Srivastava Tapasya, Chosdol Kunzang, Chattopadhayay Parthaprasad, Sarkar Chitra, Mahapatra Ashok K, Sinha Subrata
Department of Biochemistry, All India Institute of Medical Sciences, New Delhi, 110029, India.
J Neurooncol. 2007 Feb;81(3):249-55. doi: 10.1007/s11060-006-9230-1. Epub 2006 Oct 4.
The mismatch repair genes, hMLH1 (3p22) and hMSH2 (2p21), are commonly associated with accumulation of mutations and microsatellite instability. However, the status of their gene loci itself is often not addressed. In astrocytic tumors, the heterozygosity status of these genes with reference to tumor grade has not yet been determined. We have analyzed the heterozygosity status and locus specific instability in 43 glial tumors comprising 22 low grades diffuses astrocytoma (WHO Grade II, DA) and 21 glioblastoma multiforme (Grade IV GBM) using 10 microsatellite markers at 2p and 3p to elucidate the involvement of these loci in astrocytic tumorigenesis. We observed a significantly higher loss of heterozygosity (LOH) in 3p markers encompassing the hMLH1 gene locus in DA when compared to GBM (P = 0.008). In DA, while the frequency of LOH was observed to be higher in markers close to the hMLH1 gene ( approximately 40%), locus specific microsatellite instability (LSI) was higher ( approximately 30%) in markers localizing further to the gene. The frequency of LOH at markers on 2p, near the hMSH2 gene was, however, similar in DA and GBM (P = 0.451). Our results suggest that in the astrocytic tumorigenesis, LOH at the hMLH1 gene locus is an early event in tumorigenesis. However, the mismatch repair protein expression may be regulated by other cellular factors.
错配修复基因hMLH1（3p22）和hMSH2（2p21）通常与突变积累和微卫星不稳定性相关。然而，它们基因位点本身的状态常常未被涉及。在星形细胞瘤中，这些基因相对于肿瘤分级的杂合性状态尚未确定。我们使用位于2p和3p的10个微卫星标记分析了43例胶质肿瘤（包括22例低级别弥漫性星形细胞瘤（世界卫生组织二级，DA）和21例多形性胶质母细胞瘤（四级，GBM））的杂合性状态和位点特异性不稳定性，以阐明这些位点在星形细胞瘤发生中的作用。我们观察到，与GBM相比，DA中包含hMLH1基因位点的3p标记的杂合性缺失（LOH）显著更高（P = 0.008）。在DA中，虽然观察到靠近hMLH1基因的标记中LOH频率较高（约40%），但在基因定位更远的标记中位点特异性微卫星不稳定性（LSI）更高（约30%）。然而，在DA和GBM中，靠近hMSH2基因的2p标记的LOH频率相似（P = 0.451）。我们的结果表明，在星形细胞瘤发生过程中，hMLH1基因位点的LOH是肿瘤发生的早期事件。然而，错配修复蛋白的表达可能受其他细胞因子调控。
