Department of Neurosurgery, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
Neoplasia. 2012 Jan;14(1):20-8. doi: 10.1593/neo.111574.
Mutations of the NF2 gene on chromosome 22q are thought to initiate tumorigenesis in nearly 50% of meningiomas, and 22q deletion is the earliest and most frequent large-scale chromosomal abnormality observed in these tumors. In aggressive meningiomas, 22q deletions are generally accompanied by the presence of large-scale segmental abnormalities involving other chromosomes, but the reasons for this association are unknown. We find that large-scale chromosomal alterations accumulate during meningioma progression primarily in tumors harboring 22q deletions, suggesting 22q-associated chromosomal instability. Here we show frequent codeletion of the DNA repair and tumor suppressor gene, CHEK2, in combination with NF2 on chromosome 22q in a majority of aggressive meningiomas. In addition, tumor-specific splicing of CHEK2 in meningioma leads to decreased functional Chk2 protein expression. We show that enforced Chk2 knockdown in meningioma cells decreases DNA repair. Furthermore, Chk2 depletion increases centrosome amplification, thereby promoting chromosomal instability. Taken together, these data indicate that alternative splicing and frequent codeletion of CHEK2 and NF2 contribute to the genomic instability and associated development of aggressive biologic behavior in meningiomas.
NF2 基因突变被认为是近 50%脑膜瘤发生肿瘤形成的原因，而 22q 缺失是这些肿瘤中最早和最常见的大规模染色体异常。在侵袭性脑膜瘤中，22q 缺失通常伴随着涉及其他染色体的大规模节段性异常的存在，但这种关联的原因尚不清楚。我们发现，脑膜瘤进展过程中大规模染色体改变主要发生在携带 22q 缺失的肿瘤中，这表明 22q 相关的染色体不稳定性。在这里，我们显示在大多数侵袭性脑膜瘤中，DNA 修复和肿瘤抑制基因 CHEK2 与 22q 上的 NF2 频繁共缺失。此外，脑膜瘤中 CHEK2 的肿瘤特异性剪接导致功能性 Chk2 蛋白表达减少。我们表明，在脑膜瘤细胞中强制敲低 Chk2 会降低 DNA 修复。此外，Chk2 耗竭会增加中心体扩增，从而促进染色体不稳定。总之，这些数据表明 CHEK2 和 NF2 的选择性剪接和频繁共缺失导致脑膜瘤中基因组不稳定性和相关侵袭性生物学行为的发展。
