Vascular endothelial growth factor (VEGF) is a hypoxia-inducible angiogenic factor, which is known to be upregulated in most cases of glioblastoma multiforme (GBM). The expression of VEGF and its receptors in ependymomas, oligodendrogliomas, and particularly the expression during anaplastic progression of these three types of gliomas has not been studied extensively. Fifty-six gliomas, consisting of 10 ependymomas, 12 oligodendrogliomas, 3 anaplastic oligodendrogliomas, 6 astrocytomas grade II, 5 anaplastic astrocytomas, and 20 glioblastoma multiformes, were investigated for VEGF and receptor expression using in situ hybridization (ISH) and reverse transcription polymerase chain reaction (RT-PCR). Results showed that VEGF was moderately to strongly expressed in 8 of 10 ependymomas and in all anaplastic oligodendrogliomas and glioblastoma multiforme cases. These tumors displayed similar degrees of extensive necrosis and vascular proliferation, with VEGF expression consistently seen in tumor cells around necrotic areas. The VEGF expression, although present at a lower level, also was shown in 4 of 12 oligodendrogliomas, in 3 of 6 astrocytomas grade II, and in 2 of 5 anaplastic astrocytomas, with a regional rather than diffuse pattern of positive result. The findings from the in situ hybridization study correlated with the expression index, as determined by reverse transcription polymerase chain reaction. Expression of VEGF was correlated significantly with vascular proliferation (p < 10(-5)) and necrosis (p < 10(-5)), as well as with microvessel density (p = 0.002, rs = 0.41). The VEGF receptors, kinase domain region (KDR) and Fms-like-tyrosine kinase (Flt-1), also were upregulated in the tumor vasculature of glioblastoma multiforme, anaplastic oligodendrogliomas, and ependymomas with necrosis, whereas the astrocytomas grade II, anaplastic astrocytomas, and oligodendroglioma tumors tended to express a weak to nondetectable signal. Anaplastic progression in all three types of gliomas is heralded by the occurrence of small zones of VEGF-expressing cells and early vascular proliferation, followed by an accelerated phase of angiogenesis closely associated with VEGF induction around areas of necrosis and with the expression of VEGF receptors in the tumor vasculature.

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 ␤ 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 Microsatellite instability (MSI) is characterized by the expansion and contraction of small repeat sequences during DNA replication and is present in the majority of tumors in the hereditary nonpolyposis colon cancer (HNPCC) syndrome.1 HNPCC is characterized by familial occurrence of cancer in various sites, including the colon, endometrium, and urinary tract, at an early age.2 The mechanism leading to MSI is related to a defect in the DNA mismatch repair (MMR) system, of which more than 5 DNA mismatch repair (MMR) genes are now known. 3-12Mutation of the hMSH2 and hMLH1 genes accounts for more than 60% of individuals with the syndrome. In most of these series, MSI was considered positive if there was an allelic shift in a single locus only. The status of the MMR gene, be it germline or somatic, is largely unknown for these MSI-positive gliomas. On the other hand, there have been reports of increased risk for brain tumors in HNPCC kindred, 20 -22 and a few patients with Turcot's syndrome, characterized by the development of both colorectal and brain cancers, have been shown to have MSI and to harbor germline mutation in the MMR genes. 23,24 We have previously reported an unusually high incidence of colorectal carcinoma in the young Hong Kong population. 25 Coincidentally, there have been several studies reporting an unexpected tendency for the occurrence of glioblastomas and anaplastic astrocytomas in young Chinese in Taiwan, the Peop...