PTEN, DMBT1, and p16 alterations in diffusely infiltrating astrocytomas.
Losses at chromosomes 10q and 9p are genetic events implicated in the genesis of diffusely infiltrating astrocytomas. We studied the role of PTEN (10q23.3), DMBT1 (10q25.3-26.1) and p16 (9p21) tumor suppressor genes in a series of 50 low- and high-grade astrocytomas. A genetic screening for point mutations, homozygous deletions and promoter hypermethylation was done by PCR-SSCP, direct sequencing, differential PCR, and methylation specific PCR. PTEN was mutated in 23% and homozygously deleted in 9% GBMs, but not in grade II and III astrocytomas. Homozygous deletions of DMBT1 were found in 5% GBMs and 13% low-grade astrocytomas, but not in anaplastic astrocytomas. p16 suffered homozygous deletion in 27% GBMs and 13% low-grade astrocytomas, though no p16 point mutations were found in any of the 50 astrocytomas. p16 promoter hypermethylation was found in 9% GBMs and 6% low-grade astrocytomas. Our results might indicate that PTEN alterations are late genetic events in the progression of low to high-grade astrocytomas, versus DMBT1 and p16 alterations that also occur in low-grade astrocytomas, and might be considered as early genetic events. The majority of samples did not present more than one alteration. Taken together, these data suggest that there are multiple independent mechanisms to control cell growth and prevent GBM tumorigenesis, and that aberrations in several distinct pathways or at several sites within a pathway are needed to overcome these control mechanisms.
Fan
Xing
X
Molecular Neuro-Oncology Laboratory, University of Navarre Medical School, Irunlarrea s/n, E-31008 Pamplona, Spain.
Muñoz
Jorge
J
Sanko
Stephen G
SG
Castresana
Javier S
JS
D000373:Agglutinins; D001254:Astrocytoma / Q000235:genetics*; D002135:Calcium-Binding Proteins; D002879:Chromosomes, Human, Pair 10 / Q000235:genetics; D002899:Chromosomes, Human, Pair 9 / Q000235:genetics; D019175:DNA Methylation; D004268:DNA-Binding Proteins; D017353:Gene Deletion; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D016147:Genes, Tumor Suppressor; D019942:Genes, p16; D006801:Humans; D009154:Mutation; D051059:PTEN Phosphohydrolase; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics*; D016133:Polymerase Chain Reaction; D018807:Polymorphism, Single-Stranded Conformational; D011956:Receptors, Cell Surface / Q000235:genetics*; D025521:Tumor Suppressor Proteins / Q000235:genetics*
D000373:Agglutinins; D002135:Calcium-Binding Proteins; C108174:DMBT1 protein, human; D004268:DNA-Binding Proteins; D011956:Receptors, Cell Surface; D025521:Tumor Suppressor Proteins; D010744:Phosphoric Monoester Hydrolases; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human