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

We have previously reported high-frequency microsatellite instability (MSI- H) and germ-line mismatch repair gene mutation in patients with unusually y oung onset of high-grade glioma. Some of these patients developed metachron ous MSI-H colorectal cancer and conformed to the diagnosis of Turcot's synd rome. Frameshift mutation of TGF beta RII 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 c arcinomas. 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 co lorectal carcinomas had p53 mutation or protein over-expression. Flow cytom etry and comparative genomic hybridization revealed that all glioblastomas were chromosomal unstable with aneuploid DNA content, and with a variable n umber of chromosomal arm aberrations. In contrast, the colorectal carcinoma s had diploid or near-diploid DNA content with few chromosomal arm aberrati ons. The pattern of chromosomal aberrations in the two organs was different . Loss of 9p was consistently observed in all glioblastomas but not in colo rectal carcinomas. Epidermal growth factor receptor amplification was absen t in all glioblastomas and colorectal carcinomas. Our results suggest that both the frequency of p53 mutation and its effects differ greatly in the tw o organs. Following loss of mismatch repair function, p53 inactivation and chromosomal instability are not necessary for development of colorectal car cinoma, but are required for genesis of glioblastoma.