NOTCH2 Is Neither Rearranged nor Mutated in t(1;19) Positive Oligodendrogliomas

The combined deletion of 1p and 19q chromosomal arms is frequent in oligodendrogliomas (OD) and has recently been shown to be mediated by an unbalanced t(1;19) translocation. Recent studies of 1p/19q co-deleted OD suggest that the NOTCH2 gene is implicated in oligodendrocyte differentiation and may be involved in this rearrangement. The objective of the present study was to analyze the NOTCH2 locus either as a chromosomal translocation locus that may be altered by the 1p/19q recurrent rearrangement or as a gene that may be inactivated by a two hit process. We performed an array-CGH analysis of 15 ODs presenting 1p/19q co-deletion using a high-density oligonucleotide microarray spanning 1p and 19q pericentromeric regions with 377 bp average probe spacing. We showed that the 1p deletion extends to the centromere of chromosome 1 and includes the entire NOTCH2 gene. No internal rearrangement of this gene was observed. This strongly suggests that the t(1;19) translocation does not lead to an abnormal NOTCH2 structure. The analysis of the entire NOTCH2 coding sequence was performed in four cases and did not reveal any mutation therefore indicating that NOTCH2 does not harbor genetic characteristics of a tumor suppressor gene. Finally, the detailed analysis of chromosome 19 pericentromeric region led to the identification of two breakpoint clusters at 19p12 and 19q11–12. Interestingly, these two regions share a large stretch of homology. Together with previous observations of similarities between chromosome 1 and 19 alphoid sequences, this suggests that the t(1;19) translocation arises from complex intra and interchromosomal rearrangements. This is the first comprehensive deletion mapping by high density oligo-array of the 1p/19q co-deletion in oligodendroglioma tumors using a methodological approach superior to others previously applied. As such this paper provides clear evidence that the NOTCH2 gene is not physically rearranged by t(1;19) translocation of oligodendroglioma tumors.

[1]  L. Ricci-Vitiani,et al.  Loss of pericentromeric DNA methylation pattern in human glioblastoma is associated with altered DNA methyltransferases expression and involves the stem cell compartment , 2008, Oncogene.

[2]  Emmanuel Barillot,et al.  BAC array CGH distinguishes mutually exclusive alterations that define clinicogenetic subtypes of gliomas , 2007, International journal of cancer.

[3]  G. Reifenberger,et al.  Loss of NOTCH2 Positively Predicts Survival in Subgroups of Human Glial Brain Tumors , 2007, PloS one.

[4]  E. Shaw,et al.  A t(1;19)(q10;p10) mediates the combined deletions of 1p and 19q and predicts a better prognosis of patients with oligodendroglioma. , 2006, Cancer research.

[5]  P. Burger,et al.  Identification of der(1;19)(q10;p10) in Five Oligodendrogliomas Suggests Mechanism of Concurrent 1p and 19q Loss , 2006, Journal of neuropathology and experimental neurology.

[6]  I. Dunham,et al.  The DNA sequence and biological annotation of human chromosome 1 , 2006, Nature.

[7]  S. Vandenberg,et al.  Genome-wide hypomethylation in human glioblastomas associated with specific copy number alteration, methylenetetrahydrofolate reductase allele status, and increased proliferation. , 2006, Cancer research.

[8]  L. Deangelis,et al.  High-dose chemotherapy with stem cell rescue as initial therapy for anaplastic oligodendroglioma: long-term follow-up. , 2006, Neuro-oncology.

[9]  Olivier Delattre,et al.  Two types of chromosome 1p losses with opposite significance in gliomas , 2005, Annals of neurology.

[10]  Marc Ladanyi,et al.  Allelic losses at 1p36 and 19q13 in gliomas: correlation with histologic classification, definition of a 150-kb minimal deleted region on 1p36, and evaluation of CAMTA1 as a candidate tumor suppressor gene. , 2005, Clinical cancer research : an official journal of the American Association for Cancer Research.

[11]  B. Feuerstein,et al.  Chromosomal imbalances detected by array comparative genomic hybridization in human oligodendrogliomas and mixed oligoastrocytomas , 2005, Genes, chromosomes & cancer.

[12]  P. Wesseling,et al.  Molecular pathogenesis of oligodendroglial tumors , 2004, Journal of Neuro-Oncology.

[13]  Arie Perry,et al.  Notch1 and Notch2 Have Opposite Effects on Embryonal Brain Tumor Growth , 2004, Cancer Research.

[14]  D. Haussler,et al.  The structure and evolution of centromeric transition regions within the human genome , 2004, Nature.

[15]  N. Probst-Hensch,et al.  Population-based study on incidence, survival rates, and genetic alterations of low-grade diffuse astrocytomas and oligodendrogliomas , 2004, Acta Neuropathologica.

[16]  Terrence S. Furey,et al.  The DNA sequence and biology of human chromosome 19 , 2004, Nature.

[17]  E. Eichler,et al.  BAC microarray analysis of 15q11–q13 rearrangements and the impact of segmental duplications , 2004, Journal of Medical Genetics.

[18]  H. Okano,et al.  F3/Contactin Acts as a Functional Ligand for Notch during Oligodendrocyte Maturation , 2003, Cell.

[19]  Christian B. Woods,et al.  Satellite DNA hypomethylation in karyotyped Wilms tumors. , 2003, Cancer genetics and cytogenetics.

[20]  David N Louis,et al.  Oligodendroglioma: Toward Molecular Definitions in Diagnostic Neuro‐Oncology , 2003, Journal of neuropathology and experimental neurology.

[21]  S. Hirohashi,et al.  Correlation of DNA hypomethylation at pericentromeric heterochromatin regions of chromosomes 16 and 1 with histological features and chromosomal abnormalities of human breast carcinomas. , 2002, The American journal of pathology.

[22]  P. Starostik,et al.  A complex DNA-repeat structure within the Selenoprotein P promoter contains a functionally relevant polymorphism and is genetically unstable under conditions of mismatch repair deficiency , 2002, European Journal of Human Genetics.

[23]  M. Ehrlich.  DNA hypomethylation, cancer, the immunodeficiency, centromeric region instability, facial anomalies syndrome and chromosomal rearrangements. , 2002, The Journal of nutrition.

[24]  K. Hoang-Xuan,et al.  Molecular heterogeneity of oligodendrogliomas suggests alternative pathways in tumor progression , 2001, Neurology.

[25]  W. Lau,et al.  Hypomethylation of chromosome 1 heterochromatin DNA correlates with q-arm copy gain in human hepatocellular carcinoma. , 2001, The American journal of pathology.

[26]  K. Aldape,et al.  Detection of 1p and 19q loss in oligodendroglioma by quantitative microsatellite analysis, a real-time quantitative polymerase chain reaction assay. , 2001, The American journal of pathology.

[27]  B. Scheithauer,et al.  Alterations of chromosome arms 1p and 19q as predictors of survival in oligodendrogliomas, astrocytomas, and mixed oligoastrocytomas. , 2000, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[28]  R. McLendon,et al.  Molecular genetic aspects of oligodendrogliomas including analysis by comparative genomic hybridization. , 1999, The American journal of pathology.

[29]  B. Scheithauer,et al.  Localization of common deletion regions on 1p and 19q in human gliomas and their association with histological subtype , 1999, Oncogene.

[30]  D. Louis,et al.  Specific genetic predictors of chemotherapeutic response and survival in patients with anaplastic oligodendrogliomas. , 1998, Journal of the National Cancer Institute.

[31]  B. Barlogie,et al.  Jumping translocations of chromosome 1q in multiple myeloma: evidence for a mechanism involving decondensation of pericentromeric heterochromatin. , 1998, Blood.

[32]  H. Rivera,et al.  A further whole arm 1;19 translocation with alpha-satellite DNA breakage. , 1997, Genetic counseling.

[33]  D. Louis,et al.  Shared Allelic Losses on Chromosomes 1p and 19q Suggest a Common Origin of Oligodendroglioma and Oligoastrocytoma , 1995, Journal of neuropathology and experimental neurology.

[34]  A. Carnevale,et al.  Balanced reciprocal whole arm translocation t(3;9): analysis by fluorescence in situ hybridisation. , 1994, Journal of medical genetics.

[35]  C. Gravholt,et al.  Breakpoints in Robertsonian translocations are localized to satellite III DNA by fluorescence in situ hybridization. , 1992, Genomics.

[36]  M. Rocchi,et al.  A human alphoid DNA clone from the EcoRI dimeric family: genomic and internal organization and chromosomal assignment. , 1989, Genomics.