Benetkiewicz Magdalena, Idbaih Ahmed, Cousin Pierre-Yves, Boisselier Blandine, Marie Yannick, Crinière Emmanuelle, Hoang-Xuan Khê, Delattre Jean-Yves, Sanson Marc, Delattre Olivier
INSERM, Unité 830, Paris, France.
PLoS One. 2009;4(1):e4107. doi: 10.1371/journal.pone.0004107. Epub 2009 Jan 1.
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.
1p和19q染色体臂联合缺失在少突胶质细胞瘤（OD）中很常见，最近研究表明其由不平衡的t(1;19)易位介导。最近对1p/19q共缺失的OD的研究表明，NOTCH2基因与少突胶质细胞分化有关，可能参与了这种重排。本研究的目的是分析NOTCH2基因座，它既可能是一个可能因1p/19q反复重排而改变的染色体易位基因座，也可能是一个可能因双打击过程而失活的基因。我们使用平均探针间距为377 bp、覆盖1p和19q着丝粒周围区域的高密度寡核苷酸微阵列，对15例呈现1p/19q共缺失的OD进行了阵列比较基因组杂交（array-CGH）分析。我们发现1p缺失延伸至1号染色体的着丝粒，包括整个NOTCH2基因。未观察到该基因的内部重排。这强烈表明t(1;19)易位不会导致NOTCH2结构异常。对4例病例的整个NOTCH2编码序列进行分析，未发现任何突变，因此表明NOTCH2不具有肿瘤抑制基因的遗传特征。最后，对19号染色体着丝粒周围区域的详细分析导致在19p12和19q11 - 12处鉴定出两个断点簇。有趣的是，这两个区域有大片同源性。结合先前关于1号和19号染色体α卫星序列相似性的观察结果，这表明t(1;19)易位源于复杂的染色体内和染色体间重排。这是首次使用优于先前应用的方法，通过高密度寡核苷酸阵列对少突胶质细胞瘤肿瘤中的1p/19q共缺失进行全面的缺失图谱分析。因此，本文提供了明确的证据，即少突胶质细胞瘤肿瘤的t(1;19)易位不会导致NOTCH2基因发生物理重排。
