Microsatellite Instability and Mutation of DNA Mismatch Repair Genes in Gliomas

Abstract

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...

M6P/IGF2R is mutated in squamous cell carcinoma of the lung

“…The M6P/IGF2R also contains a poly-G region that is a common target for frame-shift mutations in colon, gastric, endometrial and liver tumors with mismatch repair de®ciencies and microsatellite instability (MI) (Ouyang et al, 1997;Yamada et al, 1997). Moreover, the M6P/ IGF2R is mutated in human gliomas that do not contain mutations in the TGFb type II receptor or Bax genes (Leung et al, 1998).…”

Microsatellite instability and the PTEN1 gene mutation in a subset of early onset gliomas carrying germline mutation or promoter methylation of the hMLH1 gene

“…We searched for the inactivation of the MMR genes causing severe MSI in the two gliomas and found a germline mutation and promoter methylation of the hMLH1 gene. Germline mutations of the hMLH1, hPMS2 and hMSH2 genes in lymphocyte DNAs of the patinents with Turcot's syndrome have been demonstrated previously (Hamilton et al, 1995;Miyaki et al, 1997;Leung et al, 1998).…”

“…Leung et al also reported that four of 22 malignant gliomas (WHO grade III or IV) with onset at less than 45 years of age, carried germline mutations of the hMLH1 or hMSH2 genes (Leung et al, 1998). Further detection of this type of tumor and analyses of causative mutations or methylation of the hMLH1 gene as well as other genes involved in MMR should cast new light on the genesis of early onset human glioblastomas.…”

“…In gliomas associated with Turcot's syndrome that shows an extensive MSI, germline mutations of the mismatch repair (MMR) genes, hMLH1, hPMS2 or hMSH2 have been reported (Hamilton et al, 1995;Miyaki et al, 1997;Leung et al, 1998). These ®ndings indicate that MSI are also involved in development of some gliomas.…”

Loss of heterozygosity of M6P/IGF2R gene is an early event in the development of prostate cancer

“…5,6,8 The gene contains a poly-deoxyguanine (poly-G) region that is a common mutational target in colon, gastric and endometrial tumors with mismatch repair deficiencies and microsatellite instability. [15][16][17] It is also mutated in human gliomas that do not contain mutations in either the transforming growth factor b type II receptor or Bax genes. 17 Moreover, the M6P/IGF2R is mutated in 30% of breast tumors and 60% of squamous cell carcinomas of the lung.…”