胃肠道间质瘤全基因组染色体改变和蛋白表达的研究及意义
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摘要
研究目的:胃肠道间质瘤(Gastrointestinal stromal tumor,GISTs)是一类胃肠道最常见的间叶源性肿瘤,具有不确定的恶性潜能。应用先进的分子生物学技术研究相关基因的变化与蛋白表达是当前人类恶性肿瘤研究的重要领域,对揭示肿瘤进展机制,指导治疗,预测预后有着非常重要的意义。本研究应用比较基因组杂交技术(comparative genomic hybridization,CGH)对我院近年来的GISTs标本进行了研究,并根据GISTs基因缺失、扩增的改变,筛选p16、nm23等指标,应用免疫组化技术检测并选取有价值的分子生物学指标为GISTs的遗传学改变及预后预测提供重要的参考依据。
对象和方法:收集2006-2007年间25例新鲜GISTs标本,-80℃保存,所有标本均经术后组织学和免疫组化证实为GISTs,应用比较基因组杂交技术检测所有GISTs的细胞遗传学改变;并根据GISTs基因缺失、扩增的改变选择有价值的分子标记物(p16、PTEN、p53、Cmyc、MDM2、nm23、E2F1、Ki-67),采用免疫组化方法检测近几年来有随访资料的62例GISTs的表达情况。所有统计学分析采用SPSS 11.5软件进行。
研究结果:1. PD(progressive disease-死于该肿瘤或该肿瘤发生肝脏、腹膜等邻近器官转移称为进行性疾病)。
2. 25例GISTs细胞染色体均有不同程度的变化,包括染色体全部或部分的扩增或缺失,缺失多于扩增,平均每个病例缺失和扩增的频率分别为3.12和2.2。常见的缺失包括14q(60%),1p(40%)等;常见的扩增区域主要见于17q(40%),5p(32%)等。
3(.1)62例GISTs中, p16在不同侵袭危险性GISTs中表达有差异(P<0.001),随着GISTs侵袭危险性的升高,p16表达强度降低。p16阳性细胞数小于50%的病例其PD病例数高于阳性细胞数50%-75%和阳性细胞数大于75%的病例,统计学分析,p16蛋白表达强度之间PD有差别(P<0.001)。
(2)PTEN阴性表达率19.4%,且其表达随着肿瘤分级的增高,阴性例数增多。相关性分析表明,PTEN表达与危险度分级呈显著相关性(P<0.01),但表达强度各组之间PD差异无显著性(P>0.05)。
(3)62例GISTs中有26例p53蛋白阳性表达,随肿瘤分级增高,阳性表达例数逐渐增多,肿瘤恶性度增高,p53表达增强,呈显著正相关(P<0.01)。p53(++)的病例其PD发生率高于(-)病例(P<0.05)。
(4)Cmyc在GISTs中的阳性表达率为80.6%,肿瘤恶性度增高,Cmyc表达例数增多,Cmyc表达与肿瘤分级有关(P<0.001)。Cmyc (+++)的病例与(+)和(-)的病例中PD发生率有差异(P<0.01);(++)的病例与(+)和(-)病例中PD发生率有差异(P<0.05)。
(5)MDM2在各级间的阳性率分别为0.0%,0.0%,15.8%,61.1%,高度危险组表达率明显高于其余三组,MDM2表达与肿瘤恶性度有关(P<0.05)。MDM2阳性细胞数(++)的病例PD发生率高于阳性细胞数(+)和(-)病例(P<0.05)。
(6)62例GISTs中,nm23均有不同程度的阳性表达,与肿瘤分级呈负相关性(P<0.01)。nm23阳性细胞数(+)的病例PD发生率明显高于其余两组(P<0.01)。
(7)E2F1蛋白在GISTs中的阳性率为71.0%,危险度分级与E2F1表达强度之间有显著相关性(P<0.05)。E2F1(+++)的病例中PD发生率与其它组间有差异(P均<0.01)。
(8)Ki-67在Ⅰ、Ⅱ、Ⅲ、Ⅳ级GISTs病例中的增殖指数分别为0.0%、16.7%、36.8%、94.4%,Ki-67阳性细胞数与肿瘤恶性度有关,相关性分析,二者有显著性意义(P<0.05)。研究结论:1.GISTs染色体存在着非随机的DNA拷贝数扩增或缺失的位点,提示这些位点可能含有候选的致癌基因和抑癌基因。14q和22q的缺失是GISTs发生的早期事件,具有1p缺失的GISTs患者可能预后较差,9p的缺失和17q、20q扩增可能是GISTs恶性进展的标志,8q和5p扩增的预后意义有待考证。2.p16阳性细胞数大于50%,Ki-67增殖指数可能是GISTs有价值的预后参考指标;nm23、Cmyc可以作为预测GISTs侵袭行为的指标;E2F1可能是GISTs的一个不良预后因子,但还需结合其他的分子生物学指标及更多样本例数来综合评估;MDM2敏感性较差,不适合作为GISTs预后的常规标记物;PTEN、p53能否作为GISTs的预后标记物,还有待考证。
本研究的创新点:1.本研究从胃肠道间质瘤(GISTs)的遗传学变化和预后因素两方面研究,涉及整个基因组染色体的相关基因改变。2.根据GISTs特异的基因改变,结合国内外研究现状,针对性的选取分子生物学指标,对其表达情况及与GISTs预后的关系进行探讨,完善预后评价标准。
Objective: Gastrointestinal stromal tumors(GISTs) with uncertain malignant potential is one of the most common mesenchymal tumors of the gastrointestinal tract. Applying advanced molecular biological technique to search gene alteration and protein expression is important to our understanding on tumors. It is significant to reveal formation, development mechanism, direct treatment and predict prognosis. In this study, we apply the technique of comparative genomic hybridization to detect GISTs samples, and select worthy molecular biological parameters, such as p16、nm23 et al by immunohistochemistry which were filtered by CGH according to gene loss or gain and to provide significant evidence for diagnosis and therapy of genetics alteration and prognosis of GISTs.
Subjects and methods: 25 cases of novel samples were collected from 2006-2007 and store in -80℃, after operation, all GISTs to confirm by histology and immunohistochemistry and then applying comparative genomic hybridization (CGH) technique to study tumor cytogenetic changes; according to gene loss or gain to select worthy molecular biological parameters (p16、PTEN、p53、Cmyc、MDM2、nm23、E2F1、Ki-67) to detect 62 GISTs of visit documents by immunohistochemistry in later years. Statistical analysis was performed using the SPSS 11.5 software.
Results: 1. Death from tumor or the presence of liver and abdominal metastases was considered to represent evidence for progressive disease (PD). 2. We anslyzed 25 GISTs with CGH. Results show that each one has different degree of variances, included gains and losses of partial and whole chromosome. Each case has abnormal average region, losses are more than gains, equal to 3.12 and 2.2 per case respectively. Main regions are lost at chromosomes 14q(60%), 1p(40%), et al, and gains at 17q(40%), 5p(32%), et al.
3.(1)In 62 cases of GISTs, p16 expression had significant difference in grade of GISTs(P<0.001). The PD in cases of cells expression was less than 50% with p16 immunostaining and higher than cases which cells of 50%-75% and more than 75% with p16 immunostaining(P<0.001).There was significant difference of PD in p16 expression(P<0.001).
(2) The negative expression rate of PTEN protein was 19.4% in 62 cases GISTs, and negative expression cases increased along with the risk grading raised.The expression of PTEN protein was significantly related to risk grading of GISTs (P<0.05),but no difference with PD(P>0.05).
(3)The positive expression of p53 protein was 26 cases among 62 GISTs, the higher tumor grading,the more positive cases, The expression of p53 protein was positive related to risk grading of the tumor (P<0.05). PD incidence rate in p53 (++) cases was higher than that in p53 (-) cases (P<0.05).
(4)The positive expression rate of Cmyc protein was 80.6%, the higher malignant degree,the more positive cases of Cmyc,and The expression of Cmyc protein was related to risk grading of the tumor.Rate of PD was difference between in Cmyc(+++)cases and in Cmyc (+) and Cmyc (-) cases respectively (P<0.01).Rate of PD was difference between in Cmyc(++)cases and in Cmyc(+) and Cmyc (-)cases respectively (P<0.05).
(5) Rate of MDM2 positive expression was 0.0%,0.0%,15.8%,61.1% in different grading. The expression rate in theⅣgrading was significantly higher than the others. The expression of MDM2 protein was related to the tumor malignant degree(P<0.05). PD incidence rate in MDM2 (++)cases was higher than that in MDM2(+)and (-) (P<0.05).
(6)There was positive expression of different degree of nm23 protein among 62 GISTs, but the intensity was different. The expression intensity of low risk group was higher than that of high. The expression of nm23 protein was significantly related to risk grading of the tumor(P<0.01). PD incidence rate in nm23 cases was higher than that in other grade (P<0.01).
(7)The positive expression rate of E2F1 protein was 71.0%, the expression of E2F1 was significantly related to risk grading of the tumor(P<0.05). There was difference in PD incidence rate between E2F1(+++)and other groups (P<0.01). PD incidence rate in E2F1 cases was differenc in others (P<0.01).
(8)The Ki-67 labeling index inⅠ、Ⅱ、Ⅲ、Ⅳgrading GISTs was 0.0%、16.7%、36.8%、94.4% respectively.The positive cell populations of Ki-67 was significantly related to malignant degree(P<0.05).
Conclusion: 1. There are unrandom DNA copy number gains and losses sites in chromosome, show these sites may include candidate oncogene and tumor suppressor gene. Losses of chromosomes arm 14q and 22q represent early changes related to the pathogenesis of GISTs. DNA losses of 1p might tend poor biologic behavior. Deletion of 9p and gains of 17q and 20q might represent a significant predictive marker in the malignant progression of GISTs. whether gains of 8q and9p were prognostic marker for GISTs were further confirmed .
2. p16 protein expression and Ki-67 labeling index can be as valuable reference markers to judge malignant degree of GISTs. Cmyc, nm23 can be as prognostic marker too. E2F1 may be a prognostic factor, but to judge GISTs prognosis need to combine with another molecular biology marker. MDM2 was unsuitable as prognostic markers. Other studies are necessary to confirm whether PTEN and p53 are prognostic markers for GISTs.
Research innovation: 1. In this study that covered two different fields which genetics alteration and prognosis factor of GISTs, refer to the whole genome chromosomal related gene alteration. 2. Based on specific gene alteration, with research status exterior and interior in GISTs to select directly molecular biological parameter and study relationship between protein expression and prognosis of GISTs and consummate prognostic evaluation criterion.
对象和方法:收集2006-2007年间25例新鲜GISTs标本,-80℃保存,所有标本均经术后组织学和免疫组化证实为GISTs,应用比较基因组杂交技术检测所有GISTs的细胞遗传学改变;并根据GISTs基因缺失、扩增的改变选择有价值的分子标记物(p16、PTEN、p53、Cmyc、MDM2、nm23、E2F1、Ki-67),采用免疫组化方法检测近几年来有随访资料的62例GISTs的表达情况。所有统计学分析采用SPSS 11.5软件进行。
研究结果:1. PD(progressive disease-死于该肿瘤或该肿瘤发生肝脏、腹膜等邻近器官转移称为进行性疾病)。
2. 25例GISTs细胞染色体均有不同程度的变化,包括染色体全部或部分的扩增或缺失,缺失多于扩增,平均每个病例缺失和扩增的频率分别为3.12和2.2。常见的缺失包括14q(60%),1p(40%)等;常见的扩增区域主要见于17q(40%),5p(32%)等。
3(.1)62例GISTs中, p16在不同侵袭危险性GISTs中表达有差异(P<0.001),随着GISTs侵袭危险性的升高,p16表达强度降低。p16阳性细胞数小于50%的病例其PD病例数高于阳性细胞数50%-75%和阳性细胞数大于75%的病例,统计学分析,p16蛋白表达强度之间PD有差别(P<0.001)。
(2)PTEN阴性表达率19.4%,且其表达随着肿瘤分级的增高,阴性例数增多。相关性分析表明,PTEN表达与危险度分级呈显著相关性(P<0.01),但表达强度各组之间PD差异无显著性(P>0.05)。
(3)62例GISTs中有26例p53蛋白阳性表达,随肿瘤分级增高,阳性表达例数逐渐增多,肿瘤恶性度增高,p53表达增强,呈显著正相关(P<0.01)。p53(++)的病例其PD发生率高于(-)病例(P<0.05)。
(4)Cmyc在GISTs中的阳性表达率为80.6%,肿瘤恶性度增高,Cmyc表达例数增多,Cmyc表达与肿瘤分级有关(P<0.001)。Cmyc (+++)的病例与(+)和(-)的病例中PD发生率有差异(P<0.01);(++)的病例与(+)和(-)病例中PD发生率有差异(P<0.05)。
(5)MDM2在各级间的阳性率分别为0.0%,0.0%,15.8%,61.1%,高度危险组表达率明显高于其余三组,MDM2表达与肿瘤恶性度有关(P<0.05)。MDM2阳性细胞数(++)的病例PD发生率高于阳性细胞数(+)和(-)病例(P<0.05)。
(6)62例GISTs中,nm23均有不同程度的阳性表达,与肿瘤分级呈负相关性(P<0.01)。nm23阳性细胞数(+)的病例PD发生率明显高于其余两组(P<0.01)。
(7)E2F1蛋白在GISTs中的阳性率为71.0%,危险度分级与E2F1表达强度之间有显著相关性(P<0.05)。E2F1(+++)的病例中PD发生率与其它组间有差异(P均<0.01)。
(8)Ki-67在Ⅰ、Ⅱ、Ⅲ、Ⅳ级GISTs病例中的增殖指数分别为0.0%、16.7%、36.8%、94.4%,Ki-67阳性细胞数与肿瘤恶性度有关,相关性分析,二者有显著性意义(P<0.05)。研究结论:1.GISTs染色体存在着非随机的DNA拷贝数扩增或缺失的位点,提示这些位点可能含有候选的致癌基因和抑癌基因。14q和22q的缺失是GISTs发生的早期事件,具有1p缺失的GISTs患者可能预后较差,9p的缺失和17q、20q扩增可能是GISTs恶性进展的标志,8q和5p扩增的预后意义有待考证。2.p16阳性细胞数大于50%,Ki-67增殖指数可能是GISTs有价值的预后参考指标;nm23、Cmyc可以作为预测GISTs侵袭行为的指标;E2F1可能是GISTs的一个不良预后因子,但还需结合其他的分子生物学指标及更多样本例数来综合评估;MDM2敏感性较差,不适合作为GISTs预后的常规标记物;PTEN、p53能否作为GISTs的预后标记物,还有待考证。
本研究的创新点:1.本研究从胃肠道间质瘤(GISTs)的遗传学变化和预后因素两方面研究,涉及整个基因组染色体的相关基因改变。2.根据GISTs特异的基因改变,结合国内外研究现状,针对性的选取分子生物学指标,对其表达情况及与GISTs预后的关系进行探讨,完善预后评价标准。
Objective: Gastrointestinal stromal tumors(GISTs) with uncertain malignant potential is one of the most common mesenchymal tumors of the gastrointestinal tract. Applying advanced molecular biological technique to search gene alteration and protein expression is important to our understanding on tumors. It is significant to reveal formation, development mechanism, direct treatment and predict prognosis. In this study, we apply the technique of comparative genomic hybridization to detect GISTs samples, and select worthy molecular biological parameters, such as p16、nm23 et al by immunohistochemistry which were filtered by CGH according to gene loss or gain and to provide significant evidence for diagnosis and therapy of genetics alteration and prognosis of GISTs.
Subjects and methods: 25 cases of novel samples were collected from 2006-2007 and store in -80℃, after operation, all GISTs to confirm by histology and immunohistochemistry and then applying comparative genomic hybridization (CGH) technique to study tumor cytogenetic changes; according to gene loss or gain to select worthy molecular biological parameters (p16、PTEN、p53、Cmyc、MDM2、nm23、E2F1、Ki-67) to detect 62 GISTs of visit documents by immunohistochemistry in later years. Statistical analysis was performed using the SPSS 11.5 software.
Results: 1. Death from tumor or the presence of liver and abdominal metastases was considered to represent evidence for progressive disease (PD). 2. We anslyzed 25 GISTs with CGH. Results show that each one has different degree of variances, included gains and losses of partial and whole chromosome. Each case has abnormal average region, losses are more than gains, equal to 3.12 and 2.2 per case respectively. Main regions are lost at chromosomes 14q(60%), 1p(40%), et al, and gains at 17q(40%), 5p(32%), et al.
3.(1)In 62 cases of GISTs, p16 expression had significant difference in grade of GISTs(P<0.001). The PD in cases of cells expression was less than 50% with p16 immunostaining and higher than cases which cells of 50%-75% and more than 75% with p16 immunostaining(P<0.001).There was significant difference of PD in p16 expression(P<0.001).
(2) The negative expression rate of PTEN protein was 19.4% in 62 cases GISTs, and negative expression cases increased along with the risk grading raised.The expression of PTEN protein was significantly related to risk grading of GISTs (P<0.05),but no difference with PD(P>0.05).
(3)The positive expression of p53 protein was 26 cases among 62 GISTs, the higher tumor grading,the more positive cases, The expression of p53 protein was positive related to risk grading of the tumor (P<0.05). PD incidence rate in p53 (++) cases was higher than that in p53 (-) cases (P<0.05).
(4)The positive expression rate of Cmyc protein was 80.6%, the higher malignant degree,the more positive cases of Cmyc,and The expression of Cmyc protein was related to risk grading of the tumor.Rate of PD was difference between in Cmyc(+++)cases and in Cmyc (+) and Cmyc (-) cases respectively (P<0.01).Rate of PD was difference between in Cmyc(++)cases and in Cmyc(+) and Cmyc (-)cases respectively (P<0.05).
(5) Rate of MDM2 positive expression was 0.0%,0.0%,15.8%,61.1% in different grading. The expression rate in theⅣgrading was significantly higher than the others. The expression of MDM2 protein was related to the tumor malignant degree(P<0.05). PD incidence rate in MDM2 (++)cases was higher than that in MDM2(+)and (-) (P<0.05).
(6)There was positive expression of different degree of nm23 protein among 62 GISTs, but the intensity was different. The expression intensity of low risk group was higher than that of high. The expression of nm23 protein was significantly related to risk grading of the tumor(P<0.01). PD incidence rate in nm23 cases was higher than that in other grade (P<0.01).
(7)The positive expression rate of E2F1 protein was 71.0%, the expression of E2F1 was significantly related to risk grading of the tumor(P<0.05). There was difference in PD incidence rate between E2F1(+++)and other groups (P<0.01). PD incidence rate in E2F1 cases was differenc in others (P<0.01).
(8)The Ki-67 labeling index inⅠ、Ⅱ、Ⅲ、Ⅳgrading GISTs was 0.0%、16.7%、36.8%、94.4% respectively.The positive cell populations of Ki-67 was significantly related to malignant degree(P<0.05).
Conclusion: 1. There are unrandom DNA copy number gains and losses sites in chromosome, show these sites may include candidate oncogene and tumor suppressor gene. Losses of chromosomes arm 14q and 22q represent early changes related to the pathogenesis of GISTs. DNA losses of 1p might tend poor biologic behavior. Deletion of 9p and gains of 17q and 20q might represent a significant predictive marker in the malignant progression of GISTs. whether gains of 8q and9p were prognostic marker for GISTs were further confirmed .
2. p16 protein expression and Ki-67 labeling index can be as valuable reference markers to judge malignant degree of GISTs. Cmyc, nm23 can be as prognostic marker too. E2F1 may be a prognostic factor, but to judge GISTs prognosis need to combine with another molecular biology marker. MDM2 was unsuitable as prognostic markers. Other studies are necessary to confirm whether PTEN and p53 are prognostic markers for GISTs.
Research innovation: 1. In this study that covered two different fields which genetics alteration and prognosis factor of GISTs, refer to the whole genome chromosomal related gene alteration. 2. Based on specific gene alteration, with research status exterior and interior in GISTs to select directly molecular biological parameter and study relationship between protein expression and prognosis of GISTs and consummate prognostic evaluation criterion.
引文
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