胃肠道间质瘤中c-kit及血小板来源生长因子受体基因突变研究

胃肠道间质瘤(GIST)是一种间叶源性肿瘤,由不成熟的梭形或上皮样细胞组成.有研究发现一些GIST患者存在c-kit基因突变,主要集中于临近膜区域(即exon 11编码区)Val550至Val560的11个氨基酸残基之间,突变类型多样,有无义突变、缺失突变、插入突变等[12].c-kit基因突变会导致配体不依赖的c-kit基因激活及细胞活化,最终导致人肥大细胞增生病及GIST的发生[3].多数GIST均由kit受体酪氨酸激酶持续激活引起,这类患者接受甲磺酸伊马替尼治疗效果良好.     

Advanced gastrointestinal stromal tumor patients with complete response after treatment with imatinib mesylate

AIM: Most gastrointestinal stroma! tumors (GISTs) express constitutively activated mutant isoforms of kit kinase or platelet-derived growth factor receptor alpha (PDGFRA), which are potential therapeutic targets for imatinib mesylate (Glivec). Partial response occurred in almost two thirds of GIST patients treated with Glivec. However, complete response (CR) after Glivec therapy was sporadically reported. Here we illustrated advanced GIST patients with CR after Glivec treatment. METHODS: Between January 2001 and June 2005, 42 advanced GIST patients were treated with Glivec. Patients were administered 400 mg of Glivec in 100-mg capsules, taken orally daily with food. The response of the tumor to Glivec was evaluated after one month, three months, and every three months thereafter or whenever medical need was indicated. Each tumor of patients was investigated for mutations of kit or PDGFRA. RESULTS: The median follow-up time of the 42 ad-vanced GIST patients treated with Glivec was 16.9 months (range, 1.0-47.0 months). Overall, 3 patients had complete response CR (7.1%), 26 partial response (67.8%), 5 stationary disease (11.9%), and 3 progressive disease (11.9%). The median duration of Glivec administration for the three patients was 36 months (range, 23-36 months). The median time to CR after Glivec treatment was 20 months (range, 9-26 months). Deletion and insertion mutations of c-kit exon 11 and insertion mutation of c-kit exon 9 were found in two cases and one case, respectively. CONCLUSION: Complete response (CR) can be achieved in selected advanced GIST patients treated with Glivec. The median time to CR after Glivec treatment was 20 months. Deletion and insertion mutations of kit exon 11 and insertion mutation of kit exon 9 contribute to the genetic features in these selected cases.     

Treatment of patients with advanced gastrointestinal stromal tumor of small bowel： Implications of imatinib mesylate

AIM: To examine the impact of imatinib mesylate (Glivec) on patient survival and response and its safety,and the correlation of the response rate with the kit gene mutation status. METHODS: Thirty-three of 74 (44.6%) small bowel gastrointestinal stromal tumor (GIST) patients who developed recurrence after curative resection and not treated with Glivec were classified as group A patients. Twenty-two advanced small bowel GIST patients treated with Glivec were classified as group B patients. Clinicopathological features, post-recurrence and overall survival rates were compared. Each tumor in group B patients was investigated for mutations of kit or plateletderived growth factor alpha (PDGFRA). The mutation type was correlated with clinical outcomes. The antitumor effect and safety of Glivec in group B patients were also assessed. RESULTS: Advanced small bowel GIST patients treated with Glivec had substantially longer post-recurrence survival and higher overall survival rates than those not treated with Glivec. A total of 15 patients had a partial response (PR) (67.8%). Activated mutations of c-kit were found in 16 of 19 tested patients and no PDGFRA mutant was identified. In 13 patients with GISTs harboring exon 11 kit mutations, the partial response rate (PR) was 69.3%, whereas two of three patients with tumors containing an exon 9 kit mutation had an overall response rate (ORR) of 66.7% (not significant). CONCLUSION: Glivec significantly prolongs the post-recurrence and overall survival of Asian patients with advanced GISTs. Glivec induces a sustained objective response in more than half of Asian patients with advanced small bowel GISTs. Activated mutations of kit exon 11 are detectable in the vast majority of GISTs. There is no difference in the PR rate for patients whose GISTs have kit exon 9 and exon 11 mutations.     

野生型胃肠间质瘤分子机制研究进展

胃肠道间质瘤(gastrointestinal stromal tumor,GIST)是消化系最常见的间叶源性肿瘤,80%-95%GIST存在KIT或PDGFRA基因突变,未突变者称为野生型GIST(WT-GIST).目前证实,突变型GIST对酪氨酸激酶抑制剂(tyrosine kinase inhibitor,TKI)分子靶向治疗有效.但WT-GIST通常对TKI类药物不敏感,其分子理论基础、发生机制需明确阐述.     

胃肠道间质瘤的基因突变特征与预后的关系

胃肠道间质瘤（gastrointestinal stromal tumors，GIST）中发现有c-kit基因突变和蛋白质产物的表达，是GIST研究过程中的重要里程碑。除c-kit基因外，部分GIST中还存在PDGFRA基因突变，对GIST的病因和发病机制作了重要的补充。其中，在存在c-kit基因突变的GIST患者中，检测到突变几乎主要集中在第11、9、13、17号外显子；存在有PDGFRA基因突变的GIST患者中，突变主要集中在第18、12号外显子。研究表明，GIST的基因突变特征与预后有显著的相关性。从基因水平上研究疾病、判断预后、指导用药且右甭尊的临床意义。     

胃肠道间质瘤病理诊断新进展

胃肠道间质瘤(gastrointestinal stromal tumors,GIST)是一类胃肠道最常见的间叶源性肿瘤,由于特异的酪氨酸激酶受体c-kit或血小板转化生长因子(PDGFRA)突变而引起的.GIST病理诊断必须依据大体病理学、组织病理学、免疫组织化学检测结果以及基因检测结果综合判断,正确的术前病理诊断和危险度判定对患者进行个体化治疗有着非常重要的意义.本文系统阐述近年来关于GIST病理诊断的最新进展,以及国际国内对GIST危险度分级方案的最新共识.此外本文还总结了对GIST生物学行为评估有一定参考价值的分子生物学指标,供同道参考.     

胃肠道间质瘤靶向治疗的药物遗传学研究进展

KIT和PDGFRA基因突变为胃肠道间质瘤(GIST)发生的主要分子机制,已成为诊断和治疗的靶点。不同的基因突变类型GIST对药物的反应不同,且随着酪氨酸激酶抑制剂的推广以及疾病本身的基因突变,药物耐药率逐渐提高而影响疗效,因此突变也可作为GIST预后评价的指标。在临床实践中,伊马替尼通常作为GIST的一线用药,舒尼替尼作为伊马替尼失败的二线药物。本文就GIST靶向治疗的药物遗传学研究进展作一综述。     

胃肠道间质瘤伊马替尼继发耐药治疗的研究进展

酪氨酸激酶抑制剂伊马替尼在胃肠道间质瘤(GISTs)的治疗中已取得令人瞩目的疗效,然而伊马替尼继发耐药的出现成为亟待解决的临床难题。GISTs对伊马替尼继发耐药的可能机制包括KIT/PDGFRA基因二次突变、PTEN基因丢失、触发GIST细胞进入静止期等。针对上述耐药机制,目前已提出新型酪氨酸激酶抑制剂、联合应用下游通路靶向抑制剂、较少依赖KIT/PDGFRA途径的靶向抑制剂(KIT分子伴侣抑制剂、极光激酶抑制剂等)、诱导静止期GIST细胞凋亡等解决伊马替尼继发耐药的策略,本文就相关研究进展作一综述。     

中、高危险度胃肠道间质瘤c-Kit、PDGFRA基因突变分析与临床病理观察

目的 :探讨中、高危险度胃肠道间质瘤(gastrointestinal stromal tumor, GIST)患者中c-Kit及血小板源性生长因子受体α(platelet-derived growth factor receptor-α,PDGFRA)基因突变类型与临床病理特征及预后的关系。方法:回顾性分析718例GIST患者的临床病理资料,根据2008年改良的美国国立卫生研究院(National Institutes of Health, NIH)危险度评估标准筛选出160例中、高危险度GIST,采用直接测序法检测肿瘤组织c-Kit及PDGFRA基因突变类型,电话随访临床预后。结果:160例患者中,男性71例,女性89例,年龄29～87(54.9±11.0)岁,肿瘤大小2～27(9.5±4.6) cm;肿瘤原发部位以胃肠道及胰腺为主(141例,88.1%),消化道外19例(11.9%)。组织学类型以梭形细胞型为主(150例,93.8%)。中危组47例(29.4%),高危组113例(70.6%)。中危组随访29～97(60.0±10.0)个月。除外1例合并食管鳞状细胞癌患者死亡,4例复发,其余42例均无病生存。高危组随访9～103(58.6±12.5)个月。17例患者死亡,26例复发,70例无病生存。c-Kit基因共检测151例,包括中危组43例,高危组108例。共计129例(85.4%)患者检测到c-Kit基因突变,以第11号外显子突变最为常见,其次为第9号外显子和第13号外显子突变,第17号外显子未检测到单独突变。中危组c-Kit基因突变率为93.0%,高危组突变率为82.4%。且高危组患者中检出4例c-Kit基因双外显子突变。PDGFRA共检测91例,包括中危组25例,高危组66例,共检出5例第18号外显子突变和9例同义突变(15.4%)。未检测出第12号外显子突变。结论:中、高危险度GIST患者主要为c-Kit基因突变,且以第11外显子突变最常见。高危组中见双突变,提示c-Kit基因突变类型在GIST的危险度评估中具有重要作用。     

罕见病理类型胃间质瘤——附文献复习

胃肠道间质瘤为最常见的胃肠道非上皮性肿瘤。大多数GIST病理免疫染色KIT（C-kit原癌蛋白）阳性。产生编码第三型受体型酪胺酸激酶的突变基因，包括c-kit或PDGFRA。多数胃肠道间质瘤临床上无症状，好发于老年。本文报道一例PDGFRA外显子18突变的胃肠道间质瘤。并对胃肠道间质瘤的临床、病理特点及预后加以综述。     

胃肠道间质瘤的诊治新进展

胃肠道间质瘤（GIST）是胃肠道最常见的间叶源性肿瘤,原癌基因c—kit突变是其主要发病机制之一。以CD117为代表的免疫织化学染色在其诊断中是一个重要的决定性因素。手术完整切除仍然是其首选治疗,分子靶向治疗是进展期GIST治疗上的一次飞跃,本文对GIST的诊治新进展进行综述。     

胃肠道间质瘤

胃肠道间质瘤(GIST) 是一种较少见的肿瘤,既往治疗主要以手术为主。随着病理研究的深入,发现大多数GIST存在c kit前癌基因的变异,导致kit酪氨酸激酶持续活化,STI 571 是选择性酪氨酸激酶抑制剂,在胃肠道间质瘤靶向治疗方面起重要作用。对 GIST的认识将对临床医师治疗本病有所帮助。现就GIST的流行病学、病理、临床表现、诊断及治疗进展等几方面进行综述。     

胃肠道间质瘤组织中PDGFRα和C-kit基因突变和蛋白表达的关系

目的:检测胃肠道间质瘤(GIST)中PDGFRα和C-kit基因突变及其蛋白表达的关系及在肿瘤形成中的作用.方法:采用单链象多态性聚合酶链式反应(PCR-SSCP),免疫组化和蛋白印迹(Western blot)方法,检测GIST 52例中PDGFRα和C-kit基因突变及蛋白表达情况.结果:GIST 52例中PDGFRα基因突变5例(9.6%),多见于梭形细胞型的胃源性GIST,C-kit基因突变28例(53.8%),多发生于小肠,并且这两种基因突变互相独立;PDGFRα蛋白表达率100%,C-kit蛋白的表达率为94.2%,突变的5例GIST PDGFRα强于C-kit突变的GIST,正常胃肠道组织和神经鞘瘤:突变与C-kit蛋白表达之间没有显著相关性(P=0.5332),而突变与PDGFRα蛋白表达之间呈显著相关性(P<0.0001).结论:GIST中PDGFRα和C-kit突变在部分GIST肿瘤发生过程中发挥了重要作用;突变位点与起源部位和组织学类型有关;大多GIST中蛋白表达与其基因突变关系密切.     

胃肠道间质瘤预后研究进展

胃肠道间质瘤(GIST)是人类胃肠道最常见的间叶源性肿瘤,大多数GIST有原癌基因c-kit突变.近年的研究发现,在无c-kit突变的胃肠道间质瘤中,存在血小板源性生长因子受体-α(PDGFR-α)基因的突变.此外,尚存在很多基因和蛋白参与了GIST的发生和发展.与一般胃肠道肿瘤相比,GIST在组织发生、临床病理、诊断治疗、预后等方面有着不同的特点.本文主要综述有关GIST预后的相关指标的研究进展.     

胃肠道间质瘤

胃肠道间质瘤(GIST)是一种较少见的肿瘤，既往治疗主要以手术为主。随着病理研究的深入，发现大多数GIST存在c—kit前癌基因的变异，导致kit酪氨酸激酶持续活化，STI571是选择性酪氨酸激酶抑制剂，在胃肠道间质瘤靶向治疗方面起重要作用。对GIST的认识将对临床医师治疗本病有所帮助。现就GIST的流行病学、病理、临床表现、诊断及治疗进展等几方面进行综述。     

野生型胃肠道间质瘤的诊疗进展

胃肠道间质瘤(GIST)是最常见的消化道间叶组织来源肿瘤,约10%的患者不伴有KIT和PDGFRA基因突变,称为野生型GIST。根据发病机制,可分为琥珀酸脱氢酶(SDH)缺陷型、BRAF基因突变型和1型神经纤维瘤病(NF1)基因型等不同亚型,另有约半数患者的发病机制尚不明确。野生型GIST的临床特征、病理表现和疾病治疗均具有一定特殊性。本文就野生型GIST的分子基础、发病机制和临床诊疗进展作一综述。     

胃肠道间质瘤的诊断治疗

胃肠道间质瘤(gastrointestinal stromal tumors,GIST)是消化系最常见的间叶组织源性肿瘤,是一种潜在恶性的肿瘤.其临床表现缺乏特异性,术前诊断上存在较大困难.近几年其发病机制已经逐渐被人们所认识,诊断及治疗水平上也有了很大的提高.原癌基因kit突变是其主要发病机制之一.以CD117为代表的免疫织化学染色在其诊断中作为一个重要的决定性因素.治疗上目前注重于综合治疗,手术完整切除仍然是其首选治疗,包括新辅助治疗及术后辅助治疗在内的分子靶向治疗的出现成为GIST治疗上的一次巨大进步,甲磺酸伊马替尼等选择性酪氨酸激酶抑制剂制剂的出现,给GIST患者的治疗带来了新的希望.     

Nestin及C-kit在胃肠道间质瘤中的表达及意义

目的观察胃肠道间质瘤（GIST）中Nestin和C—kit在蛋白和转录水平的表达，分析Nestin在GIST诊断、鉴别诊断及发生发展中的意义。方法应用免疫组化、逆转录（RT）-PCR和Western印迹法，检测116例胃肠道间质瘤中Nestin、C—kit的表达（其中22例同时收集新鲜组织），并收集10例正常胃肠道组织和15例平滑肌瘤作为对照。结果116例胃肠道间质瘤中104例（89．7％）Nestin表达阳性；53例良性和63例恶性GIST中分别有47例（88．7％）和57例（90．5％）Nestin表达阳性；Nestin表达水平在良、恶性组间差异无统计学意义（Χ^2=0．1，P〉0．05）。116例GIST中C—kit蛋白的阳性表达率为94．8％（110／116），Nestin和C—kt表达水平间差异无统计学意义（Χ^2=1．084，P〉0．05）。RT—PCR和Western印迹结果显示GIST均有Nestin和C—kit表达。与正常胃肠道组织和平滑肌瘤比较，差异均有统计学意义。结论在GIST中有Nestin高表达，与C—kit联合检测有助于GIST的诊断，但不能作为判断肿瘤危险度的指标。     

KIT exon 11 codon 557/558 deletion/insertion mutations define a subset of gastrointestinal stromal tumors with malignant potential

AIM： To study the association of the frequency and pattern of KIT and PDGFRA mutations and clinicopathological factors in a group of patients with gastrointestinal stromal tumors （GIST）. METHODS： Thirty patients with GIST were examined. Exons 9, 11, 13, and 17 of the KIT and exons 12 and 18 of the PDGFRA gene were analyzed for the presence of mutations by PCR amplification and direct sequencing. RESULTS： KIT or PDGFRA mutations were detected in 21 of the 30 patients （70%）. Sixteen patients had mutations within KIT exon 11, three within KIT exon 9, and two within PDGFRA exon 18. GISTs with KIT exon 9 mutations were predominantly located in the small intestine, showed a spindle cell phenotype, and were assessed as potentially malignant. GISTs with KIT exon 11 mutations were located in the stomach and intestine, showed mainly a spindle cell phenotype, and were scored as potentially malignant （P 〈 0.05）. Tumors with KIT exon 11 codon 557/558 deletion/insertion mutations were found to be associated with a potentially malignant clinical behaviour （P 〈 0.003）. GISTs with PDGFRA mutations located in stomach showed a mixed cell phenotype and were classified as of very low or low moderate malignant potential. CONCLUSION： Determination of KIT and PDGFRA mutations should be additional parameters for the better prediction of GISTs clinical behaviour. Tumors with deletion/insertion mutations affecting codons 557/558 of the KIT gene seem to represent a distinct subset of malignant GISTs.     

Stathmin在胃肠道间质瘤组织中的表达与临床病理因素之间的关系

[目的]分析原发性胃肠道间质瘤(GIST)中微管解聚蛋白(Stathmin)的表达程度与临床病理因素之间的相关性,探讨Stathmin是否是GIST患者的诊断、治疗及其预后中发挥重要作用的蛋白。[方法]采用免疫组化学技术检测96例GIST组织中Stathmin蛋白的表达,采用SPSS25.0软件统计分析Stathmin蛋白的表达水平与患者一般临床病理学特征之间的相关性。[结果]Stathmin在GIST组织中阳性率为45.8%(44/96),在GIST组织中高表达;Stathmin阳性表达与患者肿瘤危险度、CD34有统计学意义(P0.05、P0.01),与患者性别、年龄、肿瘤部位、肿块大小、浸润深度等差异无统计学意义(P0.05)。[结论]在GIST患者中Stathmin高表达与肿瘤危险度分级、CD34(+)密切相关。Stathmin有可能成为判别该病的辅助诊断及患者病情恶化的指标,为今后GIST患者的诊断、临床治疗策略及预后判断提供理论依据。