本文選題：II/III級(jí)腦膠質(zhì)瘤　切入點(diǎn)：IDH突變　出處：《首都醫(yī)科大學(xué)》2016年博士論文

【摘要】：第一部分:II/III級(jí)腦膠質(zhì)瘤基于IDH基因突變和TERT啟動(dòng)子突變的分子分型研究【目的】WHOII/III級(jí)腦膠質(zhì)瘤的臨床和分子標(biāo)記物特征都有很強(qiáng)的異質(zhì)性,并且表現(xiàn)出與膠質(zhì)母細(xì)胞瘤截然不同的分子遺傳學(xué)改變,其中部分進(jìn)展成惡性程度更高的腫瘤。目前基于基因表型的分子分型已經(jīng)成為II/III級(jí)腦膠質(zhì)瘤分型的趨勢(shì),并且已經(jīng)逐步融入到傳統(tǒng)病理學(xué)分型中,成為分型的新標(biāo)準(zhǔn)�！痉椒ā勘狙芯抗矙z測(cè)了377例低級(jí)別腦膠質(zhì)瘤患者TERT啟動(dòng)子突變情況,并分析了臨床特征,分子標(biāo)記物表達(dá)和轉(zhuǎn)錄組改變�！窘Y(jié)果】統(tǒng)計(jì)分析表明:1)377例入組患者中,有145例表現(xiàn)為TERT啟動(dòng)子突變(38.5%),與TP53突變互斥(P0.001)而與1p/19q聯(lián)合缺失正相關(guān)(P=0.002)。在所有入組患者中,TERT啟動(dòng)子突變是獨(dú)立預(yù)測(cè)預(yù)后因素(P=0.048)。在IDH突變患者中,TERT啟動(dòng)子突變預(yù)示較好的預(yù)后(P=0.018),而在IDH野生型患者中,TERT啟動(dòng)子突變患者預(yù)后較差(P=0.049)。IDH突變聯(lián)合TERT啟動(dòng)子突變可將II/III級(jí)腫瘤分為4型。1p/19q聯(lián)合缺失,TP53突變,Ki-67蛋白表達(dá),和p-MET蛋白表達(dá)分別代表IDH突變/TERT啟動(dòng)子突變組,僅IDH突變組,僅TERT啟動(dòng)子突變組,和IDH野生/TERT啟動(dòng)子野生組�！窘Y(jié)論】本研究發(fā)現(xiàn)TERT啟動(dòng)子突變聯(lián)合IDH突變可以更簡(jiǎn)單的對(duì)II/III級(jí)腦膠質(zhì)瘤患者進(jìn)行分型,可幫助臨床實(shí)現(xiàn)更精確的病理診斷。第二部分:IDH突變和MGMT啟動(dòng)子甲基化對(duì)替莫唑胺化療預(yù)測(cè)及預(yù)后意義【背景】異檸檬酸脫氫酶(IDH)基因突變和O6-鳥(niǎo)嘌呤-DNA甲基化轉(zhuǎn)移酶(MGMT)啟動(dòng)子甲基化作為生物標(biāo)記物對(duì)腦膠質(zhì)母細(xì)胞瘤的影響目前研究較少�！痉椒ā课覀兗{入了274例膠質(zhì)母細(xì)胞瘤細(xì)胞,前瞻性的收集和分析了IDH突變和MGMT啟動(dòng)子甲基化與無(wú)進(jìn)展生存期和總生存期的關(guān)系,以及對(duì)術(shù)后替莫唑胺化療的影響。【結(jié)果】對(duì)于接受了術(shù)后放療和替莫唑胺化療的膠質(zhì)母細(xì)胞瘤患者,同時(shí)具有IDH突變和MGMT啟動(dòng)子甲基化的患者生存期最長(zhǎng)(中位總生存期:35.6個(gè)月,中位無(wú)進(jìn)展生存期:27.5個(gè)月),具有其中一項(xiàng)陽(yáng)性的患者生存期其次(中位總生存期分別為:36個(gè)月和17.1個(gè)月,中位無(wú)進(jìn)展生存期分別為:12.2個(gè)月和9.9個(gè)月),兩項(xiàng)均為陰性的患者預(yù)后最差(中位總生存期:15個(gè)月,中位無(wú)進(jìn)展生存期:9.7個(gè)月)。對(duì)于IDH野生型膠質(zhì)母細(xì)胞瘤患者,接受術(shù)后放療聯(lián)合替莫唑胺化療較單純接受術(shù)后放療無(wú)進(jìn)展生存期和總生存期顯著延長(zhǎng)(總生存期:15.4個(gè)月vs9.6個(gè)月,p0.001;無(wú)進(jìn)展生存期:9.9個(gè)月vs6.5個(gè)月,p0.001)。對(duì)于IDH突變性的膠質(zhì)母細(xì)胞瘤患者,聯(lián)合治療組較單純放療組預(yù)后無(wú)顯著差異。這些結(jié)果都支持IDH突變可導(dǎo)致替莫唑胺化療抵抗。為了驗(yàn)證這個(gè)結(jié)論,我們做了IDH突變細(xì)胞系對(duì)替莫唑胺化療的敏感性試驗(yàn)�！窘Y(jié)論】本研究發(fā)現(xiàn),IDH突變和MGMT啟動(dòng)子甲基化都獨(dú)立的和膠質(zhì)母細(xì)胞瘤患者預(yù)后相關(guān),同時(shí)IDH突變可預(yù)測(cè)膠質(zhì)母細(xì)胞瘤患者術(shù)后替莫唑胺化療敏感性。
[Abstract]:Part one: molecular typing of gliomas of grade II / III based on IDH gene mutation and TERT promoter mutation; [objective] the clinical and molecular marker characteristics of WHOII/III grade gliomas are highly heterogeneous.They also exhibit molecular genetic changes distinct from glioblastoma, some of which develop into more malignant tumors.At present, the molecular typing based on gene phenotype has become the trend of II/III grade glioma classification, and has been gradually integrated into the traditional pathological classification.[methods] the mutation of TERT promoter in 377 patients with low grade glioma was detected and the clinical features were analyzed.The expression of molecular markers and transcriptional changes. [results] Statistical analysis showed that 145 out of 1 377 patients showed TERT promoter mutation (38.5%, P 0.001) and positive correlation with 1p/19q deletion (P 0.002).The mutation of TERT promoter is an independent prognostic factor in all patients.鍦↖DH紿佸彉鎮(zhèn)ｈ，

本文編號(hào)：1701773