Infrequent methylation of CDKN2A(MTS1/p16) and rare mutation of both CDKN2A and CDKN2B(MTS2/p15) in primary astrocytic tumours.
In a series of 46 glioblastomas, 16 anaplastic astrocytomas and eight astrocytomas, all tumours retaining one or both alleles of CDKN2A (48 tumours) and CDKN2B (49 tumours) were subjected to sequence analysis (entire coding region and splice acceptor and donor sites). One glioblastoma with hemizygous deletion of CDKN2A showed a missense mutation in exon 2 (codon 83) that would result in the substitution of tyrosine for histidine in the protein. None of the tumours retaining alleles of CDKN2B showed mutations of this gene. Glioblastomas with retention of both alleles of CDKN2A (14 tumours) and CDKN2B (16 tumours) expressed transcripts for these genes. In contrast, 7/13 glioblastomas with hemizygous deletions of CDKN2A and 8/11 glioblastomas with hemizygous deletions of CDKN2B showed no or weak expression. Anaplastic astrocytomas and astrocytomas showed a considerable variation in the expression of both genes, regardless of whether they retained one or two copies of the genes. The methylation status of the 5' CpG island of the CDKN2A gene was studied in all 15 tumours retaining only one allele of CDKN2A as well as in the six tumours showing no significant expression of transcript despite their retaining both CDKN2A alleles. Three tumours (one of each malignancy grade studied) were found to have partially methylated the 5' CpG island of CDKN2A. It appears that in human astrocytic gliomas point mutations of the CDKN2A and CDKN2B genes are uncommon and hypermethylation of the 5' CpG region of CDKN2A does not appear to be a major mechanism for inhibiting transcription of this gene.
Schmidt
E E
EE
Institute for Oncology and Pathology, Division of Tumour Pathology, Karolinska Hospital, Stockholm, Sweden.
Ichimura
K
K
Messerle
K R
KR
Goike
H M
HM
Collins
V P
VP
D001254:Astrocytoma / Q000235:genetics*; D001483:Base Sequence; D001932:Brain Neoplasms / Q000235:genetics*; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D019941:Cyclin-Dependent Kinase Inhibitor p16; D019175:DNA Methylation; D004273:DNA, Neoplasm / Q000737:chemistry; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008969:Molecular Sequence Data; D017354:Point Mutation; D016133:Polymerase Chain Reaction; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*
D002352:Carrier Proteins; D019941:Cyclin-Dependent Kinase Inhibitor p16; D004273:DNA, Neoplasm; D011505:Protein-Tyrosine Kinases