Concurrent inactivation of RB1 and TP53 pathways in anaplastic oligodendrogliomas

Oligodendrogliomas are characterized by frequent loss of heterozygosity (LOH) on chromosomes 1p and 19q, but additional genetic alterations are likely to be involved. In this study, we screened 28 oligodendrogliomas (WHO grade II) and 20 anaplastic oligodendrogliomas (WHO grade III) for alterations in the RB1/CDK4/p16(INK4a)/p15(INK4b) and TP53/p14(ARF)/MDM2 pathways. In oligodendrogliomas, hypermethylation of RB1 (1 case) and p14(ARF) (6 cases) were the only detectable genetic changes (7/28, 25%). In anaplastic oligodendrogliomas, the RB1/CDK4/p16(INK4a)/p15(INK4b) signaling pathway regulating the G(1) --> S transition of the cell cycle was altered in 13/20 (65%) cases, by either RB1 alteration, CDK4 amplification, or p16(INK4a)/p15(INK4b), homozygous deletion or promoter hypermethylation. Further, 50% (10/20) of anaplastic oligodendrogliomas showed alterations in the TP53 pathway through promoter hypermethylation or homozygous deletion of the p14(ARF) gene and, less frequently, through TP53 mutation or MDM2 amplification. Of 13 anaplastic astrocytomas with an altered RBI pathway, 9 (69%) also showed a dysregulatcd TP53 pathway. Thus, simultaneous disruption of the RB1/CDK4/p15(INK4a)/p15(INK4b) and the TP53/p14(ARF)/MDM2 pathways occurs in 45% (9/20) of anaplastic oligodendrogliomas, suggesting that these phenomena contribute to their malignant phenotype.