Alterations in the RB1 Pathway in Low‐grade Diffuse Gliomas Lacking Common Genetic Alterations

We recently reported that the vast majority (>90%) of low‐grade diffuse gliomas (diffuse astrocytoma, oligoastrocytoma and oligodendroglioma) carry at least one of the following genetic alterations: IDH1/2 mutation, TP53 mutation or 1p/19q loss. Only 7% of cases were triple‐negative (ie, lacking any of these alterations). In the present study, array comparative genomic hybridization (CGH) in 15 triple‐negative WHO grade II gliomas (eight diffuse astrocytomas and seven oligodendrogliomas) showed loss at 9p21 (p14ARF, p15INK4b, p16INK4a loci) and 13q14–13q32 (containing the RB1 locus) in three and two cases, respectively. Further analyses in 31 triple‐negative cases as well as a total of 160 non‐triple‐negative cases revealed that alterations in the RB1 pathway (homozygous deletion and promoter methylation of the p15INK4b, p16INK4a and RB1 genes) were significantly more frequent in triple‐negative (26%) than in non‐triple‐negative cases (11%; P = 0.0371). Multivariate analysis after adjustment for age, histology and treatment showed that RB1 pathway alterations were significantly associated with unfavorable outcome for patients with low‐grade diffuse glioma [hazard ratio, 3.024 (1.279–6.631); P = 0.0057]. These results suggest that a fraction of low‐grade diffuse gliomas lacking common genetic alterations may develop through a distinct genetic pathway, which may include loss of cell‐cycle control regulated by the RB1 pathway.

[1]  Karsten Wrede,et al.  Molecular classification of low-grade diffuse gliomas. , 2010, The American journal of pathology.

[2]  M. Ishitobi,et al.  RB1CC1 Activates RB1 Pathway and Inhibits Proliferation and Cologenic Survival in Human Cancer , 2010, PloS one.

[3]  P. Kleihues,et al.  Genetic alterations and signaling pathways in the evolution of gliomas , 2009, Cancer science.

[4]  H. Ohgaki,et al.  Whole genome amplification for array comparative genomic hybridization using DNA extracted from formalin-fixed, paraffin-embedded histological sections. , 2009, The Journal of molecular diagnostics : JMD.

[5]  Joshua M. Korn,et al.  Comprehensive genomic characterization defines human glioblastoma genes and core pathways , 2008, Nature.

[6]  B. Scheithauer,et al.  The 2007 WHO Classification of Tumours of the Central Nervous System , 2007, Acta Neuropathologica.

[7]  G. Barnett,et al.  The impact of genotype on outcome in oligodendroglioma: validation of the loss of chromosome arm 1p as an important factor in clinical decision making. , 2006, Journal of neurosurgery.

[8]  K. Ichimura,et al.  Mutations in Rb1 pathway-related genes are associated with poor prognosis in Anaplastic Astrocytomas , 2005, British Journal of Cancer.

[9]  H. Tagawa,et al.  Genome-wide array-based CGH for mantle cell lymphoma: identification of homozygous deletions of the proapoptotic gene BIM , 2005, Oncogene.

[10]  V. Collins.  Brain tumours: classification and genes , 2004, Journal of Neurology, Neurosurgery & Psychiatry.

[11]  R. Fimmers,et al.  Oligodendroglial Tumors: Refinement of Candidate Regions on Chromosome Arm 1p and Correlation of 1p/19q Status with Survival , 2004, Brain pathology.

[12]  Y. Katayama,et al.  Deregulation of the TP53/p14ARF tumor suppressor pathway in low-grade diffuse astrocytomas and its influence on clinical course. , 2003, Clinical cancer research : an official journal of the American Association for Cancer Research.

[13]  Koichi Ichimura,et al.  Short postoperative survival for glioblastoma patients with a dysfunctional Rb1 pathway in combination with no wild-type PTEN. , 2003, Clinical cancer research : an official journal of the American Association for Cancer Research.

[14]  M. Barbacid,et al.  Cyclin D-dependent kinases, INK4 inhibitors and cancer. , 2002, Biochimica et biophysica acta.

[15]  Rebecca A Betensky,et al.  Histopathological‐Molecular Genetic Correlations in Referral Pathologist‐Diagnosed Low‐Grade “Oligodendroglioma” , 2002, Journal of neuropathology and experimental neurology.

[16]  Y. Yonekawa,et al.  Concurrent Inactivation of RB1 and TP53 Pathways in Anaplastic Oligodendrogliomas , 2001, Journal of neuropathology and experimental neurology.

[17]  Y. Yonekawa,et al.  p14ARF Deletion and Methylation in Genetic Pathways to Glioblastomas , 2001, Brain pathology.

[18]  Mitsutoshi Nakamura,et al.  Promoter hypermethylation and homozygous deletion of the p14ARF and p16INK4a genes in oligodendrogliomas , 2001, Acta Neuropathologica.

[19]  James M. Roberts,et al.  CDK inhibitors: positive and negative regulators of G1-phase progression. , 1999, Genes & development.

[20]  Y. Yonekawa,et al.  PTEN (MMAC1) Mutations Are Frequent in Primary Glioblastomas (de novo) but not in Secondary Glioblastomas , 1998, Journal of neuropathology and experimental neurology.

[21]  Y. Yonekawa,et al.  Role of gemistocytes in astrocytoma progression. , 1997, Laboratory investigation; a journal of technical methods and pathology.

[22]  D. Louis,et al.  Amplification of the cyclin-dependent kinase 4 (CDK4) gene is associated with high cdk4 protein levels in glioblastoma multiforme , 1996, Acta Neuropathologica.

[23]  M. Prados,et al.  Gemistocytic astrocytomas: a reappraisal. , 1991, Journal of neurosurgery.

[24]  C. Daumas-Duport,et al.  Radiation therapy in the management of low-grade supratentorial astrocytomas. , 1989, Journal of neurosurgery.

[25]  Michelle Sy Go.  Brain tumors , 1981, Brain and Development.

[26]  Mariela C. Marazita,et al.  INK4 proteins, a family of mammalian CDK inhibitors with novel biological functions , 2007, IUBMB life.

[27]  Yasuhiro Yonekawa,et al.  Promoter Hypermethylation of the RB1 Gene in Glioblastomas , 2001, Laboratory Investigation.

[28]  R. Barnard,et al.  The classification of tumours of the central nervous system. , 1982, Neuropathology and applied neurobiology.