P53和ATRX蛋白在IDH1突变型与野生型胶质母细胞瘤表达的 相关性及生物学意义
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摘要
目的:探讨P53和ATRX蛋白在IDH1突变型与野生型胶质母细胞瘤的表达相关性及生物学意义。方法:收集广东同江医院病理科行手术切除胶质母细胞瘤后组织蜡块标本共62例(其中经免疫组织化学检测IDH1突变型胶质母细胞瘤12例,IDH1野生型胶质母细胞瘤50例),检测P53和ATRX蛋白在这两种不同基因分型胶质母细胞瘤中的表达情况及相关性,并分析其与预后的关系。结果:P53蛋白在IDH1突变型与野生型胶质母细胞瘤的表达率分别为75.00%(9/12)和30.00%(15/50),ATRX蛋白的表达率分别为16.67%(2/12)及94.00%(47/50),P53和ATRX蛋白在IDH1两种基因分型的胶质母细胞瘤的表达差异均有统计学意义(均P<0.01)。P53及ATRX的表达呈负相关(r=-0.404,P<0.01)。Cox多元回归分析结果显示IDH1基因分型、年龄及性别是影响胶质母细胞瘤(glioblastoma,GBM)生存期的危险因素(P<0.01)。结论:大部分的IDH1野生型的GBM的患者缺乏P53基因及ATRX基因的突变。IDH1野生型GBM是显著影响GBM生存期的危险因素,可以作为临床对成年GBM患者预后判断的重要指标之一。
Objective: To investigate the correlation between P53 and ATRX protein expression in IDH1 mutant and wild type glioblastoma(GBM) and its biological significance. Methods: A total of 62 cases of tissue samples were collected from the Department of Pathology of Guangdong Tongjiang Hospital(including 12 cases of IDH-1 mutant GBM, 50 cases of IDH1 wild type GBM detected by immunohistochemistry). The expression of P53 and ATRX protein in these two different genotyping GBMs were detected and their relationship with prognosis were analyzed. Results: The expression rates of P53 protein in IDH1 mutant and wild type GBM were 75.00%(9/12) and 30.00%(15/50) respectively, and the expression rates of ATRX protein were 16.67%(2/12) and 94.00%(47/50), respectively. The expression of P53 and ATRX protein in the two genotypes of IDH1 was statistically significant(P<0.01). P53 and ATRX were negatively correlated(r=-0.404, P<0.01). Cox multiple regression analysis showed that IDH1 genotype, age and sex were the risk factors of GBM survival(P<0.01). Conclusion: Most of the IDH1 wild-type GBM patients lack the P53 gene and the ATRX gene mutation. IDH1 wild-type GBM is a significant factor affecting the survival time of GBM, which can be used as one of the important indexes to judge the prognosis of adult GBM patients.
Objective: To investigate the correlation between P53 and ATRX protein expression in IDH1 mutant and wild type glioblastoma(GBM) and its biological significance. Methods: A total of 62 cases of tissue samples were collected from the Department of Pathology of Guangdong Tongjiang Hospital(including 12 cases of IDH-1 mutant GBM, 50 cases of IDH1 wild type GBM detected by immunohistochemistry). The expression of P53 and ATRX protein in these two different genotyping GBMs were detected and their relationship with prognosis were analyzed. Results: The expression rates of P53 protein in IDH1 mutant and wild type GBM were 75.00%(9/12) and 30.00%(15/50) respectively, and the expression rates of ATRX protein were 16.67%(2/12) and 94.00%(47/50), respectively. The expression of P53 and ATRX protein in the two genotypes of IDH1 was statistically significant(P<0.01). P53 and ATRX were negatively correlated(r=-0.404, P<0.01). Cox multiple regression analysis showed that IDH1 genotype, age and sex were the risk factors of GBM survival(P<0.01). Conclusion: Most of the IDH1 wild-type GBM patients lack the P53 gene and the ATRX gene mutation. IDH1 wild-type GBM is a significant factor affecting the survival time of GBM, which can be used as one of the important indexes to judge the prognosis of adult GBM patients.
引文
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14 .Heaphy CM,De Wilde RF,Jiao Y,et al.Altered telomeres in tumors with ATRX and DAXX mutations[J].Science,2011,333(6041):425.
15 .Killela PJ,Reitman ZJ,Jiao Y,et al.TERT promoter mutations occur frequently in gliomas and a subset of tumors derived from cells with low rates of self-renewal[J].Proc Natl Acad Sci USA,2013,110(15):6021-6026.
16 .Eckel-Passow JE,Lachance DH,Molinaro AM,et al.Glioma groups based on 1p/19q,IDH,and TERT promoter mutations in tumors[J].N Engl J Med,2015,372(26):2499-2508.
17 .Kannan K,Inagaki A,Silber J,et al.Whole-exome sequencing identifies ATRX mutation as a key molecular determinant in lower-grade glioma[J].Oncotarget,2012,3(10):1194-1203.
18 .Watanabe T,Nobusawa S,Kleihues P,et al.IDH1 mutations are early events in the development of astrocytomas and oligodendrogliomas[J].Am J Pathol,2009,174(4):1149-1153.
19 .R ekers NH,Sminia P,Peters G J.Towards tailored therapy of glioblastoma muhiforme[J].J Chemother,2011,23(4):187-199.
20 .Parsons DW,Jones S,Zhang X,et al.An integrated genomic analysi s of human glioblastoma multiforme[J].Science,2008,321(5897):1807-1812.
2 .Louis DN,Perry A,Reifenberger G,et al.The 2016 World Health Organization classification of tumors of the central nervous system:a summary[J].Acta Neuropathol,2016,131(6):803-820.
3 .Peiffer J,Kleihues P.Hans-Joachim Scherer(1906-1945),pioneer in glioma research[J].Brain Pathol,1999,9(2):241-245.
4 .陈海浪,陈喜文,陈德富.NAD+-依赖型异柠檬酸脱氢酶的结构和功能研究进展[J].生物技术通讯,2003,14(4):304-307.CHEN Hailang,CHEN Xiwen,CHEN Defu.Advance on structure and function of NAD+-dependent isocitrate dehydrogenase[J].Letters in Biotechnology,2003,14(4):304-307.
5 .Hartmann C,Meyer J,Balss J,et al.Type and frequency of IDH1and IDH2 mutations are related to astrocytic and oligodendroglial differentiation and age:a study of 1,010 diffuse gliomas[J].Acta Neuropathol,2009,118(4):469-474.
6 .Yan H,Parsons DW,Jin G,et al.IDH1 and IDH2 mutations in gliomas[J].N Engl J Med,2009,360(8):765-773.
7 .Gorovets D,Kannan K,Shen R,et al.IDH mutation and neuroglial developmental features define clinically distinct subclasses of lower grade diffuse astrocytic glioma[J].Clin Cancer Res,2012,18(9):2490-2501.
8 .李智.2016版世界卫生组织中枢神经系统肿瘤分类实践解读I(胶质源性肿瘤部分)[J].广东医学,2017,38(1):3-8.LI Zhi.Practical understanding of the 2016 World Health Organization classification of tumors of the central nervous system(part of glial tumor)[J].Guangdong Medical Journal,2017,38(1):3-8.
9 .Kruse JP,Gu W.Modes of p53 regulation[J].Cell,2009,137(4):609-622.
10 .Famebo M,Bykov VJ,Wiman KG.The p53 tumor suppressor:a master regulator of diverse cellular processes and therapeutic target in cancer[J].Biochem Biophys Res Commun,2010,396(1):85-89.
11 .Lai A,Kharbanda S,Pope WB,et al.Evidence for sequenced molecular evolution of IDH1 mutant glioblastoma from a distinct cell of origin[J].J Clin Oncol,2011,29(34):4482-4490.
12 .Ohgaki H,Dessen P,Jourde B,et al.Genetic pathways to Glioblastoma:a population-based study[J].Cancer Res,2004,64(19):6892-6899.
13 .Weatherall DJ,Higgs DR,Bunch C,et al.Hemoglobin H disease and mental retardation:a new syndrome or a remarkable coincidence?[J].N Engl J Med,1981,305(11):607-612.
14 .Heaphy CM,De Wilde RF,Jiao Y,et al.Altered telomeres in tumors with ATRX and DAXX mutations[J].Science,2011,333(6041):425.
15 .Killela PJ,Reitman ZJ,Jiao Y,et al.TERT promoter mutations occur frequently in gliomas and a subset of tumors derived from cells with low rates of self-renewal[J].Proc Natl Acad Sci USA,2013,110(15):6021-6026.
16 .Eckel-Passow JE,Lachance DH,Molinaro AM,et al.Glioma groups based on 1p/19q,IDH,and TERT promoter mutations in tumors[J].N Engl J Med,2015,372(26):2499-2508.
17 .Kannan K,Inagaki A,Silber J,et al.Whole-exome sequencing identifies ATRX mutation as a key molecular determinant in lower-grade glioma[J].Oncotarget,2012,3(10):1194-1203.
18 .Watanabe T,Nobusawa S,Kleihues P,et al.IDH1 mutations are early events in the development of astrocytomas and oligodendrogliomas[J].Am J Pathol,2009,174(4):1149-1153.
19 .R ekers NH,Sminia P,Peters G J.Towards tailored therapy of glioblastoma muhiforme[J].J Chemother,2011,23(4):187-199.
20 .Parsons DW,Jones S,Zhang X,et al.An integrated genomic analysi s of human glioblastoma multiforme[J].Science,2008,321(5897):1807-1812.