Heterozygosity loss at 22q and lack of INI1gene mutation in gastrointestinal stromaltumor
Heterozygosity loss at 22q and lack of INI1gene mutation in gastrointestinal stromaltumor
复制标题
胃肠道间质瘤22q杂合性缺失和INI1基因突变缺失
作者：
Yamamoto H;K ohashi K;et al.
目的：胃肠道间质瘤（GIST）是以KIT或PDGFRA基因突变为特征的肿瘤。虽然22 q染色体丢失在GIST中是常见的，但尚不清楚哪些肿瘤抑制基因可能与这种丢失相关。INI1基因位于22 q11.23，是恶性横纹肌样瘤中常见的抑癌基因，为阐明GIST中INI1基因可能随22 q11.23缺失而改变的假说，我们检测了27例GIST中INI1基因22 q11.23杂合性缺失（LOH）、纯合性缺失和突变、基因产物表达以及KIT和PDGFRA突变。无一例（0%）INI1基因纯合性缺失或突变。免疫组化结果显示，17/27例（63%）病例的INI1表达局灶性降低，且INI1蛋白水平和INI1 mRNA水平均与22 q11.23洛的存在相关。尽管22 q11.23洛缺失在高级别肿瘤中的发生率高于低级别肿瘤，但INI1的表达水平与肿瘤分级、肿瘤大小、增殖活性、cyclin D1和p16 INK4a的表达水平无关。结论：22 q11.23 LOH在GIST中的发生率较高，与KIT基因型无关，可能参与GIST的发生。然而，INI1基因的半等位基因丢失导致INI1蛋白表达减少可能对GIST的进展没有重大影响。
Objectives:Gastrointestinal stromal tumor (GIST) is characterized byKITorPDGFRAgene mutation. Although chromosomal losses of 22q are frequent in GIST, it is unclear which tumor suppressor genes might be inactivated in association with such losses. TheINI1gene, located at 22q11.23, is a tumor suppressor gene that is frequently altered in malignant rhabdoid tumor.Methods:To elucidate the hypothesis that theINI1gene might be altered along with 22q loss in GIST, we examined the loss of heterozygosity (LOH) at 22q11.23, homozygous deletion and mutation of theINI1gene, and its gene product expression as well as mutations ofKITandPDGFRAin 27 cases of GIST.Results:Among the 27 informative cases, 19 (70.4%) showed LOH of at least one of the microsatellite markers on 22q11.23. None of the cases (0%) showed homozygous deletion or mutation of theINI1gene. Immunohistochemically, the INI1 expression was focally reduced in 17/27 (63%) cases, and the INI1 protein level and INI1 mRNA level were each correlated with the presence of 22q11.23 LOH. Although the 22q11.23 LOH was more frequently present in high- than in low-grade tumors, INI1 expression level was not correlated with tumor grade, tumor size, proliferative activity and the expression levels of cyclin D1 and p16INK4a.KITmutations were found in 18/27 (66.7%) GISTs; however, theKITgenotype was not correlated with the status of LOH at 22q11.23.Conclusions:The results suggest that 22q11.23 LOH is frequently present in GIST irrespective ofKITgenotype and it might play a role in part of the development of GIST. However, the hemiallelic loss ofINI1gene causing reduced expression of INI1 protein probably does not have a major impact in the progression of GIST.