Mutations in Rb1 pathway-related genes are associated with poor prognosis in Anaplastic Astrocytomas

Abstract

Anaplastic astrocytoma (AA, WHO grade III) is, second to Glioblastoma, the most common and most malignant type of adult CNS tumour. Since survival for patients with AA varies markedly and there are no known useful prognostic or therapy response indicators, the primary purpose of this study was to examine whether knowledge of the known genetic abnormalities found in AA had any clinical value. The survival data on 37 carefully sampled AA was correlated with the results of a detailed analysis of the status of nine genes known to be involved in the development of astrocytic tumours. These included three genes coding for proteins in the p53 pathway (TP53, p14 ARF and MDM2), four in the Rb1 pathway (CDKN2A, CDKN2B, RB1 and CDK4) and PTEN and EGFR. We found that loss of both wild-type copies of any of the three tumour suppressor genes CDKN2A, CDKN2B and RB1 or gene amplification of CDK4, disrupting the Rb1 pathway, were associated with shorter survival (P ¼ 0.009). This association was consistent in multivariate analysis, including adjustment for age (P ¼ 0.013). The findings suggest that analysis of the genes coding for Rb1 pathway components provides additional prognostic information in AA patients receiving conventional therapy.

Clinical Stratification of Glioblastoma Based on Alterations in Retinoblastoma Tumor Suppressor Protein (RB1) and Association With the Proneural Subtype

“…Although some reports have suggested such an association in GBM (31), RB1 may have a more direct correlation with prognosis in lower-grade astrocytomas including World Health Organization grade II and III tumors (14, 15, 32). Our finding that alterations in RB1 are more common in the proneural subtype of GBM may reflect similarities between genetic alterations in a subset of GBMs and lower-grade astrocytomas.…”

Genomic and clinical analyses of 2p24 and 12q13‐q14 amplification in alveolar rhabdomyosarcoma: A report from the Children's Oncology Group

“…In general, the presence of this amplification is mutually exclusive with alterations of the CDKN2A locus or other lesions involving genes of the RB1 pathway, thereby indicating that CDK4 is functional in tumors with this amplicon (Ichimura et al, 1996). The association of this amplification with outcome has also been studied in several tumors, with decreased survival associated with amplification in anaplastic astrocytoma (Backlund et al, 2005) and mantle cell lymphoma (Bea et al, 1999), while no correlation with outcome was found in glioblastoma (Houillier et al, 2006). …”

Post-contrast enhancement as a clinical indicator of prognosis in patients with anaplastic astrocytoma

“…Biological markers have been sought to better differentiate gliomas based on their molecular characteristics. 9 In anaplastic astrocytomas these markers include tumour suppressor genes affecting the p53 and Rb1 pathways, 11 the activation of members of the PI3 K/ Akt/p70s6 k pathway, 12 and copy number variations in chromosome 7, 13 all of which have been shown to be significant correlates of survival. Additionally, the promoter status and expression of particular genes, specifically the DNA repair protein O6-methylguanine-DNA methyltransferase, may be used to predict the response of gliomas to certain chemotherapeutic agents.…”