Lamszus K, Lachenmayer L, Heinemann U, Kluwe L, Finckh U, Höppner W, Stavrou D, Fillbrandt R, Westphal M
Department of Neuropathology, University Hospital Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany.
Int J Cancer. 2001 Mar 15;91(6):803-8. doi: 10.1002/1097-0215(200002)9999:9999<::aid-ijc1134>3.0.co;2-p.
Ependymomas arise from the ependymal cells at different locations throughout the brain and spinal cord. These tumors have a broad age distribution with a range from less than 1 year to more than 80 years. In some intramedullary spinal ependymomas, mutations in the neurofibromatosis 2 (NF2) gene and loss of heterozygosity (LOH) on chromosome arm 22q have been described. Cytogenetic studies have also identified alterations involving chromosome arm 11q, including rearrangements at 11q13, in ependymomas. We analyzed 21 intramedullary spinal, 14 ventricular, 11 filum terminale and 6 intracerebral ependymomas for mutations in the MEN1 gene, which is located at 11q13, and mutations in the NF2 gene, which is located at 22q12, as well as for LOH on 11q and 22q. NF2 mutations were found in 6 tumors, all of which were intramedullary spinal and all of which displayed LOH 22q. Allelic loss on 22q was found in 20 cases and was significantly more frequent in intramedullary spinal ependymomas than in tumors in other locations. LOH 11q was found in 7 patients and exhibited a highly significant inverse association with LOH 22q (p<0.001). A hemizygous MEN1 mutation was identified in 3 tumors, all of which were recurrences from the same patient. Interestingly, the initial tumor corresponded to WHO grade II and displayed LOH 11q but not yet a MEN1 mutation. In 2 subsequent recurrences, the tumor had progressed to anaplastic ependymoma (WHO grade III) and exhibited a nonsense mutation in exon 10 of MEN1 (W471X) in conjunction with LOH 11q. This suggests that loss of wild-type MEN1 may be involved in the malignant progression of a subset of ependymomas. To conclude, our findings provide evidence for different genetic pathways involved in ependymoma formation and progression, which may allow to define genetically and clinically distinct tumor entities.
室管膜瘤起源于脑和脊髓不同部位的室管膜细胞。这些肿瘤的年龄分布广泛，从不到1岁到80多岁不等。在一些髓内脊髓室管膜瘤中，已报道神经纤维瘤病2（NF2）基因发生突变以及22号染色体长臂出现杂合性缺失（LOH）。细胞遗传学研究还在室管膜瘤中发现了涉及11号染色体长臂的改变，包括11q13处的重排。我们分析了21例髓内脊髓室管膜瘤、14例脑室室管膜瘤、11例终丝室管膜瘤和6例脑室内室管膜瘤，检测位于11q13的MEN1基因的突变、位于22q12的NF2基因的突变以及11q和22q上的LOH。在6例肿瘤中发现了NF2突变，所有这些肿瘤均为髓内脊髓室管膜瘤，且均显示22q的LOH。在20例病例中发现了22q的等位基因缺失，在髓内脊髓室管膜瘤中比在其他部位的肿瘤中明显更常见。在7例患者中发现了11q的LOH，并且与22q的LOH呈现高度显著的负相关（p<0.001）。在3例肿瘤中鉴定出一个半合子MEN1突变，所有这些肿瘤均为同一患者的复发病例。有趣的是，最初的肿瘤对应于世界卫生组织（WHO）二级，显示11q的LOH，但尚未出现MEN1突变。在随后的2次复发中，肿瘤进展为间变性室管膜瘤（WHO三级），并在MEN1的第10外显子中出现无义突变（W471X），同时伴有11q的LOH。这表明野生型MEN1的缺失可能参与了一部分室管膜瘤的恶性进展。总之，我们的研究结果为室管膜瘤形成和进展中涉及的不同遗传途径提供了证据，这可能有助于定义遗传和临床特征不同的肿瘤实体。
