胃癌前病灶癌变信息筛查及判癌公式初步建立
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摘要
胃癌是一种常见的恶性肿瘤,在过去的70年里,胃癌的发病率和死亡率虽有明显下降,但至今其发病率仍高居世界排名第四位,而其相关疾病死亡率仅次于肺癌,在全球范围内排名第二位。据研究统计,约50%以上的胃癌发生在胃癌前疾病如萎缩性胃炎等的基础上;一般早期胃癌的发现率约6%-20%,术后5年生存率约60%.而在进展期胃癌,患者即使接受了根治手术后,其5年生存率大约只有5%到15%,在我国至少有一半以上进展期胃癌姑息治疗的患者,平均生存期少于6个月。因此,早期诊断、早期治疗,其手术切除的可能性以及生存预后都将大大改善。如果能够准确地判断癌前病灶癌变的发生,及时给予干预阻断治疗措施,将可能有效地改善胃癌患者的预后。
但目前为止,胃癌诊断都是基于病理组织学基础之上的,这种方法无法发现或者评判从癌前病灶到胃癌的逐渐演变的生物学过程。近年来的分析研究发现了一些与胃癌前病灶相关的分子水平的变化。例如,在胃癌组织附近的肠化生粘膜中检测到了p53的突变。在胃癌和肠化生胃炎相关的胃粘膜组织中均有COX2的过表达。Boussioutas等人建立了124个胃粘膜组织的表达谱,其中包括了胃炎、肠化生和腺癌,并且发现了一系列与胃癌发展可能相关的基因。然而这些新进展并没有使胃癌的早期诊断及预后有很大的改善,并且关于胃癌前病灶的分子流行病学调查研究等较为缺乏,有关信息资料零散破碎,根本无法应用于临床判别诊断。因此研究胃癌前病灶与胃癌的生物学差异和联系,查找出能够判别癌前病灶癌变的分子信息,在病理形态学改变前甄别出早期胃癌,是胃癌一级预防研究的根本所在,也将可能为胃癌早期诊断早期治疗的实现奠定有效的基础。
本研究收集胃癌、癌前病灶以及近似正常的浅表性胃炎胃粘膜的组织样本,以及样本对应患者的临床资料信息,采用Huamn Genome U133 plus2寡核苷酸芯片分析技术,检测了33个胃癌、癌前病灶及浅表性胃炎组织,获取胃癌与癌前病灶组织的基因表达谱的差异,并通过多种生物信息学方法如SAM(微阵列置信度分析Significance analysis of microarray)、R语言平台、SVM(支持向量机Supportvector machine)留一法等筛选验证可区分胃癌及癌前病灶的差异表达基因亚集,通过GENMAPP相关生物学网站及软件,筛选可能相关的生物学通路,同时采用荧光实时定量PCR、原位杂交等技术对通路中部分胶原基因进一步验证。此外,我们还将以上基因芯片分析结果信息数据综合,通过Logistic回归分析,初步建立起胃癌前病灶癌变可能的预测公式,用ROC曲线进行了评估。并将基因芯片基因表达值进行信号转换后再次推导可能的癌变预测公式,下载NCBI GEO公共数据库中数据进行了初步的验证性判别。
通过上述实验,我们成功地建立起可供研究使用的胃癌以及癌前病灶临床组织数据库,为临床胃癌一级预防数据库的建立打下坚实基础;发现了可以将胃癌与癌前病灶相区分的基因亚集并进行了功能注释;同时发现了一条与粘附相关的生物学通路,并得到了通路相关的细胞外基质基因亚集以及胶原基因亚集,而这些基因亚集同样能够有效地将胃癌与癌前病灶相区分。而胶原系列的基因表达谱可能成为胃癌潜在的分类器。此外我们还发现了GS003,这个在病理组织学上仍然为癌前病灶,而基因水平已被分类为胃癌的样本,它有可能是存在于胃癌前病灶向胃癌转变过程中重要阶段的组织类型,有可能为准确判断胃癌前病灶癌变提供研究基础。基于上述实验结果我们初步建立了胃前病灶癌变可能的预测公式,用NCBI GEO公共数据库中数据进行验证性判别,并在小样本验证中初步得到了80%的判别一致率。本实验的发现对研究胃癌前病灶癌变,以及胃癌的早期干预阻断提供了较为重要的信息。
Gastric cancer is a common malignant tumor. Althought its incidence and mortality has an obvious decrease in the past 70 years, it is still a disease with poor prognosis and high mortality and it has a second cancer related death rate worldwide. About 50% of gastric cancers happen on the basis of premalignant diseases such as atrophic gastritis; the diagnositic rate of early gastic cancer is about 6%-20%, and for the advanced gastric cancers, 5-year survival rate is only about 5%-15% even the patients accept radical surgery, and at least more than a half advanced gastric cancer undergo pallitive surgery whose average survival time is less than 6 months. So early diagnosis, early treatment will help to improve the possibility of surgery dissection and the prognosis. Accurate judgement of premalignant lesions to malignant lesions with suitable treatment will be of great importance for human beings.
The present classification systems of gastric cancer based on pathology are failed to efficiently predict the risk of sequential development from premalignant lesions such as intestinal metaplasia and even dysplasia to malignant lesions. Recent studies of molecular biology have revealed that certain gene alterations might have associations with some premalignant lesions. For example, mutation in p53 gene was detected in intestinal metaplasia lesions adjacent to gastric tumors. Overexpression of cyclooxygenase-2 was detected in intestinal metaplasia-associated gastritis as well as gastric cancer. Boussioutas et al examined the expression profile of 124 gastric mucosa samples including gastritis, intestinal metaplasia, and adenocarcinoma and found a series of genes were probably related with tumor progression.However, there are no good biomarkers that help to efficiently diagnose early-stage gastric cancer. Besides, we also lack of molecular epidemiology research data about premalignant lesions of stomach. The already existing informatiion can not be used for clinical diagnosis. So to study the differences and relationship between gastric cancer and premalignant lesions and to find out cancerative molecular information premalignant lesions will be of high evaluation.
We collected tissue samples and clinical information of gastric cancer, premalignant lesions and superficial gastritis. Affymetrix Huamn Genome U133 plus2 oligonucleotide microarray technique was used for detection of differential expression profile of gastric cancers, premalignant lesions and superficial gastritis and we screened differential expressive gene subset and found possible related biological pathway using different kinds of bioinformatics methods such as SAM ( Significance analysis of microarray )、R、SVM( Support vector machine Heave one out and GENMAPP software. Then quantitative RT-PCR and in situ hybridization were used for verification of some pathway involved collagen genes. Based on the result of oligonucleotide microarray, a possible gastric cancer predictive formula was established and the formula was valued and confirmed using the data downloaded from the NCBI GEO database.
In conclusion, we successfully established a tissue bank and clinical material and pathological material follow up data base for gastric cancer and premalignant lesion patients which can be used for clinical primary prevention of gastric cancer. And we found subsets of genes that could separate gastric cancer and premalignant lesions and function annotation was also carried out. We also found a focal adhesion related biological pathway, and pathway related subsets of extracelluar matrix and collagen. And these subsets of genes could also separate gastric cancer and premalignant lesions effeciently. Verification of the pathway involved genes further indicated that collagen genes expression profile could be potential classifer of gastric cancer. GS003 was found, and it was a premalignant lesion with the same alteration at molecular level, but not at pathological level, as malignant lesion. This type of lesion may represent a transitional phase from premalignant status to malignant status. Possible gastric cancer predictive formulas was established and validated with downloaded NCBI GEO data, and got a 80% consistent rate..
但目前为止,胃癌诊断都是基于病理组织学基础之上的,这种方法无法发现或者评判从癌前病灶到胃癌的逐渐演变的生物学过程。近年来的分析研究发现了一些与胃癌前病灶相关的分子水平的变化。例如,在胃癌组织附近的肠化生粘膜中检测到了p53的突变。在胃癌和肠化生胃炎相关的胃粘膜组织中均有COX2的过表达。Boussioutas等人建立了124个胃粘膜组织的表达谱,其中包括了胃炎、肠化生和腺癌,并且发现了一系列与胃癌发展可能相关的基因。然而这些新进展并没有使胃癌的早期诊断及预后有很大的改善,并且关于胃癌前病灶的分子流行病学调查研究等较为缺乏,有关信息资料零散破碎,根本无法应用于临床判别诊断。因此研究胃癌前病灶与胃癌的生物学差异和联系,查找出能够判别癌前病灶癌变的分子信息,在病理形态学改变前甄别出早期胃癌,是胃癌一级预防研究的根本所在,也将可能为胃癌早期诊断早期治疗的实现奠定有效的基础。
本研究收集胃癌、癌前病灶以及近似正常的浅表性胃炎胃粘膜的组织样本,以及样本对应患者的临床资料信息,采用Huamn Genome U133 plus2寡核苷酸芯片分析技术,检测了33个胃癌、癌前病灶及浅表性胃炎组织,获取胃癌与癌前病灶组织的基因表达谱的差异,并通过多种生物信息学方法如SAM(微阵列置信度分析Significance analysis of microarray)、R语言平台、SVM(支持向量机Supportvector machine)留一法等筛选验证可区分胃癌及癌前病灶的差异表达基因亚集,通过GENMAPP相关生物学网站及软件,筛选可能相关的生物学通路,同时采用荧光实时定量PCR、原位杂交等技术对通路中部分胶原基因进一步验证。此外,我们还将以上基因芯片分析结果信息数据综合,通过Logistic回归分析,初步建立起胃癌前病灶癌变可能的预测公式,用ROC曲线进行了评估。并将基因芯片基因表达值进行信号转换后再次推导可能的癌变预测公式,下载NCBI GEO公共数据库中数据进行了初步的验证性判别。
通过上述实验,我们成功地建立起可供研究使用的胃癌以及癌前病灶临床组织数据库,为临床胃癌一级预防数据库的建立打下坚实基础;发现了可以将胃癌与癌前病灶相区分的基因亚集并进行了功能注释;同时发现了一条与粘附相关的生物学通路,并得到了通路相关的细胞外基质基因亚集以及胶原基因亚集,而这些基因亚集同样能够有效地将胃癌与癌前病灶相区分。而胶原系列的基因表达谱可能成为胃癌潜在的分类器。此外我们还发现了GS003,这个在病理组织学上仍然为癌前病灶,而基因水平已被分类为胃癌的样本,它有可能是存在于胃癌前病灶向胃癌转变过程中重要阶段的组织类型,有可能为准确判断胃癌前病灶癌变提供研究基础。基于上述实验结果我们初步建立了胃前病灶癌变可能的预测公式,用NCBI GEO公共数据库中数据进行验证性判别,并在小样本验证中初步得到了80%的判别一致率。本实验的发现对研究胃癌前病灶癌变,以及胃癌的早期干预阻断提供了较为重要的信息。
Gastric cancer is a common malignant tumor. Althought its incidence and mortality has an obvious decrease in the past 70 years, it is still a disease with poor prognosis and high mortality and it has a second cancer related death rate worldwide. About 50% of gastric cancers happen on the basis of premalignant diseases such as atrophic gastritis; the diagnositic rate of early gastic cancer is about 6%-20%, and for the advanced gastric cancers, 5-year survival rate is only about 5%-15% even the patients accept radical surgery, and at least more than a half advanced gastric cancer undergo pallitive surgery whose average survival time is less than 6 months. So early diagnosis, early treatment will help to improve the possibility of surgery dissection and the prognosis. Accurate judgement of premalignant lesions to malignant lesions with suitable treatment will be of great importance for human beings.
The present classification systems of gastric cancer based on pathology are failed to efficiently predict the risk of sequential development from premalignant lesions such as intestinal metaplasia and even dysplasia to malignant lesions. Recent studies of molecular biology have revealed that certain gene alterations might have associations with some premalignant lesions. For example, mutation in p53 gene was detected in intestinal metaplasia lesions adjacent to gastric tumors. Overexpression of cyclooxygenase-2 was detected in intestinal metaplasia-associated gastritis as well as gastric cancer. Boussioutas et al examined the expression profile of 124 gastric mucosa samples including gastritis, intestinal metaplasia, and adenocarcinoma and found a series of genes were probably related with tumor progression.However, there are no good biomarkers that help to efficiently diagnose early-stage gastric cancer. Besides, we also lack of molecular epidemiology research data about premalignant lesions of stomach. The already existing informatiion can not be used for clinical diagnosis. So to study the differences and relationship between gastric cancer and premalignant lesions and to find out cancerative molecular information premalignant lesions will be of high evaluation.
We collected tissue samples and clinical information of gastric cancer, premalignant lesions and superficial gastritis. Affymetrix Huamn Genome U133 plus2 oligonucleotide microarray technique was used for detection of differential expression profile of gastric cancers, premalignant lesions and superficial gastritis and we screened differential expressive gene subset and found possible related biological pathway using different kinds of bioinformatics methods such as SAM ( Significance analysis of microarray )、R、SVM( Support vector machine Heave one out and GENMAPP software. Then quantitative RT-PCR and in situ hybridization were used for verification of some pathway involved collagen genes. Based on the result of oligonucleotide microarray, a possible gastric cancer predictive formula was established and the formula was valued and confirmed using the data downloaded from the NCBI GEO database.
In conclusion, we successfully established a tissue bank and clinical material and pathological material follow up data base for gastric cancer and premalignant lesion patients which can be used for clinical primary prevention of gastric cancer. And we found subsets of genes that could separate gastric cancer and premalignant lesions and function annotation was also carried out. We also found a focal adhesion related biological pathway, and pathway related subsets of extracelluar matrix and collagen. And these subsets of genes could also separate gastric cancer and premalignant lesions effeciently. Verification of the pathway involved genes further indicated that collagen genes expression profile could be potential classifer of gastric cancer. GS003 was found, and it was a premalignant lesion with the same alteration at molecular level, but not at pathological level, as malignant lesion. This type of lesion may represent a transitional phase from premalignant status to malignant status. Possible gastric cancer predictive formulas was established and validated with downloaded NCBI GEO data, and got a 80% consistent rate..
引文
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