Mismatch repair deficiency is an uncommon mechanism of alkylator resistance in pediatric malignant gliomas: a report from the Children's Oncology Group

Abstract

Background: Alkylating agents are commonly used in the treatment of childhood malignant gliomas. Overexpression of O(6)-methylguanine-DNA methyltransferase (MGMT) constitutes an important mechanism for resistance to such agents, and MGMT status has been associated with outcome in several recent trials. Deficiency in mismatch repair (MMR) function has been implicated in preclinical studies as an additional potential mechanism of resistance to methylating agents, such as temozolomide, independent of tumor MGMT status. However, the frequency of this abnormality as a clinical resistance mechanism in childhood malignant gliomas has not been well characterized.

Methods: To address this issue, we examined the frequency of microsatellite instability (MSI), a marker of defective MMR, in a series of 68 tumors, derived from newly diagnosed patients treated on the Children's Cancer Group 945 study, and the Children's Oncology Group ACNS0126 and 0423 studies. MSI was assessed using a panel of six microsatellite markers, including BAT-25, BAT-26, CAT-25, D2S123, D5S346, and D17S250. MGMT immunoreactivity was assessed in parallel to allow comparison of the relative incidence of MGMT overexpression and MSI.

Results: Only three tumors had high-level MSI involving three or more markers; the remainder had no MSI at any of the loci examined. These children did not have unusual features in terms of their outcome. In contrast to the infrequency of MSI, 25 tumors (37%) exhibited MGMT overexpression as assessed by immunohistochemistry. None of the tumors with MSI exhibited overexpression of MGMT.

Conclusion: MMR deficiency is an infrequent contributor to initial alkylator resistance in children with malignant gliomas.

Figures

Fig. 1

An illustrative example of a tumor lacking MSI (A) and one with MSI in D5S346, D17S250, BAT25, and BAT26 loci (B). The arrows in (B) indicate aberrant microsatellite repeat elements, distinct in molecular weight and thus mobility on capillary electrophoretograms from the normal microsatellites, which are illustrated in (A). The length abnormalities of these nucleotide repeat sequences is indicative of microsatellite instability (MSI).

Fig. 2

An example of a pediatric malignant glioma showing absent MGMT expression (left) and overexpression (right). [Color figure can be viewed in the online issue, which is available at www.interscience.wiley.com.]