lymphocytes, vascular endothelial cells, and macrophages/microglias, which contribute to overall MGMT expression detected in tumor homogenates, and thus result in overestimation of tumor MGMT expression. Therefore, to correctly establish MGMT expression in the tumor, which could be informative of glioma sensitivity to alkylating agents, exclusion of non-neoplastic brain components from analysis is required.
| Original language | English |
|---|---|
| Pages (from-to) | 1220-1227 |
| Number of pages | 8 |
| Journal | American Journal of Surgical Pathology |
| Volume | 32 |
| Issue number | 8 |
| DOIs | |
| Publication status | Published - 2008 Aug 1 |
| Externally published | Yes |
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Keywords
- CD68
- Glioma
- MGMT
- Promoter methylation
ASJC Scopus subject areas
- Anatomy
- Surgery
- Pathology and Forensic Medicine
Cite this
Careful exclusion of non-neoplastic brain components is required for an appropriate evaluation of O6-methylguanine-DNA methyltransferase status in glioma : Relationship between immunohistochemistry and methylation analysis. / Sasai, Ken; Nodagashira, Miho; Nishihara, Hiroshi; Aoyanagi, Eiko; Wang, Lei; Katoh, Masahito; Murata, Junichi; Ozaki, Yoshimaru; Ito, Tamio; Fujimoto, Shin; Kaneko, Sadao; Nagashima, Kazuo; Tanaka, Shinya.
In: American Journal of Surgical Pathology, Vol. 32, No. 8, 01.08.2008, p. 1220-1227.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Careful exclusion of non-neoplastic brain components is required for an appropriate evaluation of O6-methylguanine-DNA methyltransferase status in glioma
T2 - Relationship between immunohistochemistry and methylation analysis
AU - Sasai, Ken
AU - Nodagashira, Miho
AU - Nishihara, Hiroshi
AU - Aoyanagi, Eiko
AU - Wang, Lei
AU - Katoh, Masahito
AU - Murata, Junichi
AU - Ozaki, Yoshimaru
AU - Ito, Tamio
AU - Fujimoto, Shin
AU - Kaneko, Sadao
AU - Nagashima, Kazuo
AU - Tanaka, Shinya
PY - 2008/8/1
Y1 - 2008/8/1
N2 - Evaluation of O-methylguanine-DNA methyltransferase (MGMT) expression is important for antiglioma therapy as many clinical trials have demonstrated that promoter hypermethylation and low level expression of MGMT are associated with an enhanced response to alkylating agents. However, here we report that the current strategies used to evaluate MGMT status in gliomas are unreliable. We observed discordance in the MGMT expression status when immunohistochemical evaluation and polymerase chain reaction-based methylation assessments were used: 73% of gliomas with methylated MGMT promoter had substantial numbers of MGMT-immunopositive tumor cells. Furthermore, when MGMT expression was tested in tumor homogenates using reverse transcription-polymerase chain reaction, 43% of tumors were found positive, in comparison to only 24%, when histologic samples were assayed immunohistochemically. To explain these inconsistencies we undertook a detailed immunohistochemical evaluation of tumor samples and found that some gliomas demonstrated remarkably high expression of MGMT in the entire tumor whereas others contained only a small immunopositive area. Additionally, we found that gliomas contained various types of non-neoplastic cells expressing MGMT, including lymphocytes, vascular endothelial cells, and macrophages/microglias, which contribute to overall MGMT expression detected in tumor homogenates, and thus result in overestimation of tumor MGMT expression. Therefore, to correctly establish MGMT expression in the tumor, which could be informative of glioma sensitivity to alkylating agents, exclusion of non-neoplastic brain components from analysis is required.
AB - Evaluation of O-methylguanine-DNA methyltransferase (MGMT) expression is important for antiglioma therapy as many clinical trials have demonstrated that promoter hypermethylation and low level expression of MGMT are associated with an enhanced response to alkylating agents. However, here we report that the current strategies used to evaluate MGMT status in gliomas are unreliable. We observed discordance in the MGMT expression status when immunohistochemical evaluation and polymerase chain reaction-based methylation assessments were used: 73% of gliomas with methylated MGMT promoter had substantial numbers of MGMT-immunopositive tumor cells. Furthermore, when MGMT expression was tested in tumor homogenates using reverse transcription-polymerase chain reaction, 43% of tumors were found positive, in comparison to only 24%, when histologic samples were assayed immunohistochemically. To explain these inconsistencies we undertook a detailed immunohistochemical evaluation of tumor samples and found that some gliomas demonstrated remarkably high expression of MGMT in the entire tumor whereas others contained only a small immunopositive area. Additionally, we found that gliomas contained various types of non-neoplastic cells expressing MGMT, including lymphocytes, vascular endothelial cells, and macrophages/microglias, which contribute to overall MGMT expression detected in tumor homogenates, and thus result in overestimation of tumor MGMT expression. Therefore, to correctly establish MGMT expression in the tumor, which could be informative of glioma sensitivity to alkylating agents, exclusion of non-neoplastic brain components from analysis is required.
KW - CD68
KW - Glioma
KW - MGMT
KW - Promoter methylation
UR - http://www.scopus.com/inward/record.url?scp=49249118859&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=49249118859&partnerID=8YFLogxK
U2 - 10.1097/PAS.0b013e318164c3f0
DO - 10.1097/PAS.0b013e318164c3f0
M3 - Article
C2 - 18580490
AN - SCOPUS:49249118859
VL - 32
SP - 1220
EP - 1227
JO - American Journal of Surgical Pathology
JF - American Journal of Surgical Pathology
SN - 0147-5185
IS - 8
ER -