Promoter methylation and expression of MGMT and the DNA mismatch repair genes MLH1, MSH2, MSH6 and PMS2 in paired primary and recurrent glioblastomas.
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Promoter methylation and expression of MGMT and the DNA mismatch repair genes MLH1, MSH2, MSH6 and PMS2 in paired primary and recurrent glioblastomas. / Felsberg, Jörg; Thon, Niklas; Eigenbrod, Sabina; Hentschel, Bettina; Sabel, Michael C; Westphal, Manfred; Schackert, Gabriele; Kreth, Friedrich Wilhelm; Pietsch, Torsten; Löffler, Markus; Weller, Michael; Reifenberger, Guido; Tonn, Jörg C; Network, German Glioma.
in: INT J CANCER, Jahrgang 129, Nr. 3, 3, 2011, S. 659-670.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - Promoter methylation and expression of MGMT and the DNA mismatch repair genes MLH1, MSH2, MSH6 and PMS2 in paired primary and recurrent glioblastomas.
AU - Felsberg, Jörg
AU - Thon, Niklas
AU - Eigenbrod, Sabina
AU - Hentschel, Bettina
AU - Sabel, Michael C
AU - Westphal, Manfred
AU - Schackert, Gabriele
AU - Kreth, Friedrich Wilhelm
AU - Pietsch, Torsten
AU - Löffler, Markus
AU - Weller, Michael
AU - Reifenberger, Guido
AU - Tonn, Jörg C
AU - Network, German Glioma
PY - 2011
Y1 - 2011
N2 - Epigenetic silencing of the O(6) -methylguanine-DNA methyltransferase (MGMT) gene promoter is associated with prolonged survival in glioblastoma patients treated with temozolomide (TMZ). We investigated whether glioblastoma recurrence is associated with changes in the promoter methylation status and the expression of MGMT and the DNA mismatch repair (MMR) genes MLH1, MSH2, MSH6 and PMS2 in pairs of primary and recurrent glioblastomas of 80 patients, including 64 patients treated with radiotherapy and TMZ after the first operation. Among the primary tumors, the MGMT promoter was methylated in 31 patients and unmethylated in 49 patients. In 71 patients (89%), the MGMT promoter methylation status of the primary tumor was retained at recurrence. MGMT promoter methylation, but not MGMT protein expression, was associated with longer progression-free survival, overall survival and postrecurrence survival (PRS). Moreover, PRS was increased under salvage chemotherapy. Investigation of primary and recurrent glioblastomas of 43 patients did not identify promoter methylation in any of the four MMR genes. However, recurrent glioblastomas demonstrated significantly lower MSH2, MSH6 and PMS2 protein expression as detected by immunohistochemistry. In conclusion, reduced expression of MMR proteins, but not changes in MGMT promoter methylation, is characteristic of glioblastomas recurring after the current standards of care.
AB - Epigenetic silencing of the O(6) -methylguanine-DNA methyltransferase (MGMT) gene promoter is associated with prolonged survival in glioblastoma patients treated with temozolomide (TMZ). We investigated whether glioblastoma recurrence is associated with changes in the promoter methylation status and the expression of MGMT and the DNA mismatch repair (MMR) genes MLH1, MSH2, MSH6 and PMS2 in pairs of primary and recurrent glioblastomas of 80 patients, including 64 patients treated with radiotherapy and TMZ after the first operation. Among the primary tumors, the MGMT promoter was methylated in 31 patients and unmethylated in 49 patients. In 71 patients (89%), the MGMT promoter methylation status of the primary tumor was retained at recurrence. MGMT promoter methylation, but not MGMT protein expression, was associated with longer progression-free survival, overall survival and postrecurrence survival (PRS). Moreover, PRS was increased under salvage chemotherapy. Investigation of primary and recurrent glioblastomas of 43 patients did not identify promoter methylation in any of the four MMR genes. However, recurrent glioblastomas demonstrated significantly lower MSH2, MSH6 and PMS2 protein expression as detected by immunohistochemistry. In conclusion, reduced expression of MMR proteins, but not changes in MGMT promoter methylation, is characteristic of glioblastomas recurring after the current standards of care.
KW - Adult
KW - Humans
KW - Male
KW - Aged
KW - Female
KW - Middle Aged
KW - Disease-Free Survival
KW - Adaptor Proteins, Signal Transducing/genetics
KW - Adenosine Triphosphatases/genetics
KW - Antineoplastic Agents/therapeutic use
KW - Brain Neoplasms/genetics/metabolism
KW - DNA Mismatch Repair/genetics
KW - DNA Repair Enzymes/genetics
KW - DNA-Binding Proteins/genetics
KW - Dacarbazine/analogs & derivatives/therapeutic use
KW - Glioblastoma/genetics/radiotherapy/therapy
KW - MutS Homolog 2 Protein/genetics
KW - Neoplasm Recurrence, Local/genetics
KW - Nuclear Proteins/genetics
KW - O(6)-Methylguanine-DNA Methyltransferase/genetics/metabolism
KW - Promoter Regions, Genetic
KW - Adult
KW - Humans
KW - Male
KW - Aged
KW - Female
KW - Middle Aged
KW - Disease-Free Survival
KW - Adaptor Proteins, Signal Transducing/genetics
KW - Adenosine Triphosphatases/genetics
KW - Antineoplastic Agents/therapeutic use
KW - Brain Neoplasms/genetics/metabolism
KW - DNA Mismatch Repair/genetics
KW - DNA Repair Enzymes/genetics
KW - DNA-Binding Proteins/genetics
KW - Dacarbazine/analogs & derivatives/therapeutic use
KW - Glioblastoma/genetics/radiotherapy/therapy
KW - MutS Homolog 2 Protein/genetics
KW - Neoplasm Recurrence, Local/genetics
KW - Nuclear Proteins/genetics
KW - O(6)-Methylguanine-DNA Methyltransferase/genetics/metabolism
KW - Promoter Regions, Genetic
M3 - SCORING: Journal article
VL - 129
SP - 659
EP - 670
JO - INT J CANCER
JF - INT J CANCER
SN - 0020-7136
IS - 3
M1 - 3
ER -
