Abstract | PURPOSE:
Glioblastomas are treated by surgical resection followed by radiotherapy [ X-ray therapy (XRT)] and the alkylating chemotherapeutic agent temozolomide. Recently, inactivating mutations in the mismatch repair gene MSH6 were identified in two glioblastomas recurrent post- temozolomide. Because mismatch repair pathway inactivation is a known mediator of alkylator resistance in vitro, these findings suggested that MSH6 inactivation was causally linked to these two recurrences. However, the extent of involvement of MSH6 in glioblastoma is unknown. We sought to determine the overall frequency and clinical relevance of MSH6 alterations in glioblastomas. EXPERIMENTAL DESIGN: RESULTS: MSH6 mutation was not observed in any pretreatment glioblastoma (0 of 40), whereas 3 of 14 recurrent cases had somatic mutations (P = 0.015). MSH6 protein expression was detected in all pretreatment (17 of 17) cases examined but, notably, expression was lost in 7 of 17 (41%) recurrences from matched post-XRT + temozolomide cases (P = 0.016). Loss of MSH6 was not associated with O(6)-methylguanine methyltransferase status. Measurements of in vivo tumor growth using three-dimensional reconstructed magnetic resonance imaging showed that MSH6-negative glioblastomas had a markedly increased rate of growth while under temozolomide treatment (3.17 versus 0.04 cc/mo for MSH6-positive tumors; P = 0.020). CONCLUSIONS:
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Authors | Daniel P Cahill, Kymberly K Levine, Rebecca A Betensky, Patrick J Codd, Candice A Romany, Linsey B Reavie, Tracy T Batchelor, P Andrew Futreal, Michael R Stratton, William T Curry, A John Iafrate, David N Louis |
Journal | Clinical cancer research : an official journal of the American Association for Cancer Research
(Clin Cancer Res)
Vol. 13
Issue 7
Pg. 2038-45
(Apr 01 2007)
ISSN: 1078-0432 [Print] United States |
PMID | 17404084
(Publication Type: Journal Article)
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Chemical References |
- Antineoplastic Agents, Alkylating
- DNA-Binding Proteins
- G-T mismatch-binding protein
- Tumor Suppressor Proteins
- Dacarbazine
- DNA Modification Methylases
- MGMT protein, human
- DNA Repair Enzymes
- Temozolomide
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Topics |
- Adult
- Aged
- Antineoplastic Agents, Alkylating
(adverse effects)
- Brain Neoplasms
(drug therapy, genetics, pathology)
- Cell Proliferation
(drug effects)
- DNA Modification Methylases
(biosynthesis, drug effects)
- DNA Repair Enzymes
(biosynthesis, drug effects)
- DNA-Binding Proteins
(biosynthesis, drug effects, genetics)
- Dacarbazine
(adverse effects, analogs & derivatives)
- Disease Progression
- Female
- Glioblastoma
(drug therapy, genetics, pathology)
- Humans
- Immunohistochemistry
- Male
- Middle Aged
- Mutation
- Neoplasm Recurrence, Local
(genetics)
- Polymerase Chain Reaction
- Temozolomide
- Tumor Suppressor Proteins
(biosynthesis, drug effects)
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