Pećina-Šlaus Nives, Kafka Anja, Bukovac Anja, Vladušić Tomislav, Tomas Davor, Hrašćan Reno
1 Laboratory of Neurooncology, Croatian Institute for Brain Research, School of Medicine, University of Zagreb, Zagreb, Croatia.
2 Department of Biology, School of Medicine, University of Zagreb, Zagreb, Croatia.
Tumour Biol. 2017 Jul;39(7):1010428317705791. doi: 10.1177/1010428317705791.
Postreplicative mismatch repair safeguards the stability of our genome. The defects in its functioning will give rise to microsatellite instability. In this study, 50 meningiomas were investigated for microsatellite instability. Two major mismatch repair genes, MLH1 and MSH2, were analyzed using microsatellite markers D1S1611 and BAT26 amplified by polymerase chain reaction and visualized by gel electrophoresis on high-resolution gels. Furthermore, genes DVL3 (D3S1262), AXIN1 (D16S3399), and CDH1 (D16S752) were also investigated for microsatellite instability. Our study revealed constant presence of microsatellite instability in meningioma patients when compared to their autologous blood DNA. Altogether 38% of meningiomas showed microsatellite instability at one microsatellite locus, 16% on two, and 13.3% on three loci. The percent of detected microsatellite instability for MSH2 gene was 14%, and for MLH1, it was 26%, for DVL3 22.9%, for AXIN1 17.8%, and for CDH1 8.3%. Since markers also allowed for the detection of loss of heterozygosity, gross deletions of MLH1 gene were found in 24% of meningiomas. Genetic changes between MLH1 and MSH2 were significantly positively correlated (p = 0.032). We also noted a positive correlation between genetic changes of MSH2 and DVL3 genes (p = 0.034). No significant associations were observed when MLH1 or MSH2 was tested against specific histopathological meningioma subtype or World Health Organization grade. However, genetic changes in DVL3 were strongly associated with anaplastic histology of meningioma (χ = 9.14; p = 0.01). Our study contributes to better understanding of the genetic profile of human intracranial meningiomas and suggests that meningiomas harbor defective cellular DNA mismatch repair mechanisms.
复制后错配修复保障了我们基因组的稳定性。其功能缺陷会导致微卫星不稳定性。在本研究中，对50例脑膜瘤进行了微卫星不稳定性研究。使用通过聚合酶链反应扩增并在高分辨率凝胶上通过凝胶电泳可视化的微卫星标记D1S1611和BAT26，分析了两个主要的错配修复基因MLH1和MSH2。此外，还研究了基因DVL3（D3S1262）、AXIN1（D16S3399）和CDH1（D16S752）的微卫星不稳定性。我们的研究表明，与自体血液DNA相比，脑膜瘤患者中持续存在微卫星不稳定性。总共38%的脑膜瘤在一个微卫星位点显示微卫星不稳定性，16%在两个位点，13.3%在三个位点。检测到的MSH2基因微卫星不稳定性百分比为14%，MLH1为26%，DVL3为22.9%，AXIN1为17.8%，CDH1为8.3%。由于这些标记物还可用于检测杂合性缺失，在24%的脑膜瘤中发现了MLH1基因的大片段缺失。MLH1和MSH2之间的基因变化呈显著正相关（p = 0.032）。我们还注意到MSH2和DVL3基因的基因变化之间存在正相关（p = 0.034）。当针对特定的组织病理学脑膜瘤亚型或世界卫生组织分级对MLH1或MSH2进行检测时，未观察到显著关联。然而，DVL3的基因变化与脑膜瘤的间变组织学密切相关（χ = 9.14；p = 0.01）。我们的研究有助于更好地了解人类颅内脑膜瘤的基因特征，并表明脑膜瘤存在有缺陷的细胞DNA错配修复机制。
