遗传性非息肉病性结直肠癌基因表达谱的初步研究
|
摘要
遗传性非息肉病性结直肠癌(hereditary nonpolyposis colorectal cancer, HNPCC)是一种常染色体显性遗传性恶性肿瘤综合征,外显率高达80%-90%,占所有结直肠癌的2%-15%。HNPCC与散发性结直肠癌(Sporadic Colerectal Cancer, SCRC)相比,无论在发病机制、临床特征,乃至治疗方案的选择和随访方案的制定上,HNPCC都具有其特殊性。目前,世界许多国家和地区都制定了一定的HNPCCI临床诊断标准,如Amsterdam标准,Bethesda指导纲要等。HNPCC发生的分子遗传学基础是错配修复基因(mismatch repair, MMR)的突变,该基因的突变能导致复制错误增加,微卫星不稳定而使多器官肿瘤发生,已定位并克隆的人MMR基因hMLHl、hMSH2、hMSH6、hMSH3、hPMSl、hPMS2等与HNPCC发生密切相关。本课题组先前已对58个符合不同临床标准的HNPCC家系先证者进行了hMSH2/hMLH1/hMSH6/hPMS2基因整个编码区胚系小突变和大片段异常及hMLH1基因启动子胚系甲基化的研究,结果发现29个家系存在MMR基因的胚系突变和2个hMLH1基因启动子胚系的完全甲基化,总的胚系异常率仅约为53.4%(31/58)。国内外研究均发现符合不同临床诊断标准的HNPCC家系中,约42%-75%的HNPCC家系能检测到hMSH2、hMLH1和hMSH6基因的胚系突变,但在那些不能完全符合AC标准的可疑HNPCC家系中,MMR基因胚系突变的检出率可能更低。临床上有一些携带MMR基因突变的HNPCC家系并不符合ACⅠ或ACⅡ标准,而将近一半临床高度怀疑HNPCC的人群不能检测到MMR基因的突变,这都表明可能还存在一部分尚未被鉴定出的基因参与HNPCC的发生过程。
随着基因芯片技术的发展,人们可以从全基因组的水平研究基因表达谱的变化,从整体上认识基因表达与肿瘤发生、发展及转移的关系。不少研究者已经运用这一工具对乳腺癌、肺癌、前列腺癌、淋巴瘤及散发性结直肠癌等肿瘤相关的基因表达谱进行了研究,而HNPCC的基因表达谱研究尚未见报道。采用基因表达谱芯片筛选HNPCC差异基因,并对其功能深入研究,是阐明HNPCC发病机制、确立HNPCC特异性诊断标志物和治疗相关的分子靶点的重要手段。
本研究收集50例符合不同临床标准的HNPCC先证者及7例散发性结直肠癌病例,首先对hMSH2/hMLH1胚系基因突变及肿瘤组织相应蛋白表达情况进行检测分析,将HNPCC分为具有MMR缺陷表型组(MLH1和/或MSH2基因突变和/或蛋白表达缺失)和无MMR缺陷表型组；然后应用Affymetrix HG-U133plus2.0寡核苷酸基因芯片技术对50例HNPCC及同期7例散发性结直肠癌肿瘤组织进行了人类全基因组表达谱芯片检测,通过SAM (significance Analysis of Microarray)软件和交集分析,筛选出符合不同临床标准的HNPCC与SCRC、MMR缺陷表型组与SCRC组之间的差异表达基因,分析与SCRC不同的HNPCC基因表达谱特征,确定与MMR缺陷表型密切相关的基因；对显著表达差异的基因采用real-time PCR和免疫组化进行验证,以期发现HNPCC发生可能相关的基因,找到代表MMR缺陷表型的分子标签。
本研究共分为三个部分：
目的：对50例符合不同临床标准的HNPCC家系先证者病理资料进行分析并完成hMSH2、hMLH1蛋白及其中26例基因突变检测。
方法：符合Amsterdam标准家系7个、复旦标准家系9个和Bethesda指导纲要患者34例收入本项临床病理研究。收集家系先证者外周血样本10ml以供提取基因组DNA,以7例同期散发性结直肠癌为对照。利用PCR技术分别扩增2个基因共35个外显子,PCR产物纯化后进行DNA测序,并对测序结果进行分析。免疫组化采用Envision二步法。
结果：在26个HNPCC先证者中共发现8个hMSH2/hMLH1突变,其中符合AC标准的4例(4/8),BG标准4例。50例中蛋白表达缺失17例(16/50),包括已检测到突变的8例。
结论：hMSH2、hMLH1基因突变率及蛋白表达缺失率分别为30.8%和34%；免疫组化检测错配修复蛋白的表达对错配修复基因的突变有很好的初筛作用,Amsterdam标准对预示突变最敏感。仍有一部分符合临床标准的HNPCC患者不能检测到MMR基因的异常。
目的：筛选HNPCC与SCRC、具有MMR缺陷表型组与SCRC组差异基因。
方法：收集第一部分50例HNPCC患者及同期7例SCRC新鲜肿瘤标本,Trizol法提取组织RNA,制备靶标(双链cDNA合成、纯化,体外转录合成生物素标记cRNA、纯化、片段化),利用Affymetrix真核表达谱芯片杂交,清洗染色并扫描；应用SAM等软件对差异基因进行分析,结合MAS等分析工具对筛选基因进行初步的生物学功能分析。
结果：获得HNPCC与SCRC组差异表达基因425个,符合AC组与SCRC组差异表达基因445个,符合复旦推荐标准与SCRC组差异表达基因469个,符合BG组与SCRC组差异基因153个,RB组与SCRC组差异基因613个,MMR缺陷表型组与SCRC组差异表达基因662个(q-value<5%, Fold change≥2)。经统计学分析、文献挖掘及聚类分析结果筛选出HNPCC与SCRC差异基因58个,代表MMR缺陷表型基因11个。
结论：58个基因组成的表达模式代表了HNPCC与SCRC之间MMR基因之外的差异表达基因,具有MMR缺陷表型组与AC组基因表达谱相似,有11个基因可以构成这一表达模式；这些差异表达基因可能在HNPCC的发病中起重要的生物学作用。
目的：收集第二部分57个病例并增加55例(包括6例HNPCC和49例SCRC)验证HNPCC与SCRC部分差异表达基因,筛选并分析与MMR缺陷表型相关的分子标签。
方法：采用实时荧光定量PCR和免疫组化分别从mRNA和蛋白水平检测HNPCC和SCRC肿瘤组织中ANPEP/CD13、MTA-2、APCDD1和HEPACAM的表达,分析这四个基因在两组中的表达与基因芯片结果的符合情况,分析它们在具有MMR缺陷表型组与SCRC组之间的差异。
结果：ANPEP/CD13、MTA-2、APCDD1和HEPACAM在基因和蛋白水平的表达与基因芯片结果一致。经统计学分析发现这四个基因在MMR缺陷表型组的表达与在CRC组的表达有明显差异,ANPEP、MTA-2在MMR基因异常组显著上调,APCDD1和HEPACAM在MMR基因异常组显著下调。
结论：ANPEP/CD13、MTA-2、APCDD1和HEPACAM可能与HNPCC发生有关,并可望成为提示MMR缺陷表型的分子标签。
Hereditary nonpolyposis colorectal cancer(HNPCC) is one of the most common autosomal dominantly inherited cancers syndrome, accounts for 2%-15% of all colorectal cancers and the penetrance reach up to 80%-90%. Compare with sporadic colorectal cancer(SCRC), HNPCC shows its own characteristcs associated with the molecular mechanism,clinical features,the methods for treatment and management of HNPCC kindreds. Therefore, to differentiate the HNPCC from SCRC is very important and it will interest not only in the clinic but also in genetic counseling of HNPCC kindreds. Now, many countries and territories have established the clinical diagnostic criteria for HNPCC, such as Amsterdam Criteria and Bethesda Guidelines. The molecular genetics basis of HNPCC was the mutation of mismatch repair gene, which can induce the increasement of misreplications, microsatellites instability and then result in tumorigenesis of many organs.Now, human MMR gene which has been locolized and cloned as hMLH1、hMSH2、hMSH6、hMSH3、hPMS1、hPMS2 and so on were closely associated with HNPCC. The former two account for a large majority of mutations found in HNPCC families from various countries. Previously, We detected germline mutations and large genomic variantions of the entire coding regions of hMSH2lhMLH1/hMSH6 genes and the methylation of hMLHl promoter in 58 HNPCC families fulfilling different cliinical criteria, and the final germline-variation rate of Chinese HNPCC was 53.4%(31/58). It has been reported that the germline mutation of hMSH2, hMLHl and hMSH6 was about 42%-75% in HNPCC families fulfilling different clinical criteria, while the mutation rate of MMR gene in the atypical HNPCC family was likely to less. Some HNPCC families which can found the mutation of MMR gene didn't fulfil any clinical criteria, one the other hand, more than fifty percent suspected HNPCC patients can't found mutation of MMR gene. Therefore, the tumorigenesis of HNPCC must be associated with other disease genes which has not been verified.
With the development of gene chip technic, people can study the gene expression profile on the level of genomewide, and recognize the relationship of the gene expreesion and tumorigenesis, progress and metastasis on a whole level. Many related reseach has been reported on the gene expression profile of breast cancer, lung cancer, protaste cancer, lymphoma SCRC and so on. But the study on the HNPCC gene expression has not been reported up till now.
In this study, we collected 50 HNPCC families fulfilling different clinical criteria, detected the germline mutation and protein expreesion of MLH1 and MSH2, then we devided the 50 samples into two groups:MMR-proficient and MMR-deficient phenome. Secondly, we use the the Human Genome U133A GeneChip array (Affymetrix) to analysis the the gene expreesion of this 50 samples and another 7 SCRC samples. Thirdly, we screen the differential expression gene of the HNPCC and SCRC, MMR-proficient and MMR-deficient phenome, constructed the gene signature of HNPCC and MMR-deficient tumors. Finally, we demonstrated the robustness of the signature by transferring it to a real-time RT-PCR and IHC platform.This two-step classification approach can identify MMR-deficient phenome as well as HNPCC cases merits further gene expression studies to identify prognostic signatures.
The current research project is comprised for the following three parts:
Object:To analyse the expression of hMLH1 and hMSH2 protein in 50 HNPCC probands fulfilling defferent clinical criteria and the germline mutation of hMLHl and hMSH2 gene in 26 probands.
Methods:The peripheral blood was collected from the probands of 26 HNPCC families fulfilling different clinical criterial, of which 7 families fulfilled AC,19 kindreds fit BG. Genomic DNA was extracted following the manafacturer's protocol and used as the template to amplify 35 exons of the 2 genes by PCR. PCR products were purified and used as the template for direct DNA sequencing. The results of sequencing were analysed by different bioanalysis software. To further investigate the pathological effects of detected missense mutations, we analyse the same exon of hPMS2 gene using PCR-based sequencing in 130 healthy persons without family history. IHC envision two step method was performed.
Results:8 germline mutation of hMLHl and hMSH2 was found in 26 HNPCC probands families.4 fulfilled AC and 4 fulfilled BG.17 probands was found to be hMLHl and hMSH2 protein deficient.
Conclusions:The rate of germline mutation and protein expression was 30.8% and 34%. AC are the most sensitve clinical creteria to predict mutations. Immunohistochemical staining are reliable screening method with high predictive value for the detection of mutation. Some suspected HNPCC patients can't found mutation of MMR gene.
Object:To screen the differential genes between HNPCC and SCRC, MMR-proficient and MMR-deficient phenotype.
Methods:Collected the 50 HNPCC probands and 7 SCRC tumor specimen. Labelling of RNA, hybridisation and scanning. Biotin-labelled cRNA was prepared from 10μg of total RNA and hybridised to the Human Genome U133A GeneChip array (Affymetrix). The readings from the quantitative scanning were analysed by SAM and the CapitalBio(?) Molecule Annotation System V4.0.
Results:Results in 425 differential expression genes btween HNPCC and SCRC,445 genes between AC and SCRC,469 between FD and SCRC,153 between BG1 and SCRC,613 between RB and SCRC,662 between RB and SCRC for further analysis.
Conclusions:58 gene was found for further analysis and to accompany the differential genes between HNPCC and SCRC besides MMR gene. A eleven-gene signature was constructed to seperating MMR-proficient and MMR-deficient phenotype.
Object:To demonstrate the differential expression genes between HNPCC and SCRC, screen and preliminary identify molecular signature of MMR-deficient phenotype in 112 cases(included the 57 cases in part 2).
Methods:Tissue section from 28 HNPCC and 28 SCRC patients were examined using real-time quantitative reverse transcription polymerase chain reaction(RQ-RT-PCR) technique for ANPEP, MTA2, APCDD1 and HEPACAM, and immunohistochemistry for the expression of the former three genes. Another 56 cases of HNPCC and SCRC were also used to perform the former three genes immunostaining. Demonstrate the exression of the four genes in different groups.
Results:The expression of ANPEP, MTA2 in HNPCC was significantly higher than in SCRC, while APCDD1, HEPACAM was lower in HNPCC. The results was coincidence with the gene chip. The expression of these four genes was also different between the group of MMR-proficient and MMR-deficient phenotype.
Conclusions:ANPEP, MTA2, APCDD1 and HEPACAM may be a signature capable of separating HNPCC and SCRC as well as MMR-proficient and MMR-deficient phenotype.
随着基因芯片技术的发展,人们可以从全基因组的水平研究基因表达谱的变化,从整体上认识基因表达与肿瘤发生、发展及转移的关系。不少研究者已经运用这一工具对乳腺癌、肺癌、前列腺癌、淋巴瘤及散发性结直肠癌等肿瘤相关的基因表达谱进行了研究,而HNPCC的基因表达谱研究尚未见报道。采用基因表达谱芯片筛选HNPCC差异基因,并对其功能深入研究,是阐明HNPCC发病机制、确立HNPCC特异性诊断标志物和治疗相关的分子靶点的重要手段。
本研究收集50例符合不同临床标准的HNPCC先证者及7例散发性结直肠癌病例,首先对hMSH2/hMLH1胚系基因突变及肿瘤组织相应蛋白表达情况进行检测分析,将HNPCC分为具有MMR缺陷表型组(MLH1和/或MSH2基因突变和/或蛋白表达缺失)和无MMR缺陷表型组；然后应用Affymetrix HG-U133plus2.0寡核苷酸基因芯片技术对50例HNPCC及同期7例散发性结直肠癌肿瘤组织进行了人类全基因组表达谱芯片检测,通过SAM (significance Analysis of Microarray)软件和交集分析,筛选出符合不同临床标准的HNPCC与SCRC、MMR缺陷表型组与SCRC组之间的差异表达基因,分析与SCRC不同的HNPCC基因表达谱特征,确定与MMR缺陷表型密切相关的基因；对显著表达差异的基因采用real-time PCR和免疫组化进行验证,以期发现HNPCC发生可能相关的基因,找到代表MMR缺陷表型的分子标签。
本研究共分为三个部分：
目的：对50例符合不同临床标准的HNPCC家系先证者病理资料进行分析并完成hMSH2、hMLH1蛋白及其中26例基因突变检测。
方法：符合Amsterdam标准家系7个、复旦标准家系9个和Bethesda指导纲要患者34例收入本项临床病理研究。收集家系先证者外周血样本10ml以供提取基因组DNA,以7例同期散发性结直肠癌为对照。利用PCR技术分别扩增2个基因共35个外显子,PCR产物纯化后进行DNA测序,并对测序结果进行分析。免疫组化采用Envision二步法。
结果：在26个HNPCC先证者中共发现8个hMSH2/hMLH1突变,其中符合AC标准的4例(4/8),BG标准4例。50例中蛋白表达缺失17例(16/50),包括已检测到突变的8例。
结论：hMSH2、hMLH1基因突变率及蛋白表达缺失率分别为30.8%和34%；免疫组化检测错配修复蛋白的表达对错配修复基因的突变有很好的初筛作用,Amsterdam标准对预示突变最敏感。仍有一部分符合临床标准的HNPCC患者不能检测到MMR基因的异常。
目的：筛选HNPCC与SCRC、具有MMR缺陷表型组与SCRC组差异基因。
方法：收集第一部分50例HNPCC患者及同期7例SCRC新鲜肿瘤标本,Trizol法提取组织RNA,制备靶标(双链cDNA合成、纯化,体外转录合成生物素标记cRNA、纯化、片段化),利用Affymetrix真核表达谱芯片杂交,清洗染色并扫描；应用SAM等软件对差异基因进行分析,结合MAS等分析工具对筛选基因进行初步的生物学功能分析。
结果：获得HNPCC与SCRC组差异表达基因425个,符合AC组与SCRC组差异表达基因445个,符合复旦推荐标准与SCRC组差异表达基因469个,符合BG组与SCRC组差异基因153个,RB组与SCRC组差异基因613个,MMR缺陷表型组与SCRC组差异表达基因662个(q-value<5%, Fold change≥2)。经统计学分析、文献挖掘及聚类分析结果筛选出HNPCC与SCRC差异基因58个,代表MMR缺陷表型基因11个。
结论：58个基因组成的表达模式代表了HNPCC与SCRC之间MMR基因之外的差异表达基因,具有MMR缺陷表型组与AC组基因表达谱相似,有11个基因可以构成这一表达模式；这些差异表达基因可能在HNPCC的发病中起重要的生物学作用。
目的：收集第二部分57个病例并增加55例(包括6例HNPCC和49例SCRC)验证HNPCC与SCRC部分差异表达基因,筛选并分析与MMR缺陷表型相关的分子标签。
方法：采用实时荧光定量PCR和免疫组化分别从mRNA和蛋白水平检测HNPCC和SCRC肿瘤组织中ANPEP/CD13、MTA-2、APCDD1和HEPACAM的表达,分析这四个基因在两组中的表达与基因芯片结果的符合情况,分析它们在具有MMR缺陷表型组与SCRC组之间的差异。
结果：ANPEP/CD13、MTA-2、APCDD1和HEPACAM在基因和蛋白水平的表达与基因芯片结果一致。经统计学分析发现这四个基因在MMR缺陷表型组的表达与在CRC组的表达有明显差异,ANPEP、MTA-2在MMR基因异常组显著上调,APCDD1和HEPACAM在MMR基因异常组显著下调。
结论：ANPEP/CD13、MTA-2、APCDD1和HEPACAM可能与HNPCC发生有关,并可望成为提示MMR缺陷表型的分子标签。
Hereditary nonpolyposis colorectal cancer(HNPCC) is one of the most common autosomal dominantly inherited cancers syndrome, accounts for 2%-15% of all colorectal cancers and the penetrance reach up to 80%-90%. Compare with sporadic colorectal cancer(SCRC), HNPCC shows its own characteristcs associated with the molecular mechanism,clinical features,the methods for treatment and management of HNPCC kindreds. Therefore, to differentiate the HNPCC from SCRC is very important and it will interest not only in the clinic but also in genetic counseling of HNPCC kindreds. Now, many countries and territories have established the clinical diagnostic criteria for HNPCC, such as Amsterdam Criteria and Bethesda Guidelines. The molecular genetics basis of HNPCC was the mutation of mismatch repair gene, which can induce the increasement of misreplications, microsatellites instability and then result in tumorigenesis of many organs.Now, human MMR gene which has been locolized and cloned as hMLH1、hMSH2、hMSH6、hMSH3、hPMS1、hPMS2 and so on were closely associated with HNPCC. The former two account for a large majority of mutations found in HNPCC families from various countries. Previously, We detected germline mutations and large genomic variantions of the entire coding regions of hMSH2lhMLH1/hMSH6 genes and the methylation of hMLHl promoter in 58 HNPCC families fulfilling different cliinical criteria, and the final germline-variation rate of Chinese HNPCC was 53.4%(31/58). It has been reported that the germline mutation of hMSH2, hMLHl and hMSH6 was about 42%-75% in HNPCC families fulfilling different clinical criteria, while the mutation rate of MMR gene in the atypical HNPCC family was likely to less. Some HNPCC families which can found the mutation of MMR gene didn't fulfil any clinical criteria, one the other hand, more than fifty percent suspected HNPCC patients can't found mutation of MMR gene. Therefore, the tumorigenesis of HNPCC must be associated with other disease genes which has not been verified.
With the development of gene chip technic, people can study the gene expression profile on the level of genomewide, and recognize the relationship of the gene expreesion and tumorigenesis, progress and metastasis on a whole level. Many related reseach has been reported on the gene expression profile of breast cancer, lung cancer, protaste cancer, lymphoma SCRC and so on. But the study on the HNPCC gene expression has not been reported up till now.
In this study, we collected 50 HNPCC families fulfilling different clinical criteria, detected the germline mutation and protein expreesion of MLH1 and MSH2, then we devided the 50 samples into two groups:MMR-proficient and MMR-deficient phenome. Secondly, we use the the Human Genome U133A GeneChip array (Affymetrix) to analysis the the gene expreesion of this 50 samples and another 7 SCRC samples. Thirdly, we screen the differential expression gene of the HNPCC and SCRC, MMR-proficient and MMR-deficient phenome, constructed the gene signature of HNPCC and MMR-deficient tumors. Finally, we demonstrated the robustness of the signature by transferring it to a real-time RT-PCR and IHC platform.This two-step classification approach can identify MMR-deficient phenome as well as HNPCC cases merits further gene expression studies to identify prognostic signatures.
The current research project is comprised for the following three parts:
Object:To analyse the expression of hMLH1 and hMSH2 protein in 50 HNPCC probands fulfilling defferent clinical criteria and the germline mutation of hMLHl and hMSH2 gene in 26 probands.
Methods:The peripheral blood was collected from the probands of 26 HNPCC families fulfilling different clinical criterial, of which 7 families fulfilled AC,19 kindreds fit BG. Genomic DNA was extracted following the manafacturer's protocol and used as the template to amplify 35 exons of the 2 genes by PCR. PCR products were purified and used as the template for direct DNA sequencing. The results of sequencing were analysed by different bioanalysis software. To further investigate the pathological effects of detected missense mutations, we analyse the same exon of hPMS2 gene using PCR-based sequencing in 130 healthy persons without family history. IHC envision two step method was performed.
Results:8 germline mutation of hMLHl and hMSH2 was found in 26 HNPCC probands families.4 fulfilled AC and 4 fulfilled BG.17 probands was found to be hMLHl and hMSH2 protein deficient.
Conclusions:The rate of germline mutation and protein expression was 30.8% and 34%. AC are the most sensitve clinical creteria to predict mutations. Immunohistochemical staining are reliable screening method with high predictive value for the detection of mutation. Some suspected HNPCC patients can't found mutation of MMR gene.
Object:To screen the differential genes between HNPCC and SCRC, MMR-proficient and MMR-deficient phenotype.
Methods:Collected the 50 HNPCC probands and 7 SCRC tumor specimen. Labelling of RNA, hybridisation and scanning. Biotin-labelled cRNA was prepared from 10μg of total RNA and hybridised to the Human Genome U133A GeneChip array (Affymetrix). The readings from the quantitative scanning were analysed by SAM and the CapitalBio(?) Molecule Annotation System V4.0.
Results:Results in 425 differential expression genes btween HNPCC and SCRC,445 genes between AC and SCRC,469 between FD and SCRC,153 between BG1 and SCRC,613 between RB and SCRC,662 between RB and SCRC for further analysis.
Conclusions:58 gene was found for further analysis and to accompany the differential genes between HNPCC and SCRC besides MMR gene. A eleven-gene signature was constructed to seperating MMR-proficient and MMR-deficient phenotype.
Object:To demonstrate the differential expression genes between HNPCC and SCRC, screen and preliminary identify molecular signature of MMR-deficient phenotype in 112 cases(included the 57 cases in part 2).
Methods:Tissue section from 28 HNPCC and 28 SCRC patients were examined using real-time quantitative reverse transcription polymerase chain reaction(RQ-RT-PCR) technique for ANPEP, MTA2, APCDD1 and HEPACAM, and immunohistochemistry for the expression of the former three genes. Another 56 cases of HNPCC and SCRC were also used to perform the former three genes immunostaining. Demonstrate the exression of the four genes in different groups.
Results:The expression of ANPEP, MTA2 in HNPCC was significantly higher than in SCRC, while APCDD1, HEPACAM was lower in HNPCC. The results was coincidence with the gene chip. The expression of these four genes was also different between the group of MMR-proficient and MMR-deficient phenotype.
Conclusions:ANPEP, MTA2, APCDD1 and HEPACAM may be a signature capable of separating HNPCC and SCRC as well as MMR-proficient and MMR-deficient phenotype.
引文
[1]Jarvinen HJ, Aarnio M, Mustonen H, et al. Controlled 15-year trial on screening for colorectal cancer in families with hereditary nonpolyposis colorectal cancer. Gastroenterology 118:829-834,2000
[2]Lindor NM, Rabe K, Petersen GM, et al.Lower cancer incidence in Amsterdam-Ⅰ criteria families without mismatch repair deficiency:familial colorectal cancer type Ⅹ[J]. JAMA,2005,293:1979-985.
[3]顾国利,周晓武,王石林.遗传性非息肉病性大肠癌的研究进展[J].世界华人消化杂志,2007；15：3115-3121
[4]Yan SY, Zhou XY, Du X, et al. Three novel missense germline mutations in different exons of MSH6 gene in Chinese hereditary non-polyposis colorectal cancer families[J]. World J Gastroenterol 2007; 13:5021-5024
[5]Zhou HH, Yan SY, Zhou XY, et al. MLH1 promoter germline-methylation in selected probands of Chinese hereditary non-polyposis colorectal cancer families[J]. World J Gastroenterol 2008;14:7329-7334
[6]Cai Q, Sun MH, Fu G,, et al. Mutation analysis of hMSH2 and hMLH1 genes in Chinese hereditary nonpolyposis colorectal cancer families[J]. Zhonghua Binglixue Zazhi 2003; 32:323-328
[7]Wang CF, Zhou XY, Zhang TM,, et al. The analysis for mRNA mutation of MLH1, MSH2 genes and the gene diagnosis for hereditary nonpolyposis colorectal cancer. Zhonghua Yixue Yichuanxue Zazhi 2006; 23:32-36
[8]Wang CF, Zhou XY, Zhang TM,, et al. Detection of germline mutations of hMLH1 and hMSH2 based on cDNA sequencing in China. World J Gastroenterol 2005; 11:6620-6623
[9]Stormorken AT, Bowitz-Lothe IM, Noren T, et al. Immunohistochemistry identifies carriers of mismatch repair gene defects causing hereditary nonpolyposis colorectal Cancer[J]. J Clin Oncol.2005;23:4705-4712
[10]Southey MC, Jenkins MA, Mead L, et al. Use of molecular tumor characteristics to prioritize mismatch repair gene testing in early-onset colorectal cancer[J]. J Clin Oncol.2005;23:6524-6532
[11]Barnetson RA, Tenesa A, Farrington SM, et al. Identification and survival of carriers of mutations in DNA mismatch-repair genes in colon cancer[J]. N Engl J Med. 2006;354:2751-2763
[12]Niessen RC, Berends MJ, Wu Y, et al. Identification of mismatch repair gene mutations in young patients with and patients with multiple HNPCC-associated tumours[J]. Gut.2006;55:1781-1788
[13]Heinen CD, Schmutte C, Fishel R. DNA repair and tumorigenesis Lessons from hereditary cancer syndromes[J]. Cancer Biol Ther,2002,1:477-485
[14]蔡崎,孙孟红,陆洪芬,等.中国人遗传性非息肉病性结直肠癌错配修复缺陷表型分析[J].中华肿瘤杂志,2003,25：420-424
[15]Lindor NM, Burgart LJ, Leontovich O, et al. Immmunohistochemistry versus microsatellite instability testing in phenotyping colorectal tumors[J].Clin Oncol,2002, 20:1043-1048
[16]Cawkwell L, Gray S, Murgatroyd H, et al. Choice of management strategy for colorectal cancer based on a diagnostic immunohistoehemical test for defective mismatch repair Gut[J].1999,45:409-415
[17]Lindor NM, Burgart LJ, Leontovich O, et al. Immunohistochemistry versus microsatellite instability testing in phenotyping colorectal tumors[J]. J Clin Oncol 20:1043-1048,2002
[18]Grady W. Genomic instability and colon cancer[J]. Cancer Metastasis Rev, 2004,23:11-27
[19]Kadiyska TK, Kaneva RP, Nedin DQet al. Novel MLH1 frameshift mutation in an extended hereditary nonpolyposis colorectal cancer family[J]. World J Gastroenterol,2006; 12:7848-7851
[20]Liu SR, Zhao B, Wang ZJ, et al. Clinical features and mismatch repair gene mutation screening in Chinese patients with hereditary nonpolyposis colorectal carcinoma[J]. World J Gastroenterol,2004; 10:2647-2651
[21]Wahlberg SS, Schmeits J, Thomas G, et al. Evaluation of microsatellite instability and immunohistochemistry for the prediction of germ-line MSH2 and MLH1 mutations in hereditary nonpolyposis colon cancer families[J]. Cancer Res, 2002,62:3485-3492,
[22]Peltomaki P:Role of DNA mismatch repair defects in the pathogenesis of human cancer[J]. J Clin Oncol,2003,21:1174-1179,
[23]陶雅军,陈英杰,刘健.微卫星DNA不稳定性与遗传性非息肉病性大肠癌的相关性研究[J].实用医学杂志,2005；21：2157-2158
[24]顾国利,魏学明,任力,等.TβRⅡ,MMP-7, TIMP-2表达及在HNPCC侵袭转移中的作用[J].世界华人消化杂志,2007；15：1103-1109
[25]Montgomery E, Goggins M, Zhou S, et al. Nuclear localization of Dpc4 (Madh4, Smad4) in colorectal carcinomas and relation to mismatch repair/transforming growth factor-beta receptor defects[J]. Am J Pathol,2001; 158:537-542
[26]Kuismanen SA, Moisio AL, Schweizer P,et al. Endometrial and colorectal tumors from patients with hereditary nonpolyposis colon cancer display different patterns of microsatellite instability [J]. Am J Pathol,2002; 160:1953-1958
[27]Benachenhou N, Guiral S, Gorska-Flipot I, et al. Allelic losses and DNA methylation at DNA mismatch repair loci in sporadic colorectal cancer[J]. Carcinogenesis,1998; 19:1925-1929
[28]Knudsen NO, Nielsen FC, Vinther L, et al. Nuclear localization of human DNA mismatch repair protein exonuclease 1 (hEXO1) [J]. Nucleic Acids Res,2007; 35: 2609-2619
[29]Kim JC, Lee KH, Ka IH,et al. Characterization of mutator phenotype in familial colorectal cancer patients not fulfilling amsterdam criteria[J]. Clin Cancer Res 2004; 10:6159-6168
[30]Botand CR, Koi M,Chang DK, et al. The biochemical basis of microsatellite instability and abnormal immunohistochemistry and clinical behavior in Lynch syndrome:from bench to bedside[J]. FamCancer,2008,7:41-52.
[31]Martinez-Bouzas C, Beristain E, Ojembarrena E, et al. A study on MSH2 and MLH1 mutations in hereditary nonpolyposis colorectal cancer families from the Basque Country, describing four new germline mutations.[J]. Fam Cancer.2009,8: 533-539
[32]Shia J, Klimstra DS, Nafa K, et al. Value of immunohistochemical detection of DNA mismatch repair proteins in predicting germline mutation in hereditary colorectal neoplasms. AmJ Surg Pathol,2005,29:96-104
[33]蔡三军,徐烨,陆洪芬,等.hMLH1和hMSH2蛋白表达在遗传性非息肉病性大肠癌诊断中的应用.中华消化杂志,2004,24：143-146
[34]Lipton LR., Johnson V, Cumming C, et al..Refining the Amsterdam Criteria and Bethesda Guidelines:Testing Algorithms for the Prediction of Mismatch Repair Mutation Status in the Familial Cancer Clinic[J]. J Clin Oncol,2004,22:4934-4942
[35]徐烨,蔡三军,孙孟红,等.检测微卫星不稳在中国遗传性非息肉病性结直肠癌患者诊断中的应用[J].中国癌症杂志,2006,16：128-131
[36]Cai Q, Sun MH,Lu HF, et al. Clinicopathological and molecular genetic analysis of 4 typical Chinese HNPCC families[J]. World J Gastroenterol,2001, 7:805-810.
[37]Wang CF, Zhou XY, Zhang TM,et al. Two novel germline mutations of MLH1 and investigation of their pathobiology in hereditary non-polyposis colorectal cancer families in China[J]. World J Gastroenterol,2007;13:6254-6258
[38]Wu Y, Berends MJ, Sijmons RH, et al. A role for MLH3 in hereditary nonpolyposis colorectal cancer[J]. Nat Genet 2002;29:137-138
[39]Bronner CE, Baker SM, Morrision PT, et al.Mutation in the DNA mismatch repair gene homologue hMLH 1 is associated with hereditary non-polyposis colon cancer[J]. Nature,1994,368:258-261
[40]Liu B, Parsons R, Papadopoulos N, et al. Analysis of mismatch repair genes in hereditary non-polyposis colorectal cancer patients[J]. Nature Medicine,1996, 2:169-174
[41]Lipton LR, Johnson V, Cummings C, et al. Refining the Amsterdam Criteria and Bethesda Guidelines:Testing Algorithms for the Prediction of Mismatch Repair Mutation Status in the Familial Cancer Clinic[J].J Clin Oncolo,2004,24:4934-4943
[42]Chaves P, Cruz C, Lage P, et al. Immunohistochemical detection of mismatch repair gene proteins as a useful tool for the identification of colorectal carcinoma with the mutator phenotype[J]. J pathol,2000,191:355-360
[43]Chao EC, Lipkin SM.Molecular models for the tissue specificity of DNA mismatch repair-deficient carcinogenesis[J]. Nucleic Acids Research,2006, 34:840-852
[44]Woerner SM, Kloor M, Doeberitz MK, et al.Microsatellite instability in the development of DNA mismatch repair deficient tumors[J]. Cancer Biomarkers,2006,2:69-86
[45]Imai K, Yamamoto H.Carcinogenesis and microsatellite instability:the interrelationship between genetics and epigenetics[J]. Carcinogenesis,2008, 29:673-680
[46]张英辉,盛剑秋,耿洪刚,等.遗传性非息肉病性结直肠癌中环氧合酶2的表达及与错配修复基因表达和微卫星不稳定的相关性[J].中华医学杂志,2009,89：1377-1381
[47]Bonis PA, Trikalinos TA, Chung M, et al. Hereditary nonpolyposis colorectal cancendiagnostic strategies and their implications[J]. Evid Rep Tachnol Assess(Full Rep),2007,150:1-180
[48]Zhang L. Immunohistochemistry versus microsatellite instability testing for screening colorectal cancer patients at risk for hereditary nonpolyposis colorectal cancer syndrome. Part Ⅱ. The utility of microsatellite instability testing[J]. J Mol Diagn,2008,10:301-307.
[49]Tusher VG, Tibshirani R, Chu G. Significance analysis of microarrays[J]. PNAS. 2001,410:511,625,121.
[50]Bittner M, Meltzer P, Chen Y, et al. Molecular classification of cutaneous malignant melanoma by gene expression profiling[J].Nature.2000,406:536-540.
[51]Garber ME, Troyanskaya OG, Schlunens K, et al.Diversity of gene expression in adenocarcinoma of the lung[J]. PNAS,2001,98:13784-13789.
[52]Liotta, L.A, Kohn, E.C. Cancer's deadly signature[J].Nat Genet.2003,33:10-11.
[53]Notterman DA, Alon U, Sierk AJ, et al. Transcriptional gene expression profiles of colorectal adenoma, adenoeareinoma, and normal tissue examined by oligonueleotide arrays[J].Cancer Res.2001,61:3124-3130.
[54]Kitahara O, Furukawa Y, Tanaka T, et al. Alterations of gene expression during colorecta] carcinogenesis revealed by cDNA microarrays after laser-capture microdisseetion of tumor tissues and normal epithelia[J].Cancer Res,2001,61: 3544-3549
[55]Forte A, Sanctis RD, Leonetti G, et al. Dietary chemoprevention of colorectal cancer[J]. Ann Ital Chir,2008,79:261-267
[56]Marshall, JR.Prevention of colorectal cancer:diet,chemoprevention,and life style[J]. Gastroenterol Clin North Am,2008,37:73-82
[57]Larsson SC, Giovannucci E, Bergkvist L, et al. Whole grain consumption and risk of colorectal cancer: a population-based cohort of 60,000 women[J]. Br J Cancer,2005,92:1803-1807.
[58]Kruh(?)ffer M, Jensen JL, Laiho P, et al. Gene expression signatures for colorectal cancer microsatellite status and HNPCC[J].Br J Cancer,2005,92:2240-2248
[59]Segal E.Friedman N, Koller D, et al. A module map showing conditional activity of expression modules in cancer[J].Nat Genet.2004,36:1090-1098.
[60]Segal E, Shapira M, Regev A, et al. Module networks:identifying regulatory modules and their condition-specific regulators from gene expression data[J]. Nat Genet,2003,34,166-176.
[61]周斌,周总光,夏庆杰,等APCDD1在直肠癌及结直肠腺瘤中的定量表达[J].中华实验外科杂志,2006,23：1351-1352
[62]Moh MC, Zhang T, Lee Zl, et al.Expression of hepaCAM is downregulated in cancers and induces senescence-like growth arrest via a p53/p21-dependent pathway in human breast cancer cells.Carcinogenesis,2008,29:2298-2305
[63]Livak KJ, Schmittgvn TD. Analysis of relative gene expression data using real time quantitative PCR and the 2-ΔΔCT mcthod[J]. Methods,2001,25:402-408
[64]Kehlen A, Lendeckel U, Dralle H, et al. Biological Significance of Aminopeptidase N/CD13 in Thyroid Carcinomas[J]. Cancer res,2003,63:8500-8506
[65]Tokuhara T, Hattori N, Ishida H, et al.Clinical Significance of Aminopeptidase Nin Non SmallCell Lung Cancer[J].Clin Cancer Res,2006,12:3971-3977
[66]Ikeda N, Nakajima Y, Tokuhara T, et al. Clinical significance of aminopeptidase N/CD13 expression in human pancreatic carcinoma[J]. Clin Cancer Res,2003,9:1503-1508
[67]Wiese AH, Auer J, Lassmann S, et al. Identification of gene signatures for invasive colorectal tumor cells[J]. Cancer Detection and Prevention, 2007,31:282-295
[68]Zhang Y, Ng H H, Erdjument-Bromage H, et al. Analysis of the NuRD subunits reveals a histone deacetylase complex and a connection with DNA methylation[J]. Genes,1999,13:1924-1935
[69]Cui Y, Niu A, Pestell R, et al.Metastasis-associated protein 2 is a repressor of estrogen receptor a whose overexpressionleads toestrogen-independent growth of human breast cancer cells[J]. Molecular Endocrinology,2006,20:2020-2035
[70]Ji YX, Zhang P, Lu YP, et al. Expression of MTA2 gene in ovarian epithelial cancer and its clinical implication[J]. J Huazhong University of Science and Technology[Med Sci],2006,26:359-362
[71]Lee H, Ryu SH, Hong SS, et al.Overexpression of metastasis-associated protein 2 is associated with hepatocellular carcinoma size and differentiation [J]. J of Gastroenterology and Hepatology,2009,24:1445-1450
[72]Takahashi M, Fujita M, Furukana Y, et al. Isolation of a novel human gene,APCDD1, as a direct target of the D·Catenin/T-Cell factor 4 corn-plex with probable involvement in colorectal carcinogenesis. Cancer Research,2002,62: 5651-5656
[73]Moh MC, Lee LH, Shen S.Cloning and characterization of hepaCAM, a novel Ig-like cell adhesion molecule suppressed in human hepatocellular carcinoma[J].J of Hepatology,2005,42:833-841
[74]Moh MC, Zhang T, Lee LH, et al.Expression of hepaCAM is downregulated in cancers and induces senescence-like growth arrest via a p53/p21-dependent pathway in human breast cancer cells[J].Caiciogenesis,2008,29:2298-2305
[75]He YF, Wu XH, Luo CL, et al. Functional significance of the hepaCam gene in bladder cancer[J]. BMC cancer,2010,10:83
[76]Hsieh P, Yamane K. DNA mismatch repair:Molecular mechanism, cancer, and ageing[J]. Mech Ageing Dev,2008; 129:391-407
[77]Grady W. Genomic instability and colon cancer[J]. Cancer Metastasis Rev,2004, 23:11-27.
[78]Xu YF, Pasche B. TGF-β signaling alterations and susceptibility to colorectal cancer[J]. Human Molecular Genetics,2007,16:R14-R20
[79]Miyaki M, Yamaguchi T, Lijima T, et al. Somatic Mutations of the CDC4 (FBXW7) Gene in Hereditary Colorectal Tumors[J]. Oncology 2009;76:430-434
[80]Johnson V, Volikos E, Halford SE, et al. Exon 3 β-catenin mutations are specifically associated with colorectal carcinomas in hereditary non-polyposis colorectal cancer syndrome[J]. Gut 2005;54:264-267
[81]Van't Veer, L.J, Dai H, Vijver MJ, et al.Gene expression profiling predicts clinical outeome of breast cancer[J].Nature.2002,415:530-536
[1]Cunningham C, Dunlop MG. Molecular genetic basis of colorectal cancer Susceptibility[J]. Br J Sueg,1996,83:321-329.
[2]Liu T, Wahlberg S, Burek E, et al. Microsatellite instability as a predictor of a mutation in a DNA mismatch repair gene in familial colorectal cancer[J]. Genes Chromosomes Cancer,2000,27:17-25
[3]Debniak T, Kurzaawski G, Gorski B, et al. Value of pedigree/clinicaldata, imm unohistochenistry and microsatellite instability analyses in reducing the cost of determ ining hMLHl and hMSH2 gene mutations in patients with colorectal cancer[J]. Eur J Cancer,2000,36:49-54
[4]D'Emilia JC, Rodriguez-Bigas MA, Petrelli NJ. The clinical and genetic manifestations of hereditary nonpolyposis coloectal carcinoma[J]. Am J Surg,1995, 169:368-372
[5]SHEN XS, ZHAO B, WANG ZJ. Clinical features and hMSH2/hMLH1 germ-line mutations in Chinese patients with hereditary nonpolyposis colorectal cancer[J]. Chin Med J 2008;121:1265-1268
[6]Pehomaki PT. Genetic basis of hereditary nonpo lyposis colorectal carcinoma(HNPCC) [J]. Ann Med.1994,26:215-219
[7]Fishel R, Lescoe MK, Rao MR, et al. The human mutator gene homolog MSH2 and its association with hereditary nonpolyposis colon cancer[J]. Cell,1993, 75:1027-1038
[8]Hadziavdic V, Pavlovic-Calic N, Eminovic I. Molecular analysis:microsatellity instability and loss of heterozygosity of tumor suppressor gene in hereditary non-polyposis colorectal cancers (HNPCC) [J]..Bosn J Basic Med Sci,2009,9:10-18
[9]Aarnio M, Sankila R, Pukkala E, et al. Cancer risk in mutation carriers of DNA-mismatch-repair genes[J].. Int J Cancer,1999,81:214-218
[10]Millar AL, Pal T, Madlensky L, et al. Mismatch repair gene defects contribute to the genetic basis of double primary cancers of the colorectum and endometrium[J]. Hum Mol Genet,1999,8:823-829.
[11]Drotschmann K, Clark AB, Tran HT, et al. Mutator phenotypes of yeast strains heterozygous for mutations in the MSH2 gene[J]. Proc Natl Acad Sci USA,1999,96: 2970-2975.
[12]Watson P, Lynch HT. Cancer risk in mismatch repair gene mutation carriers[J]. Familial Cancer,2001,24:57-60.
[13]Jacob S, Praz F. DNA mismatch repair defeets:role in colorectal carcinogenesis [J]. Bioehimie,2002,84:27-47
[14]Mitchell Iu, Farrington SM, Dunlop MG, et al. Mismatch repair genes hMLH1 and hMSH2 and colorectal cancer:a HuGE review[J]. Am J Epidemiol,2002,156: 885-902.
[15]Chan TL, Chan YW, Ho JW, et al. MSH2 c1452-1455delAATG is a founder mutation and an important cause of hereditary nonpolyposis colorectal cancer in the southern chinese population[J]. Am J Hum Genet,2004,74:1035-1042
[16]Hitchins M, Williams R, Cheong K, et al. MLH1 germline epimutations as a factor in hereditary nonpolyposis colorectal cancer[J]. Gastroenterology, 2005;129:1392-9
[17]Wagner A, Hendriks Y, Meije-Heijboer EJ, et al. Atypical HNPCC owing toMSH6 germlinemutations:analysis of a large Dutch pedigree[J]. J Med Genet,2001, 38:18-322
[18]Rey JM, Noruzinia M, Brouillet JP, et al. Six novel heterozygous MLH1, MSH2, and MSH6 and one homozygous MLH1 germline mutations in hereditary nonpolyposis colorectal cancer[J]. Cancer Genet Cytogenet,2004; 155:149-51
[19]颜士岩,周晓燕,蔡三军,等.中国人遗传性非息肉病性结直肠癌MSH6基因胚系突变的测序研究[J].中华医学遗传学杂志,2007,24：640-645
[20]Aaltonen L A, Peltomaki P, Mecklin P G, et al. Replication errors in benign and malignant tumors from hereditary nonpolyposis colorectal cancer patients[J]. Cancer Res,1994,54:1645-1648
[21]刘文志,尹家俊,王亚东,等.中国北方人HN PCC微卫星不稳定性的研究[J]. 中华肿瘤防治杂志,2007,14：1527-1530
[22]Sheng JQ, Zhang H, Ji M,et al. Genetic diagnosis strategy of hereditary non-polyposis colorectal cancer[J]. World J Gastroenterol 2009; 15:983-989
[23]Bianchi F, Galizia E, Catalani R, et al. CAT25 is a mononucleotide marker to identify HNPCC patients[J]. J Mol Diagn,2009;11:248-52
[24]Shin KH, Shin J H, Kim JH, et al. Mutational analysis of promoters of mismatch repair genes hMSH2 and hMLH1 in hereditary nonpolyposis colorectal cancer and early onset colorectal cancer patients:identification of three novel ge rm-line mutations in promoter of the hMSH2 gene[J]. Cancer Res,2002,62:38-42
[25]Xinafianos G, Liloglou T, Prime W, et al. hMLHl an d hMSH2 Expression Correlates with Allelie Imbalance on Chromosome 3p in Non Small Cell Lung Carcinomas[J]. Cancer Research,2000,60:4216-4221
[26]金黑鹰,崔龙,高军孟,等.hMLH1/hMSH2基因启动子变异在遗传性非息肉病性结直肠癌发生中的作用[J].中华胃肠外科杂志,2003,6：243-246
[27]Zhou HH, Yan SY, Zhou XY,et al. MLH1 promoter germline-methylation in selected probands of Chinese hereditary non-polyposis colorectal cancer families[J]. World J Gastroenterol 2008; 14:7329-7334
[28]Scherer SJ, Welter C, Zang KD, et al. Specific in vitro binding of p53 to the promoter region of the human mis match repair gene hMSH2[J]. Biochem Biophys Res Comnun,1996,221:722-728
[29]程慧玉,金黑鹰,崔龙,等.p53基因的变异在遗传性非息肉病性结直肠癌发病中的作用[J].外科理论与实践,2004,9：212-214
[30]Togo G,Okamoto M,Shiratori Y,et al. Does Mutation of Transforming Growth Factor-β Type Ⅱ Receptor Gene Play an important Role in Colorectal Polyps[J]? Digestive Diseases and Sciences,19999:1803-1809
[31]张宏,盛剑秋,李世荣,等.hEXO1基因突变与中国人遗传性非息肉病性结直肠癌的相关性[J].胃肠病学和肝病学杂志,2006,1：95-97
[32]Kariola R,Abdel-Rahman WM, Ollikainen M et al. APC and β-catenin protein expression patterns in HNPCC-related endometrial and colorectal cancers[J]. Familial Cancer,2005,4:187-190
[33]Johnson V, Volikos E, Halford SE, et al. Exon 3 beta-catenin mutations are specifically associated with colorectal carcinomas in hereditary non-polyposis colorectal cancer syndrome[J]. Gut,2005;54:264-267
[34]Bian Y, Caldes T, Wijnen J, Franken P,et al. TGFBR1*6A may contribute to hereditary colorectal cancer[J]. J Clin Oncol.2005;23:3074-3078
[35]Wasielewski M, Vasen H, Wijnen J,et al. CHEK2 1100delC is a susceptibility allele for HNPCC-related colorectal cancer[J]. Clin Cancer Res,2008; 14:4989-4894
[36]Zecevic M, Amos CI, Gu X, et al. IGF1 gene polymorphism and risk for hereditary nonpolyposis colorectal cancer[J]. J Natl Cancer Inst,2006;98:139-143
[37]Reeves SG, Rich D, Meldrum CJ, et al. IGF1 is a modifier of disease risk in hereditary non-polyposis colorectal cancer[J]. Int J Cancer.2008;123:1339-1343
[38]Miyaki M,Yamaguchi T,Iijima T,et al. Somatic mutations of the CDC4 (FBXW7) gene in hereditary colorectal tumors[J]. Oncology,2009;76:430-434
[39]Shi Z, Johnstone D, Talseth-Palmer BA, et al. Haemochromatosis HFE gene polymorphisms as potential modifiers of hereditary nonpolyposis colorectal cancer risk and onset age[J]. Int J Cancer.2009, 1;125:78-83
[40]McGivern A, Wynter CV, Whitehall VL, et al. Promoter hypermethylation frequency and BRAF mutations distinguish hereditary non-polyposis colon cancer from sporadic MSI-H colon cancer[J]. Fam Cancer.2004;3:101-107
[41]Huang J, Zheng S, Jin SH, Zhang SZ. Somatic mutations of APC gene in carcinomas from hereditary non-polyposis colorectal cancer patients[J]. World J Gastroenterol,2004; 10:834-836
[42]Yamamoto H, Min Y, Itoh F, et al. Differential involvement of the hypermethylator phenotype in hereditary and sporadic colorectal cancerswith high-frequencymicrosatellite instability[J]. Genes Chromosomes Cancer,2002; 33: 322-325
[43]Lynch HT, Lynch JF. Hereditary nonpolyposis colorectal cancer[J]. Semin Surg Oncol,2000,18:305-313
[44]Sheng JQ, Zhang H, Ji M,et al. Genetic diagnosis strategy of hereditary non-polyposis colorectal cance[J]. World J Gastroenterol 2009; 15:983-989
[45]Deng G, Peng E, Gum J, et al. Methylation of hMLHl promoter correlates with the gene silencing with a region-specific manner in colorectal cancer[J]. Br J Cancer 2002; 86:574-579
[2]Lindor NM, Rabe K, Petersen GM, et al.Lower cancer incidence in Amsterdam-Ⅰ criteria families without mismatch repair deficiency:familial colorectal cancer type Ⅹ[J]. JAMA,2005,293:1979-985.
[3]顾国利,周晓武,王石林.遗传性非息肉病性大肠癌的研究进展[J].世界华人消化杂志,2007；15：3115-3121
[4]Yan SY, Zhou XY, Du X, et al. Three novel missense germline mutations in different exons of MSH6 gene in Chinese hereditary non-polyposis colorectal cancer families[J]. World J Gastroenterol 2007; 13:5021-5024
[5]Zhou HH, Yan SY, Zhou XY, et al. MLH1 promoter germline-methylation in selected probands of Chinese hereditary non-polyposis colorectal cancer families[J]. World J Gastroenterol 2008;14:7329-7334
[6]Cai Q, Sun MH, Fu G,, et al. Mutation analysis of hMSH2 and hMLH1 genes in Chinese hereditary nonpolyposis colorectal cancer families[J]. Zhonghua Binglixue Zazhi 2003; 32:323-328
[7]Wang CF, Zhou XY, Zhang TM,, et al. The analysis for mRNA mutation of MLH1, MSH2 genes and the gene diagnosis for hereditary nonpolyposis colorectal cancer. Zhonghua Yixue Yichuanxue Zazhi 2006; 23:32-36
[8]Wang CF, Zhou XY, Zhang TM,, et al. Detection of germline mutations of hMLH1 and hMSH2 based on cDNA sequencing in China. World J Gastroenterol 2005; 11:6620-6623
[9]Stormorken AT, Bowitz-Lothe IM, Noren T, et al. Immunohistochemistry identifies carriers of mismatch repair gene defects causing hereditary nonpolyposis colorectal Cancer[J]. J Clin Oncol.2005;23:4705-4712
[10]Southey MC, Jenkins MA, Mead L, et al. Use of molecular tumor characteristics to prioritize mismatch repair gene testing in early-onset colorectal cancer[J]. J Clin Oncol.2005;23:6524-6532
[11]Barnetson RA, Tenesa A, Farrington SM, et al. Identification and survival of carriers of mutations in DNA mismatch-repair genes in colon cancer[J]. N Engl J Med. 2006;354:2751-2763
[12]Niessen RC, Berends MJ, Wu Y, et al. Identification of mismatch repair gene mutations in young patients with and patients with multiple HNPCC-associated tumours[J]. Gut.2006;55:1781-1788
[13]Heinen CD, Schmutte C, Fishel R. DNA repair and tumorigenesis Lessons from hereditary cancer syndromes[J]. Cancer Biol Ther,2002,1:477-485
[14]蔡崎,孙孟红,陆洪芬,等.中国人遗传性非息肉病性结直肠癌错配修复缺陷表型分析[J].中华肿瘤杂志,2003,25：420-424
[15]Lindor NM, Burgart LJ, Leontovich O, et al. Immmunohistochemistry versus microsatellite instability testing in phenotyping colorectal tumors[J].Clin Oncol,2002, 20:1043-1048
[16]Cawkwell L, Gray S, Murgatroyd H, et al. Choice of management strategy for colorectal cancer based on a diagnostic immunohistoehemical test for defective mismatch repair Gut[J].1999,45:409-415
[17]Lindor NM, Burgart LJ, Leontovich O, et al. Immunohistochemistry versus microsatellite instability testing in phenotyping colorectal tumors[J]. J Clin Oncol 20:1043-1048,2002
[18]Grady W. Genomic instability and colon cancer[J]. Cancer Metastasis Rev, 2004,23:11-27
[19]Kadiyska TK, Kaneva RP, Nedin DQet al. Novel MLH1 frameshift mutation in an extended hereditary nonpolyposis colorectal cancer family[J]. World J Gastroenterol,2006; 12:7848-7851
[20]Liu SR, Zhao B, Wang ZJ, et al. Clinical features and mismatch repair gene mutation screening in Chinese patients with hereditary nonpolyposis colorectal carcinoma[J]. World J Gastroenterol,2004; 10:2647-2651
[21]Wahlberg SS, Schmeits J, Thomas G, et al. Evaluation of microsatellite instability and immunohistochemistry for the prediction of germ-line MSH2 and MLH1 mutations in hereditary nonpolyposis colon cancer families[J]. Cancer Res, 2002,62:3485-3492,
[22]Peltomaki P:Role of DNA mismatch repair defects in the pathogenesis of human cancer[J]. J Clin Oncol,2003,21:1174-1179,
[23]陶雅军,陈英杰,刘健.微卫星DNA不稳定性与遗传性非息肉病性大肠癌的相关性研究[J].实用医学杂志,2005；21：2157-2158
[24]顾国利,魏学明,任力,等.TβRⅡ,MMP-7, TIMP-2表达及在HNPCC侵袭转移中的作用[J].世界华人消化杂志,2007；15：1103-1109
[25]Montgomery E, Goggins M, Zhou S, et al. Nuclear localization of Dpc4 (Madh4, Smad4) in colorectal carcinomas and relation to mismatch repair/transforming growth factor-beta receptor defects[J]. Am J Pathol,2001; 158:537-542
[26]Kuismanen SA, Moisio AL, Schweizer P,et al. Endometrial and colorectal tumors from patients with hereditary nonpolyposis colon cancer display different patterns of microsatellite instability [J]. Am J Pathol,2002; 160:1953-1958
[27]Benachenhou N, Guiral S, Gorska-Flipot I, et al. Allelic losses and DNA methylation at DNA mismatch repair loci in sporadic colorectal cancer[J]. Carcinogenesis,1998; 19:1925-1929
[28]Knudsen NO, Nielsen FC, Vinther L, et al. Nuclear localization of human DNA mismatch repair protein exonuclease 1 (hEXO1) [J]. Nucleic Acids Res,2007; 35: 2609-2619
[29]Kim JC, Lee KH, Ka IH,et al. Characterization of mutator phenotype in familial colorectal cancer patients not fulfilling amsterdam criteria[J]. Clin Cancer Res 2004; 10:6159-6168
[30]Botand CR, Koi M,Chang DK, et al. The biochemical basis of microsatellite instability and abnormal immunohistochemistry and clinical behavior in Lynch syndrome:from bench to bedside[J]. FamCancer,2008,7:41-52.
[31]Martinez-Bouzas C, Beristain E, Ojembarrena E, et al. A study on MSH2 and MLH1 mutations in hereditary nonpolyposis colorectal cancer families from the Basque Country, describing four new germline mutations.[J]. Fam Cancer.2009,8: 533-539
[32]Shia J, Klimstra DS, Nafa K, et al. Value of immunohistochemical detection of DNA mismatch repair proteins in predicting germline mutation in hereditary colorectal neoplasms. AmJ Surg Pathol,2005,29:96-104
[33]蔡三军,徐烨,陆洪芬,等.hMLH1和hMSH2蛋白表达在遗传性非息肉病性大肠癌诊断中的应用.中华消化杂志,2004,24：143-146
[34]Lipton LR., Johnson V, Cumming C, et al..Refining the Amsterdam Criteria and Bethesda Guidelines:Testing Algorithms for the Prediction of Mismatch Repair Mutation Status in the Familial Cancer Clinic[J]. J Clin Oncol,2004,22:4934-4942
[35]徐烨,蔡三军,孙孟红,等.检测微卫星不稳在中国遗传性非息肉病性结直肠癌患者诊断中的应用[J].中国癌症杂志,2006,16：128-131
[36]Cai Q, Sun MH,Lu HF, et al. Clinicopathological and molecular genetic analysis of 4 typical Chinese HNPCC families[J]. World J Gastroenterol,2001, 7:805-810.
[37]Wang CF, Zhou XY, Zhang TM,et al. Two novel germline mutations of MLH1 and investigation of their pathobiology in hereditary non-polyposis colorectal cancer families in China[J]. World J Gastroenterol,2007;13:6254-6258
[38]Wu Y, Berends MJ, Sijmons RH, et al. A role for MLH3 in hereditary nonpolyposis colorectal cancer[J]. Nat Genet 2002;29:137-138
[39]Bronner CE, Baker SM, Morrision PT, et al.Mutation in the DNA mismatch repair gene homologue hMLH 1 is associated with hereditary non-polyposis colon cancer[J]. Nature,1994,368:258-261
[40]Liu B, Parsons R, Papadopoulos N, et al. Analysis of mismatch repair genes in hereditary non-polyposis colorectal cancer patients[J]. Nature Medicine,1996, 2:169-174
[41]Lipton LR, Johnson V, Cummings C, et al. Refining the Amsterdam Criteria and Bethesda Guidelines:Testing Algorithms for the Prediction of Mismatch Repair Mutation Status in the Familial Cancer Clinic[J].J Clin Oncolo,2004,24:4934-4943
[42]Chaves P, Cruz C, Lage P, et al. Immunohistochemical detection of mismatch repair gene proteins as a useful tool for the identification of colorectal carcinoma with the mutator phenotype[J]. J pathol,2000,191:355-360
[43]Chao EC, Lipkin SM.Molecular models for the tissue specificity of DNA mismatch repair-deficient carcinogenesis[J]. Nucleic Acids Research,2006, 34:840-852
[44]Woerner SM, Kloor M, Doeberitz MK, et al.Microsatellite instability in the development of DNA mismatch repair deficient tumors[J]. Cancer Biomarkers,2006,2:69-86
[45]Imai K, Yamamoto H.Carcinogenesis and microsatellite instability:the interrelationship between genetics and epigenetics[J]. Carcinogenesis,2008, 29:673-680
[46]张英辉,盛剑秋,耿洪刚,等.遗传性非息肉病性结直肠癌中环氧合酶2的表达及与错配修复基因表达和微卫星不稳定的相关性[J].中华医学杂志,2009,89：1377-1381
[47]Bonis PA, Trikalinos TA, Chung M, et al. Hereditary nonpolyposis colorectal cancendiagnostic strategies and their implications[J]. Evid Rep Tachnol Assess(Full Rep),2007,150:1-180
[48]Zhang L. Immunohistochemistry versus microsatellite instability testing for screening colorectal cancer patients at risk for hereditary nonpolyposis colorectal cancer syndrome. Part Ⅱ. The utility of microsatellite instability testing[J]. J Mol Diagn,2008,10:301-307.
[49]Tusher VG, Tibshirani R, Chu G. Significance analysis of microarrays[J]. PNAS. 2001,410:511,625,121.
[50]Bittner M, Meltzer P, Chen Y, et al. Molecular classification of cutaneous malignant melanoma by gene expression profiling[J].Nature.2000,406:536-540.
[51]Garber ME, Troyanskaya OG, Schlunens K, et al.Diversity of gene expression in adenocarcinoma of the lung[J]. PNAS,2001,98:13784-13789.
[52]Liotta, L.A, Kohn, E.C. Cancer's deadly signature[J].Nat Genet.2003,33:10-11.
[53]Notterman DA, Alon U, Sierk AJ, et al. Transcriptional gene expression profiles of colorectal adenoma, adenoeareinoma, and normal tissue examined by oligonueleotide arrays[J].Cancer Res.2001,61:3124-3130.
[54]Kitahara O, Furukawa Y, Tanaka T, et al. Alterations of gene expression during colorecta] carcinogenesis revealed by cDNA microarrays after laser-capture microdisseetion of tumor tissues and normal epithelia[J].Cancer Res,2001,61: 3544-3549
[55]Forte A, Sanctis RD, Leonetti G, et al. Dietary chemoprevention of colorectal cancer[J]. Ann Ital Chir,2008,79:261-267
[56]Marshall, JR.Prevention of colorectal cancer:diet,chemoprevention,and life style[J]. Gastroenterol Clin North Am,2008,37:73-82
[57]Larsson SC, Giovannucci E, Bergkvist L, et al. Whole grain consumption and risk of colorectal cancer: a population-based cohort of 60,000 women[J]. Br J Cancer,2005,92:1803-1807.
[58]Kruh(?)ffer M, Jensen JL, Laiho P, et al. Gene expression signatures for colorectal cancer microsatellite status and HNPCC[J].Br J Cancer,2005,92:2240-2248
[59]Segal E.Friedman N, Koller D, et al. A module map showing conditional activity of expression modules in cancer[J].Nat Genet.2004,36:1090-1098.
[60]Segal E, Shapira M, Regev A, et al. Module networks:identifying regulatory modules and their condition-specific regulators from gene expression data[J]. Nat Genet,2003,34,166-176.
[61]周斌,周总光,夏庆杰,等APCDD1在直肠癌及结直肠腺瘤中的定量表达[J].中华实验外科杂志,2006,23：1351-1352
[62]Moh MC, Zhang T, Lee Zl, et al.Expression of hepaCAM is downregulated in cancers and induces senescence-like growth arrest via a p53/p21-dependent pathway in human breast cancer cells.Carcinogenesis,2008,29:2298-2305
[63]Livak KJ, Schmittgvn TD. Analysis of relative gene expression data using real time quantitative PCR and the 2-ΔΔCT mcthod[J]. Methods,2001,25:402-408
[64]Kehlen A, Lendeckel U, Dralle H, et al. Biological Significance of Aminopeptidase N/CD13 in Thyroid Carcinomas[J]. Cancer res,2003,63:8500-8506
[65]Tokuhara T, Hattori N, Ishida H, et al.Clinical Significance of Aminopeptidase Nin Non SmallCell Lung Cancer[J].Clin Cancer Res,2006,12:3971-3977
[66]Ikeda N, Nakajima Y, Tokuhara T, et al. Clinical significance of aminopeptidase N/CD13 expression in human pancreatic carcinoma[J]. Clin Cancer Res,2003,9:1503-1508
[67]Wiese AH, Auer J, Lassmann S, et al. Identification of gene signatures for invasive colorectal tumor cells[J]. Cancer Detection and Prevention, 2007,31:282-295
[68]Zhang Y, Ng H H, Erdjument-Bromage H, et al. Analysis of the NuRD subunits reveals a histone deacetylase complex and a connection with DNA methylation[J]. Genes,1999,13:1924-1935
[69]Cui Y, Niu A, Pestell R, et al.Metastasis-associated protein 2 is a repressor of estrogen receptor a whose overexpressionleads toestrogen-independent growth of human breast cancer cells[J]. Molecular Endocrinology,2006,20:2020-2035
[70]Ji YX, Zhang P, Lu YP, et al. Expression of MTA2 gene in ovarian epithelial cancer and its clinical implication[J]. J Huazhong University of Science and Technology[Med Sci],2006,26:359-362
[71]Lee H, Ryu SH, Hong SS, et al.Overexpression of metastasis-associated protein 2 is associated with hepatocellular carcinoma size and differentiation [J]. J of Gastroenterology and Hepatology,2009,24:1445-1450
[72]Takahashi M, Fujita M, Furukana Y, et al. Isolation of a novel human gene,APCDD1, as a direct target of the D·Catenin/T-Cell factor 4 corn-plex with probable involvement in colorectal carcinogenesis. Cancer Research,2002,62: 5651-5656
[73]Moh MC, Lee LH, Shen S.Cloning and characterization of hepaCAM, a novel Ig-like cell adhesion molecule suppressed in human hepatocellular carcinoma[J].J of Hepatology,2005,42:833-841
[74]Moh MC, Zhang T, Lee LH, et al.Expression of hepaCAM is downregulated in cancers and induces senescence-like growth arrest via a p53/p21-dependent pathway in human breast cancer cells[J].Caiciogenesis,2008,29:2298-2305
[75]He YF, Wu XH, Luo CL, et al. Functional significance of the hepaCam gene in bladder cancer[J]. BMC cancer,2010,10:83
[76]Hsieh P, Yamane K. DNA mismatch repair:Molecular mechanism, cancer, and ageing[J]. Mech Ageing Dev,2008; 129:391-407
[77]Grady W. Genomic instability and colon cancer[J]. Cancer Metastasis Rev,2004, 23:11-27.
[78]Xu YF, Pasche B. TGF-β signaling alterations and susceptibility to colorectal cancer[J]. Human Molecular Genetics,2007,16:R14-R20
[79]Miyaki M, Yamaguchi T, Lijima T, et al. Somatic Mutations of the CDC4 (FBXW7) Gene in Hereditary Colorectal Tumors[J]. Oncology 2009;76:430-434
[80]Johnson V, Volikos E, Halford SE, et al. Exon 3 β-catenin mutations are specifically associated with colorectal carcinomas in hereditary non-polyposis colorectal cancer syndrome[J]. Gut 2005;54:264-267
[81]Van't Veer, L.J, Dai H, Vijver MJ, et al.Gene expression profiling predicts clinical outeome of breast cancer[J].Nature.2002,415:530-536
[1]Cunningham C, Dunlop MG. Molecular genetic basis of colorectal cancer Susceptibility[J]. Br J Sueg,1996,83:321-329.
[2]Liu T, Wahlberg S, Burek E, et al. Microsatellite instability as a predictor of a mutation in a DNA mismatch repair gene in familial colorectal cancer[J]. Genes Chromosomes Cancer,2000,27:17-25
[3]Debniak T, Kurzaawski G, Gorski B, et al. Value of pedigree/clinicaldata, imm unohistochenistry and microsatellite instability analyses in reducing the cost of determ ining hMLHl and hMSH2 gene mutations in patients with colorectal cancer[J]. Eur J Cancer,2000,36:49-54
[4]D'Emilia JC, Rodriguez-Bigas MA, Petrelli NJ. The clinical and genetic manifestations of hereditary nonpolyposis coloectal carcinoma[J]. Am J Surg,1995, 169:368-372
[5]SHEN XS, ZHAO B, WANG ZJ. Clinical features and hMSH2/hMLH1 germ-line mutations in Chinese patients with hereditary nonpolyposis colorectal cancer[J]. Chin Med J 2008;121:1265-1268
[6]Pehomaki PT. Genetic basis of hereditary nonpo lyposis colorectal carcinoma(HNPCC) [J]. Ann Med.1994,26:215-219
[7]Fishel R, Lescoe MK, Rao MR, et al. The human mutator gene homolog MSH2 and its association with hereditary nonpolyposis colon cancer[J]. Cell,1993, 75:1027-1038
[8]Hadziavdic V, Pavlovic-Calic N, Eminovic I. Molecular analysis:microsatellity instability and loss of heterozygosity of tumor suppressor gene in hereditary non-polyposis colorectal cancers (HNPCC) [J]..Bosn J Basic Med Sci,2009,9:10-18
[9]Aarnio M, Sankila R, Pukkala E, et al. Cancer risk in mutation carriers of DNA-mismatch-repair genes[J].. Int J Cancer,1999,81:214-218
[10]Millar AL, Pal T, Madlensky L, et al. Mismatch repair gene defects contribute to the genetic basis of double primary cancers of the colorectum and endometrium[J]. Hum Mol Genet,1999,8:823-829.
[11]Drotschmann K, Clark AB, Tran HT, et al. Mutator phenotypes of yeast strains heterozygous for mutations in the MSH2 gene[J]. Proc Natl Acad Sci USA,1999,96: 2970-2975.
[12]Watson P, Lynch HT. Cancer risk in mismatch repair gene mutation carriers[J]. Familial Cancer,2001,24:57-60.
[13]Jacob S, Praz F. DNA mismatch repair defeets:role in colorectal carcinogenesis [J]. Bioehimie,2002,84:27-47
[14]Mitchell Iu, Farrington SM, Dunlop MG, et al. Mismatch repair genes hMLH1 and hMSH2 and colorectal cancer:a HuGE review[J]. Am J Epidemiol,2002,156: 885-902.
[15]Chan TL, Chan YW, Ho JW, et al. MSH2 c1452-1455delAATG is a founder mutation and an important cause of hereditary nonpolyposis colorectal cancer in the southern chinese population[J]. Am J Hum Genet,2004,74:1035-1042
[16]Hitchins M, Williams R, Cheong K, et al. MLH1 germline epimutations as a factor in hereditary nonpolyposis colorectal cancer[J]. Gastroenterology, 2005;129:1392-9
[17]Wagner A, Hendriks Y, Meije-Heijboer EJ, et al. Atypical HNPCC owing toMSH6 germlinemutations:analysis of a large Dutch pedigree[J]. J Med Genet,2001, 38:18-322
[18]Rey JM, Noruzinia M, Brouillet JP, et al. Six novel heterozygous MLH1, MSH2, and MSH6 and one homozygous MLH1 germline mutations in hereditary nonpolyposis colorectal cancer[J]. Cancer Genet Cytogenet,2004; 155:149-51
[19]颜士岩,周晓燕,蔡三军,等.中国人遗传性非息肉病性结直肠癌MSH6基因胚系突变的测序研究[J].中华医学遗传学杂志,2007,24：640-645
[20]Aaltonen L A, Peltomaki P, Mecklin P G, et al. Replication errors in benign and malignant tumors from hereditary nonpolyposis colorectal cancer patients[J]. Cancer Res,1994,54:1645-1648
[21]刘文志,尹家俊,王亚东,等.中国北方人HN PCC微卫星不稳定性的研究[J]. 中华肿瘤防治杂志,2007,14：1527-1530
[22]Sheng JQ, Zhang H, Ji M,et al. Genetic diagnosis strategy of hereditary non-polyposis colorectal cancer[J]. World J Gastroenterol 2009; 15:983-989
[23]Bianchi F, Galizia E, Catalani R, et al. CAT25 is a mononucleotide marker to identify HNPCC patients[J]. J Mol Diagn,2009;11:248-52
[24]Shin KH, Shin J H, Kim JH, et al. Mutational analysis of promoters of mismatch repair genes hMSH2 and hMLH1 in hereditary nonpolyposis colorectal cancer and early onset colorectal cancer patients:identification of three novel ge rm-line mutations in promoter of the hMSH2 gene[J]. Cancer Res,2002,62:38-42
[25]Xinafianos G, Liloglou T, Prime W, et al. hMLHl an d hMSH2 Expression Correlates with Allelie Imbalance on Chromosome 3p in Non Small Cell Lung Carcinomas[J]. Cancer Research,2000,60:4216-4221
[26]金黑鹰,崔龙,高军孟,等.hMLH1/hMSH2基因启动子变异在遗传性非息肉病性结直肠癌发生中的作用[J].中华胃肠外科杂志,2003,6：243-246
[27]Zhou HH, Yan SY, Zhou XY,et al. MLH1 promoter germline-methylation in selected probands of Chinese hereditary non-polyposis colorectal cancer families[J]. World J Gastroenterol 2008; 14:7329-7334
[28]Scherer SJ, Welter C, Zang KD, et al. Specific in vitro binding of p53 to the promoter region of the human mis match repair gene hMSH2[J]. Biochem Biophys Res Comnun,1996,221:722-728
[29]程慧玉,金黑鹰,崔龙,等.p53基因的变异在遗传性非息肉病性结直肠癌发病中的作用[J].外科理论与实践,2004,9：212-214
[30]Togo G,Okamoto M,Shiratori Y,et al. Does Mutation of Transforming Growth Factor-β Type Ⅱ Receptor Gene Play an important Role in Colorectal Polyps[J]? Digestive Diseases and Sciences,19999:1803-1809
[31]张宏,盛剑秋,李世荣,等.hEXO1基因突变与中国人遗传性非息肉病性结直肠癌的相关性[J].胃肠病学和肝病学杂志,2006,1：95-97
[32]Kariola R,Abdel-Rahman WM, Ollikainen M et al. APC and β-catenin protein expression patterns in HNPCC-related endometrial and colorectal cancers[J]. Familial Cancer,2005,4:187-190
[33]Johnson V, Volikos E, Halford SE, et al. Exon 3 beta-catenin mutations are specifically associated with colorectal carcinomas in hereditary non-polyposis colorectal cancer syndrome[J]. Gut,2005;54:264-267
[34]Bian Y, Caldes T, Wijnen J, Franken P,et al. TGFBR1*6A may contribute to hereditary colorectal cancer[J]. J Clin Oncol.2005;23:3074-3078
[35]Wasielewski M, Vasen H, Wijnen J,et al. CHEK2 1100delC is a susceptibility allele for HNPCC-related colorectal cancer[J]. Clin Cancer Res,2008; 14:4989-4894
[36]Zecevic M, Amos CI, Gu X, et al. IGF1 gene polymorphism and risk for hereditary nonpolyposis colorectal cancer[J]. J Natl Cancer Inst,2006;98:139-143
[37]Reeves SG, Rich D, Meldrum CJ, et al. IGF1 is a modifier of disease risk in hereditary non-polyposis colorectal cancer[J]. Int J Cancer.2008;123:1339-1343
[38]Miyaki M,Yamaguchi T,Iijima T,et al. Somatic mutations of the CDC4 (FBXW7) gene in hereditary colorectal tumors[J]. Oncology,2009;76:430-434
[39]Shi Z, Johnstone D, Talseth-Palmer BA, et al. Haemochromatosis HFE gene polymorphisms as potential modifiers of hereditary nonpolyposis colorectal cancer risk and onset age[J]. Int J Cancer.2009, 1;125:78-83
[40]McGivern A, Wynter CV, Whitehall VL, et al. Promoter hypermethylation frequency and BRAF mutations distinguish hereditary non-polyposis colon cancer from sporadic MSI-H colon cancer[J]. Fam Cancer.2004;3:101-107
[41]Huang J, Zheng S, Jin SH, Zhang SZ. Somatic mutations of APC gene in carcinomas from hereditary non-polyposis colorectal cancer patients[J]. World J Gastroenterol,2004; 10:834-836
[42]Yamamoto H, Min Y, Itoh F, et al. Differential involvement of the hypermethylator phenotype in hereditary and sporadic colorectal cancerswith high-frequencymicrosatellite instability[J]. Genes Chromosomes Cancer,2002; 33: 322-325
[43]Lynch HT, Lynch JF. Hereditary nonpolyposis colorectal cancer[J]. Semin Surg Oncol,2000,18:305-313
[44]Sheng JQ, Zhang H, Ji M,et al. Genetic diagnosis strategy of hereditary non-polyposis colorectal cance[J]. World J Gastroenterol 2009; 15:983-989
[45]Deng G, Peng E, Gum J, et al. Methylation of hMLHl promoter correlates with the gene silencing with a region-specific manner in colorectal cancer[J]. Br J Cancer 2002; 86:574-579
© 2004-2018 中国地质图书馆版权所有 京ICP备05064691号 京公网安备11010802017129号 地址：北京市海淀区学院路29号 邮编：100083 电话：办公室：(+86 10)66554848；文献借阅、咨询服务、科技查新：66554700 |