Abstract
Malignant astrocytomas are the most aggressive primary brain tumors with a poor prognosis despite optimal treatment. Dysfunction of mismatch repair (MMR) system accelerates the accumulation of mutations throughout the genome causing uncontrolled cell growth. The aim of this study was to characterize the MMR system defects that could be involved in malignant astrocytoma pathogenesis. We analyzed protein expression and promoter methylation of MLH1, MSH2 and MSH6 as well as microsatellite instability (MSI) and MMR gene mutations in a set of 96 low- and high-grade astrocytomas. Forty-one astrocytomas failed to express at least one MMR protein. Loss of MSH2 expression was more frequent in low-grade astrocytomas. Loss of MLH1 expression was associated with MLH1 promoter hypermethylation and MLH1 -93G>A promoter polymorphism. However, MSI was not related with MMR protein expression and only 5% of tumors were MSI-High. Furthermore, the incidence of tumors carrying germline mutations in MMR genes was low and only one glioblastoma was associated with Lynch syndrome. Interestingly, survival analysis identified that tumors lacking MSH6 expression presented longer overall survival in high-grade astrocytoma patients treated only with radiotherapy while MSH6 expression did not modify the prognosis of those patients treated with both radiotherapy and chemotherapy. Our findings suggest that MMR system alterations are a frequent event in malignant astrocytomas and might help to define a subgroup of patients with different outcome.
Highlights
Malignant gliomas account for 70% of all primary brain tumors with an incidence rate adjusted to the European Standard Population of 5.27 per 100 000 persons per year [1]
We have performed a molecular characterization of mismatch repair (MMR) system defects in malignant astrocytomas and we have evaluated the influence of these alterations in patient outcome
MMR protein expression MLH1, MSH2 and MSH6 protein expression was determined in the 96 tumor tissues included in the tissue microarray
Summary
Malignant gliomas account for 70% of all primary brain tumors with an incidence rate adjusted to the European Standard Population of 5.27 per 100 000 persons per year [1]. The majority of these patients display progressive disease and subsequent death. The most common and devastating brain tumor in adults is glioblastoma (grade IV) with a median survival of approximately 12-14 months despite optimal treatment [2,3]. Patients with anaplastic astrocytoma (grade III) survive for nearly 1.5 years, and those with lowgrade astrocytomas (grade II) can survive for as long as 5-10 years [4,5]. Initiation and progression of malignant astrocytomas are related to their genetic and chromosomal alterations. In this context, recent molecular and genetic studies have identified different markers that help to determine prognosis and likelihood of therapeutic response [6,7,8,9,10]
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