Chromosomal instability and p53 inactivation are required for genesis of glioblastoma but not for colorectal cancer in patients with germline mismatch repair gene mutation

Abstract

We have previously reported high-frequency microsatellite instability (MSI-H) and germ-line mismatch repair gene mutation in patients with unusually young onset of high-grade glioma. Some of these patients developed metachronous MSI-H colorectal cancer and conformed to the diagnosis of Turcot's syndrome. Frameshift mutation of TGFbRII was present in all the colorectal carcinomas but not in brain tumours. We further characterized the genetic pathways of tumour evolution in these metachronous gliomas and colorectal carcinomas. All MSI-H glioblastomas had inactivation of both alleles of the p53 gene and showed over-expression of the p53 protein while none of the colorectal carcinomas had p53 mutation or protein over-expression. Flow cytometry and comparative genomic hybridization revealed that all glioblastomas were chromosomal unstable with aneuploid DNA content, and with a variable number of chromosomal arm aberrations. In contrast, the colorectal carcinomas had diploid or near-diploid DNA content with few chromosomal arm aberrations. The pattern of chromosomal aberrations in the two organs was di erent. Loss of 9p was consistently observed in all glioblastomas but not in colorectal carcinomas. Epidermal growth factor receptor ampli®cation was absent in all glioblastomas and colorectal carcinomas. Our results suggest that both the frequency of p53 mutation and its e ects di er greatly in the two organs. Following loss of mismatch repair function, p53 inactivation and chromosomal instability are not necessary for development of colorectal carcinoma, but are required for genesis of glioblastoma. Oncogene (2000) 19, 4079 ± 4083.

Early-onset colorectal cancer with stable microsatellite DNA and near-diploid chromosomes

“…A second group of colorectal cancers are near diploid, but show substantial microsatellite instability (MIN), due invariably to de®ciency in mismatch repair Ionov et al, 1993;Thibodeau et al, 1993;Peltomaki et al, 1993;Liu et al, 1996). Such tumours often but not always express normal p53 and display relatively few chromosome imbalances as detected by comparative genomic hybridization (CGH) (Ionov et al, 1993;Remvikos et al, 1995;Schlegel et al, 1995;Cottu et al, 1996;Konishi et al, 1996;Olschwang et al, 1997;Leung et al, 2000). Recently, we have drawn attention to a further group associated with neardiploid DNA content, few examples of chromosome imbalances, and stable microsatellite DNA (Georgiades et al, 1999), here called the microsatellite and chromosome stable (MACS) group.…”

Lack of EGF receptor contributes to drug sensitivity of human germline cells

“…Although mutations in proto-oncogenes (c-ret) as well as DNA MMR genes have been linked to germline tumours (van Puijenbroek et al, 1997;Leung et al, 2000), alteration of EGFR in germcell tumours has not been reported. This study showed that germline tumour cells not only exhibited lower EGFR expression but also were highly sensitive to DNA-damaging drugs, suggesting that the lack of EGFR expression contributes at least in part to the drug sensitivity of germline cells.…”

Brain Tumors and the Lynch Syndrome

“…Apart from the inactivation of the alleles of the predisposing gene, additional somatic changes in tumor tissues may make a difference. In TS patients with (heterozygous) germline mutation in MSH2, TP53 inactivation and chromosomal instability were found to be required for the genesis of glioblastoma but not for colorectal carcinoma, which in turn seemed to require TGFβRII frameshift mutation (Leung et al, 2000).…”

“…The loss of MMR protein expression may (Leung et al, 2000) or may not (Gylling et al, 2008) lead to MSI (Table 4). Since the detection of MSI by conventional techniques requires the presence of at least one major tumor clone which exhibits microsatellite repeat length deviating from the normal allele size, the apparent absence of MSI in brain tumors may have an alternative explanation based on clonal heterogeneity.…”