Microsatellite instability and mutation of DNA mismatch repair genes in gliomas.

Microsatellite instability (MSI) has been identified in various human cancers, particularly those associated with the hereditary nonpolyposis colorectal cancer syndrome. Although gliomas have been reported in a few hereditary nonpolyposis colorectal cancer syndrome kindred, data on the incidence of MSI in gliomas are conflicting, and the nature of the mismatch repair (MMR) defect is not known. We established the incidence of MSI and the underlying MMR gene mutation in 22 patients ages 45 years or less with sporadic high-grade gliomas (17 glioblastomas, 3 anaplastic astrocytomas, and 2 mixed gliomas, grade III). Using five microsatellite loci, four patients (18%) had high level MSI, with at least 40% unstable loci. Germline MMR gene mutation was detected in all four patients, with inactivation of the second allele of the corresponding MMR gene or loss of protein expression in the tumor tissue. Frameshift mutation in the mononucleotide tract of insulin-like growth factor type II receptor was found in one high-level MSI glioma, but none was found in the transforming growth factor beta type II receptor and the Bax genes. There was no family history of cancer in three of the patients, and although one patient did have a family history of colorectal carcinoma, the case did not satisfy the Amsterdam criteria for hereditary nonpolyposis colorectal cancer syndrome. Three patients developed metachronous colorectal adenocarcinomas, fitting the criteria of Turcot's syndrome. Thus, MSI and germline MMR gene mutation is present in a subset of young glioma patients, and these patients and their family members are at risk of developing other hereditary nonpolyposis colorectal cancer syndrome-related tumors, in particular colorectal carcinomas. These results have important implications in the genetic testing and management of young patients with glioma and their families.