嗜铬细胞瘤全基因组拷贝数变化分析和相关基因的研究
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摘要
研究目的：
1.对散发型嗜铬细胞瘤细胞的全基因组DNA拷贝数异常(Copy number variations CNVs)和杂合性缺失(Loss of heterozygosity LOH)的系统分析,发现与肿瘤相关的拷贝数变化和杂合性缺失的所在染色体区位,筛选所涉及嗜铬细胞瘤肿瘤相关基因或者分子标志物,为嗜铬细胞瘤的诊断与治疗提供新的参考资料。
2.分析所筛选基因m-RNA的表达水平在良性与恶性嗜铬细胞瘤中的分布差异,寻找鉴别良恶性嗜铬细胞瘤的分子遗传学标记物,并证明应用SNP芯片是筛选肿瘤相关基因有效性方法。
材料与方法：
1.应用Affymetrix公司GeneChip SNP 6.0芯片检测5例嗜铬细胞瘤(包括肿瘤组织和自身白细胞)全基因组的DNA拷贝数异常(包括扩增和缺失)和LoH。
2.分析SNP 6.0芯片检测结果；筛选DNA发生缺失、扩增区域或LoH区域内含基因为嗜铬细胞瘤肿瘤相关基因。
3.入选北京协和医院2000年至2008年明确诊断的嗜铬细胞瘤29例,其中良性组19例,恶性组10例。另取12例正常肾上腺髓质组织为正常对照组。提取各组细胞DNA。应用实时定量PCR (real-time PCR)方法检测各组候选基因的m-RNA表达情况。
4.统计分析候选基因m-RNA的表达水平在不同病理类型(良／恶性)嗜铬瘤中的的分布差异,分析候选基因与嗜铬细胞瘤临床病理类型及预后之间的关系。
结果：
1.5例嗜铬细胞瘤组织与配对的正常细胞相比,5例均发生缺失的染色体是1p21.1—1p21.2;4例或4例以上嗜铬细胞瘤发生缺失的染色体主要是1p、3q和11p。
2.5例嗜铬细胞瘤组织细胞与配对的正常细胞相比,4例或4例以上嗜铬细胞瘤发生扩增的染色体主要是5q。
3.5例嗜铬细胞瘤组织与配对的正常细胞相比,5例嗜铬细胞瘤,都发生LOH。其中4例发生染色体1 p、11 p、11q的LOH；共同区域和基因为：11p15.13和SOX6;3例发生染色体5q的LOH,共同区域和基因为：5q31.3和NRG2；2例发生染色体3p、6q的LOH。
4.在3例共同发生缺失的染色体5q31.3含基因NRG2以及其同源基因NRG1为候选基因。
5. NRG2-mRNA在良性嗜铬细胞瘤、恶性嗜铬细胞瘤和正常肾上腺髓质组织内均有表达,在嗜铬细胞瘤中表达显著低于正常肾上腺髓质(P<0.01);而在良恶性嗜铬细胞瘤组之间无显著性差异(P>0.05)。NRG1-mRNA在恶性嗜铬细胞瘤中表达显著高于良性嗜铬细胞瘤(P<0.05)。
结论：
1. SNP6.0芯片能够有效发现和精确定位嗜铬细胞流全基因组DNA拷贝数的微小变化和LoH区域,可以发现新的染色体CNV区域。
2.DNA发生扩增或缺失可能与肿瘤的发生发展有关,可能是肿瘤的发病基础。检测结果为进一步定位筛选和克隆与嗜铬细胞瘤相关基因提供了重要的线索和理论信息。
3. NRG2 m-RNA的表达下调的基础可能与嗜铬细胞瘤染色体NRG2存在LoH有关,可能是参与嗜铬细胞瘤发生发展的分子机制；NRG1-mRNA在恶性嗜铬细胞流中的表达良明显高于良性嗜铬细胞瘤,可作为鉴别良恶性嗜铬细胞瘤的标记物,作为嗜铬细胞预后的判断因素。
4.SNP芯片是筛选嗜铬细胞瘤肿瘤相关基因有效的方法。
Summary
Purpose:
1. Systemic analysis of copy number variations (CNVs) and loss of heterozygosity (LOH) in sporadic pheochromocytoma cells genome DNA,discovery tumor-related changes of copy number and and loss of heterozygosity where chromosomal location, screening pheochromocytoma tumor-associated genes or molecular markers to provide a new reference. for the diagnosis of pheochromocytoma and treatment. 2. Analysis the differences of selected gene's m-RNA expression level between benign and malignant pheochromocytomas,look for molecular genetics markers for the diagnosis of benign and malignant pheochromocytoma, and to prove SNP array is an effective method of screening the tumor-related genes.
Materials and methods:
1. Apply Affymetrix Inc. GeneChip SNP 6.0 chip to detect whole genome DNA copy number variations (including amplification and deletion) and LoH in 5 cases of pheochromocytoma (including tumor tissue and their own peripheral blood leucocyte).
2. Analysis of SNP 6.0 chip test results; screening CNV or LoH region,and find the pheochromocytoma tumor-related genes.
3.29 patients dignosised as pheochromocytoma from 2000 to 2008 in PUMCH were enrolled. including 19 cases of benign and 10 cases of malignant, Take another 12 cases of normal adrenal medulla tissue as normal control group. Extract cell DNA and apply Real time quantitative PCR (real-time PCR) to detect candidate genes m-RNA expression level in each group.
4. Statistical analysis of candidate gene m-RNA expression levels in different histological types of(benign/malignant) adrenal tumor.discovery the relationship between candidate genes expression levels with Pathological classification and prognosis of pheochromocytoma
Results:
1.5 cases of pheochromocytoma tissue compared with matched normal cells,5 cases of chromosome deletion occurred in 1p21.1-1p21.2; 4 cases of pheochromocytoma occurring deletion of chromosome 1p is mainly,3q and 11p.
2.5 cases of pheochromocytoma cells compared with matched normal cells,4 cases of pheochromocytoma occurring mainly amplification of chromosome 5q.
3.5 cases of pheochromocytoma cell compared with matched normal cells, all cases of pheochromocytoma have undergone LOH.4 cases had chromosomes 1p, 11p, 11q of LOH, common regional and gene:11p15.13 and SOX6; 3 cases had chromosome 5q of LOH, common regional and gene:5q31.3 and NRG2; 2 cases had chromosome 3p,6q of LOH.
4. Common occurrence in the three cases of chromosome 5q31.3 LoH containing the NRG1 gene,NRG1 gene and its homologous gene NRG2 was selected as candidate genes.
5. NRG2-mRNA was expressed in benign pheochromocytoma, malignant pheochromocytoma and normal adrenal medulla tissue. was significantly lower in pheochromocytoma than in the adrenal medulla (P<0.01); but had no significant difference between benign and malignant pheochromocytoma group (P> 0.05). NRG1-mRNA expression in malignant pheochromocytomas was significantly higher than in benign pheochromocytomas (P<0.05)。
Conclusion:
1. SNP6.0 chip can effectively detect and precisely locate pheochromocytoma whole-genome small area DNA copy number changes and LoH, can discover new CNV regions of chromosomes.
2. deletion or amplification of DNA may occur with tumor development, which may be the basis of tumor pathogenesis. Test results for further screening and localization of pheochromocytoma-related genes provide important clues and theoretical information.
3. NRG2 m-RNA expression reduced in pheochromocytoma may be basis of the existence of chromosome NRG2 LoH, which may be involved in the development of pheochromocytoma molecular mechanisms; NRG1-mRNA expression level in malignant pheochromocytoma was significantly higher than the expression of benign pheochromocytoma, can be used as molecular markers for malignant pheochromocytoma, and as pheochromocytoma prognosis factor.
4. SNP chips is an effective method of screening pheochromocytoma tumor-associated genes
1.对散发型嗜铬细胞瘤细胞的全基因组DNA拷贝数异常(Copy number variations CNVs)和杂合性缺失(Loss of heterozygosity LOH)的系统分析,发现与肿瘤相关的拷贝数变化和杂合性缺失的所在染色体区位,筛选所涉及嗜铬细胞瘤肿瘤相关基因或者分子标志物,为嗜铬细胞瘤的诊断与治疗提供新的参考资料。
2.分析所筛选基因m-RNA的表达水平在良性与恶性嗜铬细胞瘤中的分布差异,寻找鉴别良恶性嗜铬细胞瘤的分子遗传学标记物,并证明应用SNP芯片是筛选肿瘤相关基因有效性方法。
材料与方法：
1.应用Affymetrix公司GeneChip SNP 6.0芯片检测5例嗜铬细胞瘤(包括肿瘤组织和自身白细胞)全基因组的DNA拷贝数异常(包括扩增和缺失)和LoH。
2.分析SNP 6.0芯片检测结果；筛选DNA发生缺失、扩增区域或LoH区域内含基因为嗜铬细胞瘤肿瘤相关基因。
3.入选北京协和医院2000年至2008年明确诊断的嗜铬细胞瘤29例,其中良性组19例,恶性组10例。另取12例正常肾上腺髓质组织为正常对照组。提取各组细胞DNA。应用实时定量PCR (real-time PCR)方法检测各组候选基因的m-RNA表达情况。
4.统计分析候选基因m-RNA的表达水平在不同病理类型(良／恶性)嗜铬瘤中的的分布差异,分析候选基因与嗜铬细胞瘤临床病理类型及预后之间的关系。
结果：
1.5例嗜铬细胞瘤组织与配对的正常细胞相比,5例均发生缺失的染色体是1p21.1—1p21.2;4例或4例以上嗜铬细胞瘤发生缺失的染色体主要是1p、3q和11p。
2.5例嗜铬细胞瘤组织细胞与配对的正常细胞相比,4例或4例以上嗜铬细胞瘤发生扩增的染色体主要是5q。
3.5例嗜铬细胞瘤组织与配对的正常细胞相比,5例嗜铬细胞瘤,都发生LOH。其中4例发生染色体1 p、11 p、11q的LOH；共同区域和基因为：11p15.13和SOX6;3例发生染色体5q的LOH,共同区域和基因为：5q31.3和NRG2；2例发生染色体3p、6q的LOH。
4.在3例共同发生缺失的染色体5q31.3含基因NRG2以及其同源基因NRG1为候选基因。
5. NRG2-mRNA在良性嗜铬细胞瘤、恶性嗜铬细胞瘤和正常肾上腺髓质组织内均有表达,在嗜铬细胞瘤中表达显著低于正常肾上腺髓质(P<0.01);而在良恶性嗜铬细胞瘤组之间无显著性差异(P>0.05)。NRG1-mRNA在恶性嗜铬细胞瘤中表达显著高于良性嗜铬细胞瘤(P<0.05)。
结论：
1. SNP6.0芯片能够有效发现和精确定位嗜铬细胞流全基因组DNA拷贝数的微小变化和LoH区域,可以发现新的染色体CNV区域。
2.DNA发生扩增或缺失可能与肿瘤的发生发展有关,可能是肿瘤的发病基础。检测结果为进一步定位筛选和克隆与嗜铬细胞瘤相关基因提供了重要的线索和理论信息。
3. NRG2 m-RNA的表达下调的基础可能与嗜铬细胞瘤染色体NRG2存在LoH有关,可能是参与嗜铬细胞瘤发生发展的分子机制；NRG1-mRNA在恶性嗜铬细胞流中的表达良明显高于良性嗜铬细胞瘤,可作为鉴别良恶性嗜铬细胞瘤的标记物,作为嗜铬细胞预后的判断因素。
4.SNP芯片是筛选嗜铬细胞瘤肿瘤相关基因有效的方法。
Summary
Purpose:
1. Systemic analysis of copy number variations (CNVs) and loss of heterozygosity (LOH) in sporadic pheochromocytoma cells genome DNA,discovery tumor-related changes of copy number and and loss of heterozygosity where chromosomal location, screening pheochromocytoma tumor-associated genes or molecular markers to provide a new reference. for the diagnosis of pheochromocytoma and treatment. 2. Analysis the differences of selected gene's m-RNA expression level between benign and malignant pheochromocytomas,look for molecular genetics markers for the diagnosis of benign and malignant pheochromocytoma, and to prove SNP array is an effective method of screening the tumor-related genes.
Materials and methods:
1. Apply Affymetrix Inc. GeneChip SNP 6.0 chip to detect whole genome DNA copy number variations (including amplification and deletion) and LoH in 5 cases of pheochromocytoma (including tumor tissue and their own peripheral blood leucocyte).
2. Analysis of SNP 6.0 chip test results; screening CNV or LoH region,and find the pheochromocytoma tumor-related genes.
3.29 patients dignosised as pheochromocytoma from 2000 to 2008 in PUMCH were enrolled. including 19 cases of benign and 10 cases of malignant, Take another 12 cases of normal adrenal medulla tissue as normal control group. Extract cell DNA and apply Real time quantitative PCR (real-time PCR) to detect candidate genes m-RNA expression level in each group.
4. Statistical analysis of candidate gene m-RNA expression levels in different histological types of(benign/malignant) adrenal tumor.discovery the relationship between candidate genes expression levels with Pathological classification and prognosis of pheochromocytoma
Results:
1.5 cases of pheochromocytoma tissue compared with matched normal cells,5 cases of chromosome deletion occurred in 1p21.1-1p21.2; 4 cases of pheochromocytoma occurring deletion of chromosome 1p is mainly,3q and 11p.
2.5 cases of pheochromocytoma cells compared with matched normal cells,4 cases of pheochromocytoma occurring mainly amplification of chromosome 5q.
3.5 cases of pheochromocytoma cell compared with matched normal cells, all cases of pheochromocytoma have undergone LOH.4 cases had chromosomes 1p, 11p, 11q of LOH, common regional and gene:11p15.13 and SOX6; 3 cases had chromosome 5q of LOH, common regional and gene:5q31.3 and NRG2; 2 cases had chromosome 3p,6q of LOH.
4. Common occurrence in the three cases of chromosome 5q31.3 LoH containing the NRG1 gene,NRG1 gene and its homologous gene NRG2 was selected as candidate genes.
5. NRG2-mRNA was expressed in benign pheochromocytoma, malignant pheochromocytoma and normal adrenal medulla tissue. was significantly lower in pheochromocytoma than in the adrenal medulla (P<0.01); but had no significant difference between benign and malignant pheochromocytoma group (P> 0.05). NRG1-mRNA expression in malignant pheochromocytomas was significantly higher than in benign pheochromocytomas (P<0.05)。
Conclusion:
1. SNP6.0 chip can effectively detect and precisely locate pheochromocytoma whole-genome small area DNA copy number changes and LoH, can discover new CNV regions of chromosomes.
2. deletion or amplification of DNA may occur with tumor development, which may be the basis of tumor pathogenesis. Test results for further screening and localization of pheochromocytoma-related genes provide important clues and theoretical information.
3. NRG2 m-RNA expression reduced in pheochromocytoma may be basis of the existence of chromosome NRG2 LoH, which may be involved in the development of pheochromocytoma molecular mechanisms; NRG1-mRNA expression level in malignant pheochromocytoma was significantly higher than the expression of benign pheochromocytoma, can be used as molecular markers for malignant pheochromocytoma, and as pheochromocytoma prognosis factor.
4. SNP chips is an effective method of screening pheochromocytoma tumor-associated genes
引文
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