Abstract
The multiple tumor suppressor 1 (MTS1) gene encoding the p16 inhibitor of cyclin-dependent kinase 4 is deleted or mutated in a wide variety of human tumor cell lines, but the importance of this gene as a tumor suppressor in vivo appears to be highly dependent on tumor type. Because MTS1/p16/CDKN2 and the homologous MTS2/p15 gene map to a region of chromosome 9p21, which is frequently deleted in malignant gliomas, we searched for lesions of these genes in primary biopsies of glioblastoma multiforme (GBM). Our analysis confirms a sizable frequency of homozygous deletion of MTS1/p16/CDKN2 (9/27 cases) and also reveals a low but detectable frequency of intragenic DNA lesions (one point mutation in exon 2 leading to premature termination) among GBMs that retain one or both copies of the gene. No mutations were found in exon 2 of MTS2/p15 (12 cases examined), and one GBM showed a DNA deletion breakpoint in the 30 kb between MTS1/p16/CDKN2 and MTS2/p15 resulting in deletion of MTS1/p16/CDKN2 with retention of MTS2/p15. In contrast to the high-grade tumors, none of 12 low-grade gliomas showed MTS1/p16/CDKN2 deletions. These data support a role for MTS1/p16/CDKN2 as a tumor suppressor gene in the in vivo evolution of GBMs. Given that two tumors with hemizygous MTS1/p16/CDKN2 deletions and loss of heterozygosity for chromosome 9p21 did not contain detectable intragenic mutations, there may be one or more additional relevant 9p21 tumor suppressor genes.