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 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 TGFbetaRII 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 different. Loss of 9p was consistently observed in all glioblastomas but not in colorectal carcinomas. Epidermal growth factor receptor amplification was absent in all glioblastomas and colorectal carcinomas. Our results suggest that both the frequency of p53 mutation and its effects differ 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.
Leung
S Y
SY
Department of Pathology, Queen Mary Hospital, The University of Hong Kong, Hong Kong.
Yuen
S T
ST
Chan
T L
TL
Chan
A S
AS
Ho
J W
JW
Kwan
K
K
Fan
Y W
YW
Hung
K N
KN
Chung
L P
LP
Wyllie
A H
AH
D000230:Adenocarcinoma / Q000235:genetics* / Q000473:pathology; D000328:Adult; D020137:Base Pair Mismatch / Q000235:genetics*; D001932:Brain Neoplasms / Q000235:genetics* / Q000473:pathology; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D002869:Chromosome Aberrations; D002872:Chromosome Deletion; D002899:Chromosomes, Human, Pair 9 / Q000235:genetics; D003062:Codon / Q000235:genetics; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000473:pathology; D004260:DNA Repair / Q000235:genetics*; D004273:DNA, Neoplasm / Q000235:genetics; D066246:ErbB Receptors / Q000235:genetics; D005434:Flow Cytometry; D005784:Gene Amplification; D015972:Gene Expression Regulation, Neoplastic; D016158:Genes, p53; D005909:Glioblastoma / Q000235:genetics* / Q000473:pathology; D006801:Humans; D018895:Microsatellite Repeats; D009363:Neoplasm Proteins / Q000096:biosynthesis; D016609:Neoplasms, Second Primary / Q000235:genetics / Q000473:pathology; D009386:Neoplastic Syndromes, Hereditary / Q000235:genetics* / Q000473:pathology; D009693:Nucleic Acid Hybridization; D009928:Organ Specificity; D011003:Ploidies; D013577:Syndrome; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis
D003062:Codon; D004273:DNA, Neoplasm; D009363:Neoplasm Proteins; D016159:Tumor Suppressor Protein p53; D066246:ErbB Receptors