Novel MSH6 Mutations in Treatment-Naïve Glioblastoma and Anaplastic Oligodendroglioma Contribute to Temozolomide Resistance Independently of MGMT Promoter Methylation

Aug 1, 2014Clinical cancer research : an official journal of the American Association for Cancer Research

New MSH6 gene changes linked to temozolomide resistance in untreated glioblastoma and anaplastic oligodendroglioma, separate from MGMT methylation

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Abstract

Eleven previously unreported mutations in the MSH6 gene were identified in nine different glioma samples and six paired brain tumor-initiating cell lines.

Endogenous MSH6 mutations may exist in gliomas before alkylator therapy.
Mutations in MSH6 were found in three oligodendrogliomas and two treatment-naïve gliomas.
These mutations influence the sensitivity of brain tumor-initiating cells to temozolomide, regardless of MGMT promoter methylation status.
The presence of MSH6 mutations could affect treatment outcomes in at least two histologic subtypes of adult glial tumors.

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PURPOSE: The current standard of care for glioblastoma (GBM) involves a combination of surgery, radiotherapy, and temozolomide chemotherapy, but this regimen fails to achieve long-term tumor control. Resistance to temozolomide is largely mediated by expression of the DNA repair enzyme MGMT; however, emerging evidence suggests that inactivation of MSH6 and other mismatch repair proteins plays an important role in temozolomide resistance. Here, we investigate endogenous MSH6 mutations in GBM, anaplastic oligodendroglial tumor tissue, and corresponding brain tumor-initiating cell lines (BTIC).

EXPERIMENTAL DESIGN: MSH6 sequence and MGMT promoter methylation were determined in human tumor samples and BTICs. Sensitivity to temozolomide was evaluated in vitro using BTICs in the absence and presence of O(6)-benzylguanine to deplete MGMT. The influence of MGMT and MSH6 status on in vivo sensitivity to temozolomide was evaluated using intracranial BTIC xenografts.

RESULTS: We identified 11 previously unreported mutations in MSH6 in nine different glioma samples and six paired BTIC lines from adult patients. In addition, MSH6 mutations were documented in three oligodendrogliomas and two treatment-naïve gliomas, both previously unreported findings. These mutations were found to influence the sensitivity of BTICs to temozolomide both in vitro and in vivo, independent of MGMT promoter methylation status.

CONCLUSIONS: These data demonstrate that endogenous MSH6 mutations may be present before alkylator therapy and occur in at least two histologic subtypes of adult glial neoplasms, with this report serving as the first to note these mutations in oligodendroglioma. These findings broaden our understanding of the clinical response to temozolomide in gliomas.

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Novel MSH6 Mutations in Treatment-Naïve Glioblastoma and Anaplastic Oligodendroglioma Contribute to Temozolomide Resistance Independently of MGMT Promoter Methylation

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