MSH6 Mutations May Influence Temozolomide Resistance in Treatment-Naive Gliomas Independent of MGMT Methylation

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Resistance to temozolomide in glioblastoma has been thought to be largely mediated by expression of the DNA repair enzyme MGMT, although there are data suggesting a role for inactivation of MSH6 and other mismatch repair proteins.

In a study reported in Clinical Cancer Research, Nguyen and colleagues identified 11 previously unreported mutations in MSH6 in 9 different glioma samples and 6 paired brain tumor–initiating cell lines from adult patients; MSH6 mutations were also identified in 3 oligodendrogliomas and 2 treatment-naive gliomas, both representing previously unreported findings, according to the investigators.

Evaluation of the effect of MGMT and MSH6 status on sensitivity to temozolomide using intracranial brain tumor initiating cell line xenografts showed that the mutations influenced temozolomide sensitivity both in vitro and in vivo in a manner independent of MGMT promoter methylation status.

The investigators concluded, “These data demonstrate that endogenous MSH6 mutations may be present prior to alkylator therapy and occur in at least two histological subtypes of adult glial neoplasms, with this being the first report of these mutations in oligodendroglioma. These findings broaden our understanding of clinical response to [temozolomide] in gliomas.” ■

Nguyen SA, et al: Clin Cancer Res. July 30, 2014 (early release online).




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