云南省家族性腺瘤性息肉病家系收集保存及其APC基因分析
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摘要
目的：通过对云南省家族性腺瘤性息肉病(FAP)家系的收集,抢救和保存云南省FAP家系遗传资源,为FAP预防、诊治及病因的研究提供遗传性标本。同时,对FAP相关致病基因APC基因进行分析,探讨云南省FAP相关致病基因突变特点,初步建立符合云南省FAP家系的筛查方案。
方法：对昆明医学院第一附属医院、云南省肿瘤医院、红河州和大理州等多家医院近10年的结直肠癌患者的病案调查,筛选FAP患者,以及这些医院近3年门诊、肠镜室、相关科室新发FAP患者的收集,通过电话联系患者并登门随访,经知情同意后,由其介绍和引导其直系和旁系各级亲属进行遗传学咨询,并以先证者为中心绘制家系图谱,采集患者及其家系成员外周静脉血,及提取手术患者离体后组织标本(包括肿瘤、瘤旁、远端正常组织)、石蜡包埋切片,分别提取DNA,利用已建立的云南省遗传性大肠癌标本库进行标本保存和信息管理。应用聚合酶链反应(PCR)方法对FAP家系先证者DNA进行APC基因扩增,DNA直接测序法进行APC基因全编码区测序,应用Mutation Surveyor软件分析测序结果,参考美国国家生物技术信息中心(NCBI)网站上APC基因序列,进行序列比对,确定突变位点,再根据突变位点筛查其家系高危亲属。
结果：共收集10个FAP家系,其中包括1个白族家系,2个彝族家系和7个汉族家系,并采集家系中主要成员血液标本96份,组织标本4份,蜡块组织7份,并提取DNA,保存于云南省遗传性大肠癌标本库。10个FAP家系先证者中,1个汉族家系先证者检出APC基因致病突变(10%),此突变存在于APC基因第15外显子c.3587C>A(S1196X);随后对该家系另外8名成员进行该突变位点筛查,其中7人有此突变；其余9个FAP家系未查出APC基因有意义的突变。
结论：通过对云南省FAP家系的收集,抢救和保存云南省FAP家系宝贵的遗传资源,为后期FAP预防诊治及病因的研究提供现代分子肿瘤学要求的遗传性标本,提高云南省遗传性大肠癌标本库的应用价值。首次在云南省开展FAP家系APC基因突变分析,并发现国内尚未见报道的APC基因15号外显子c.3587C>A(S1196X)无义突变。云南省FAP患者APC基因致病突变发生率(10%)明显低于国内外报道,未检出APC基因致病突变的FAP患者可能存在其他发病的机制。针对目前APC基因低突变结果,初步建立符合云南省FAP家系的基因和肠镜两套筛查方案。
Objective:To rescue and preserve the genetic resources of familial adenomatous polyposis (FAP) by collecting FAP pedigrees in Yunnan Province,and to provide genetic samples for prevention, treatment and etiology research of FAP. Meanwhile, to analysis the APC gene that predispose the disease susceptibility in patients with FAP from Yunnan Province and explore the mutation features of disease gene FAP-related and initial establish suitable program of screening FAP pedigree in Yunnan Province.
Methods:Screening FAP patients through investigating the cases of colorectal cancer patients in the past 10 years and collecting new FAP patients of the endoscopy room, out-patients and the relevant departments nearly 3 years from the First Affiliated Hospital of Kunming Medical College, Yunnan Province Cancer Hospital, Red River State Hospital and Dali State Hospita. Using patients contacted by phone and door follow-up as index patients, the pedigree and all lineal and collateral relatives were interviewed. Peripheral venous blood samples of individuals were collected from these families. Collecting tissue specimens (including tumors, normal tissues beside or outside tumors) and paraffin-embedded sections of operative patients. These specimens were preserved in the Yunnan Province of hereditary colorectal cancer tissure bank. The whole coding region of APC gene of the FAP family probands were screened for germline mutations by using polymerase chain reaction (PCR) and DNA direct sequencing, and Mutation Surveyor software analyze sequencing results. Reference the APC gene sequence on the NCBI website to determine the sites of mutation and according to the sites of mutation screening high-risk relatives of their family.
Results:Total of 10 FAP pedigrees were collected, including a Bai pedigree,2 Yi pedigrees and 7 Han pedigrees. There are 96 blood specimens,4 tissue specimens and 7 paraffin-embedded sections.DNA of all family members are extracted in reserve. Among the 10 probands subjected to genetic analysis of the APC gene, mutation was detected in 1 han proband (10%), which is the C to A transversion resulting in a stop codon at codon 1196 within exon15(c.3587C＞A,S1196X).Subsequently, another 8 members in APC gene mutaition family,7 of them have this mutation. The remaining 9 FAP pedigrees without identified significant mutation of APC gene.
Conclusions:Through the collection of FAP family in Yunnan Province, rescue and preserve valuable genetic resources of FAP pedigrees, in order to provid the genetic samples of requirements of modern molecular oncology for future treatment, prevention and etiology research of FAP, and improve the value of the Yunnan Province of hereditary colorectal cancer tissure bank. We first analyze the APC gene mutations of FAP pedigree in Yunnan Province and found nonsense mutation has not been reported that the APC gene exon 15 c.3587C＞A(S1196X) in China. Among patients with FAP in Yunnan Province, the incidence of APC gene mutations was significantly lower than other areas at home and abroad is reported. others pathogenesis may exist in FAP patients without APC gene mutation. Aiming at results of APC gene mutations with low, establish two sets of suitable program of screening FAP pedigree in Yunnan Province.
方法：对昆明医学院第一附属医院、云南省肿瘤医院、红河州和大理州等多家医院近10年的结直肠癌患者的病案调查,筛选FAP患者,以及这些医院近3年门诊、肠镜室、相关科室新发FAP患者的收集,通过电话联系患者并登门随访,经知情同意后,由其介绍和引导其直系和旁系各级亲属进行遗传学咨询,并以先证者为中心绘制家系图谱,采集患者及其家系成员外周静脉血,及提取手术患者离体后组织标本(包括肿瘤、瘤旁、远端正常组织)、石蜡包埋切片,分别提取DNA,利用已建立的云南省遗传性大肠癌标本库进行标本保存和信息管理。应用聚合酶链反应(PCR)方法对FAP家系先证者DNA进行APC基因扩增,DNA直接测序法进行APC基因全编码区测序,应用Mutation Surveyor软件分析测序结果,参考美国国家生物技术信息中心(NCBI)网站上APC基因序列,进行序列比对,确定突变位点,再根据突变位点筛查其家系高危亲属。
结果：共收集10个FAP家系,其中包括1个白族家系,2个彝族家系和7个汉族家系,并采集家系中主要成员血液标本96份,组织标本4份,蜡块组织7份,并提取DNA,保存于云南省遗传性大肠癌标本库。10个FAP家系先证者中,1个汉族家系先证者检出APC基因致病突变(10%),此突变存在于APC基因第15外显子c.3587C>A(S1196X);随后对该家系另外8名成员进行该突变位点筛查,其中7人有此突变；其余9个FAP家系未查出APC基因有意义的突变。
结论：通过对云南省FAP家系的收集,抢救和保存云南省FAP家系宝贵的遗传资源,为后期FAP预防诊治及病因的研究提供现代分子肿瘤学要求的遗传性标本,提高云南省遗传性大肠癌标本库的应用价值。首次在云南省开展FAP家系APC基因突变分析,并发现国内尚未见报道的APC基因15号外显子c.3587C>A(S1196X)无义突变。云南省FAP患者APC基因致病突变发生率(10%)明显低于国内外报道,未检出APC基因致病突变的FAP患者可能存在其他发病的机制。针对目前APC基因低突变结果,初步建立符合云南省FAP家系的基因和肠镜两套筛查方案。
Objective:To rescue and preserve the genetic resources of familial adenomatous polyposis (FAP) by collecting FAP pedigrees in Yunnan Province,and to provide genetic samples for prevention, treatment and etiology research of FAP. Meanwhile, to analysis the APC gene that predispose the disease susceptibility in patients with FAP from Yunnan Province and explore the mutation features of disease gene FAP-related and initial establish suitable program of screening FAP pedigree in Yunnan Province.
Methods:Screening FAP patients through investigating the cases of colorectal cancer patients in the past 10 years and collecting new FAP patients of the endoscopy room, out-patients and the relevant departments nearly 3 years from the First Affiliated Hospital of Kunming Medical College, Yunnan Province Cancer Hospital, Red River State Hospital and Dali State Hospita. Using patients contacted by phone and door follow-up as index patients, the pedigree and all lineal and collateral relatives were interviewed. Peripheral venous blood samples of individuals were collected from these families. Collecting tissue specimens (including tumors, normal tissues beside or outside tumors) and paraffin-embedded sections of operative patients. These specimens were preserved in the Yunnan Province of hereditary colorectal cancer tissure bank. The whole coding region of APC gene of the FAP family probands were screened for germline mutations by using polymerase chain reaction (PCR) and DNA direct sequencing, and Mutation Surveyor software analyze sequencing results. Reference the APC gene sequence on the NCBI website to determine the sites of mutation and according to the sites of mutation screening high-risk relatives of their family.
Results:Total of 10 FAP pedigrees were collected, including a Bai pedigree,2 Yi pedigrees and 7 Han pedigrees. There are 96 blood specimens,4 tissue specimens and 7 paraffin-embedded sections.DNA of all family members are extracted in reserve. Among the 10 probands subjected to genetic analysis of the APC gene, mutation was detected in 1 han proband (10%), which is the C to A transversion resulting in a stop codon at codon 1196 within exon15(c.3587C＞A,S1196X).Subsequently, another 8 members in APC gene mutaition family,7 of them have this mutation. The remaining 9 FAP pedigrees without identified significant mutation of APC gene.
Conclusions:Through the collection of FAP family in Yunnan Province, rescue and preserve valuable genetic resources of FAP pedigrees, in order to provid the genetic samples of requirements of modern molecular oncology for future treatment, prevention and etiology research of FAP, and improve the value of the Yunnan Province of hereditary colorectal cancer tissure bank. We first analyze the APC gene mutations of FAP pedigree in Yunnan Province and found nonsense mutation has not been reported that the APC gene exon 15 c.3587C＞A(S1196X) in China. Among patients with FAP in Yunnan Province, the incidence of APC gene mutations was significantly lower than other areas at home and abroad is reported. others pathogenesis may exist in FAP patients without APC gene mutation. Aiming at results of APC gene mutations with low, establish two sets of suitable program of screening FAP pedigree in Yunnan Province.
引文
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[1]Elizabeth H,Dani B, Paul R.Familial adenomatous polyposis. Orphanet Journal of Rare Diseases,2009,4:22.e:http://www.ojrd.com/content/4/1/22.
[2]于恩达,徐晓东,孟荣贵.家族性腺瘤性息肉病的临床特点及研究现状.第二军医大学学报,2006,27(4)：349-352.
[3]蔡善荣,余捷凯,蒋文智,等.构建血清蛋白质质谱模型判别FAP与散发性肠腺瘤.中华肿瘤杂志,2009,31(3)：192-195.
[4]周欣,周建农,尚俊清,等.家族性腺瘤性息肉病患者结直肠癌变的外科预防.结直肠肛门外科,2008,14(2)：78-82.
[5]Edlich R,Cross CL,Wack CA,et al.Revolutionary advances in the diagnosis and treatment of Familial Adenomatous Polyposis.J Environ Pathol Toxicol Oncol,2009,28(1):47-52.
[6]Petersen GM,Slack J,Nakamura.Screening guidelines and premorbid diagnosis of familial adenomatous polyposis. Gastroenterology,1991,100(6):1658-1671.
[7]Herrera L,Kakati S,GibasL,el al.Gardner syndrome in a man with an interstitial deletion of 5q.Am J med Genel,1986,25(3):473-476.
[8]Bodmer WF,Bailey C,Bodmer J.et al.Localization of the gene for familial adenomatous polyposis on chromosome 5.Nature,1987,328(6131):614.
[9]Groden J,Thliveris A,Samowiz W,et al.Identification and characterization of the Familial adenomatous polyposisi coli gene. Cell,1991,66(3):589-600.
[10]Okamoto H,Mineta T,Nakahara Y, et al. Molecular analysis of astrocytoma associated with Turcot syndrome type 1 case report. Neurol Med Chir(Tokyo),2004,44(3):124-128.
[11]Burt RW,LeppertMF,SlatteryML,et al.Genetic testing and phenotype in a large kindred with attenuated familial adenomatous polyposis.Gastroenterology,2004,127(2):4442451.
[12]Jo WS,Chung DC.Genetics of hereditary colorectal cancer.Semin oncol,2005,32(1):11-23.
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[18]Aretz S,Uhlhaas S,Goergens H, et al.MUTYH-associatedpolyposis:70 of 71 patients with biallelic mutations present with an attenuated or a typical phenotype.Int J Cancer,2006,119(4):807-814.
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[20]Parker AR,Eshleman JR.Human MutY:genestructure,protein functionsand interactions,and rolein carcino genesis.Cell Mol Life Sci,2003,60(10):2064-83.
[21]Russo MT,De Luca QDegan P,et al.Different DNA repair strategies to combat the Threat froms 8-oxoguanine.Mutat Res,2007,614(1-2):69-76.
[22]Boldogh I,Milligan D,Lee MS,et al.hMYH cellcycle-dependent expression,subcellular localization and association with replication foci:evidence suggesting replication-coupled repair of adenine:8-oxo guanine mispairs.Nocleic Acids Res,2001,29(13):2802-09.
[23]Sampson JR,Jones S,Dolwani S,et al.Mutyh(MYH) and colorectal.cancer.Biochem Soc Trans, 2005,33 (Pt4):679-683.
[24]Cheadle JP,Sampson JR.Exposing the MYtH about base excision repair and human inherited disease.Hum Mol Genet,2003,12(2):R159-165.
[25]Jenkins MA,Croitoru ME,Monga N,et al.risk of colorectal cancer in monoallelic and biallelic carriers of MYH mutations:a population-based case-family study.Cancer Epidemiol Biomarkers Prev,2006,15(2):312-314.
[26]Farrington SM,Tenesa A,Bametson R,et al.Germline susceptibility to colorectal cancer due to base-excision repair gene defect.Am J Hum Genet,2005,77(1):112-119.
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[1]Elizabeth H,Dani B, Paul R.Familial adenomatous polyposis. Orphanet Journal of Rare Diseases,2009,4:22.e:http://www.ojrd.com/content/4/1/22.
[2]于恩达,徐晓东,孟荣贵.家族性腺瘤性息肉病的临床特点及研究现状.第二军医大学学报,2006,27(4)：349-352.
[3]蔡善荣,余捷凯,蒋文智,等.构建血清蛋白质质谱模型判别FAP与散发性肠腺瘤.中华肿瘤杂志,2009,31(3)：192-195.
[4]周欣,周建农,尚俊清,等.家族性腺瘤性息肉病患者结直肠癌变的外科预防.结直肠肛门外科,2008,14(2)：78-82.
[5]Edlich R,Cross CL,Wack CA,et al.Revolutionary advances in the diagnosis and treatment of Familial Adenomatous Polyposis.J Environ Pathol Toxicol Oncol,2009,28(1):47-52.
[6]Petersen GM,Slack J,Nakamura.Screening guidelines and premorbid diagnosis of familial adenomatous polyposis. Gastroenterology,1991,100(6):1658-1671.
[7]Herrera L,Kakati S,GibasL,el al.Gardner syndrome in a man with an interstitial deletion of 5q.Am J med Genel,1986,25(3):473-476.
[8]Bodmer WF,Bailey C,Bodmer J.et al.Localization of the gene for familial adenomatous polyposis on chromosome 5.Nature,1987,328(6131):614.
[9]Groden J,Thliveris A,Samowiz W,et al.Identification and characterization of the Familial adenomatous polyposisi coli gene. Cell,1991,66(3):589-600.
[10]Okamoto H,Mineta T,Nakahara Y, et al. Molecular analysis of astrocytoma associated with Turcot syndrome type 1 case report. Neurol Med Chir(Tokyo),2004,44(3):124-128.
[11]Burt RW,LeppertMF,SlatteryML,et al.Genetic testing and phenotype in a large kindred with attenuated familial adenomatous polyposis.Gastroenterology,2004,127(2):4442451.
[12]Jo WS,Chung DC.Genetics of hereditary colorectal cancer.Semin oncol,2005,32(1):11-23.
[13]Al-Tassan N,Chmieln H,Maynard J,et al.Inherited variants of MYH associated with somatic G:C＞T:A mutations in colorectal tumors.Nat Genet,2002,50(2):227-232.
[14]Sieber OM,Lipton L,Crabtree M,et al.Multiple colorectal adenomas,classic adenomatous polyposis,and germline mutations in MYH.N EnglJ Med,2003,348(9):791-799.
[15]Sampson JR,Dolwani S,Jones S,et al.Autosomal recessive colorectal adenomatous polyposis due to inherited mutations of MYH.Lancet,2003,362(9377):39-41.
[16]Wang L, Baudhuin LM, Boardman LA, et al. MYH mutations in patients with attenuated and classical polyposis and with young-onset colorectal cancer without polyps. Gastroenterology, 2004,127(1):9-16.
[17]Doxey BW,Kuwada SK,Burt RW.Inherited polyposis syndromes:Molecular mechanisms. clinicopathology, and genetic testing.Clin Gatroenterol Hepatol,2005,3(7):633-641.
[18]Aretz S,Uhlhaas S,Goergens H, et al.MUTYH-associatedpolyposis:70 of 71 patients with biallelic mutations present with an attenuated or a typical phenotype.Int J Cancer,2006,119(4):807-814.
[19]Chow E,Thirlwell C,Macrae F,et al.Colorectal cancer and inherited mutations in base-excision repair.Lancet Oncol,2004,5 (10):600-606.
[20]Parker AR,Eshleman JR.Human MutY:genestructure,protein functionsand interactions,and rolein carcino genesis.Cell Mol Life Sci,2003,60(10):2064-83.
[21]Russo MT,De Luca QDegan P,et al.Different DNA repair strategies to combat the Threat froms 8-oxoguanine.Mutat Res,2007,614(1-2):69-76.
[22]Boldogh I,Milligan D,Lee MS,et al.hMYH cellcycle-dependent expression,subcellular localization and association with replication foci:evidence suggesting replication-coupled repair of adenine:8-oxo guanine mispairs.Nocleic Acids Res,2001,29(13):2802-09.
[23]Sampson JR,Jones S,Dolwani S,et al.Mutyh(MYH) and colorectal.cancer.Biochem Soc Trans, 2005,33 (Pt4):679-683.
[24]Cheadle JP,Sampson JR.Exposing the MYtH about base excision repair and human inherited disease.Hum Mol Genet,2003,12(2):R159-165.
[25]Jenkins MA,Croitoru ME,Monga N,et al.risk of colorectal cancer in monoallelic and biallelic carriers of MYH mutations:a population-based case-family study.Cancer Epidemiol Biomarkers Prev,2006,15(2):312-314.
[26]Farrington SM,Tenesa A,Bametson R,et al.Germline susceptibility to colorectal cancer due to base-excision repair gene defect.Am J Hum Genet,2005,77(1):112-119.
[27]Nielsen M,Franken PF,Reinards TH,et al.Multiplicity in polyp countand extra colonic manifest-ations in 40 Dutch patients with MYH associated polyposis coli(MAp).J Med Genet,2005,42(9):e54.
[28]Baglioni S,Melean QGensini F,et al.A Kindred with MYH-AssociatedPolyposis and Pilomatricomas. Am J Med Genet A,2005,134(2):212-214.
[28]Renkonen ET, Nieminen P, Abdel-Rahman WM,et al.Adenomatous polyposis families that screen APC mutation-negative by conventional methods are genetically heterogeneous.J Clin Oncol,2005,23(24):5651-59.
[29]Armstrong JG, Davies DR, Guy SP, et al. APC mutations in familial adenomatous polyposis families in the Northwest of England. Hum Mutat,1997,10(5):376-380.
[30]Russell AM, Zhang J, Luz J, et al. Prevalence of MYH germline mutations in Swiss APC mutation-negative polyposis patients.Int J Cancer,2006,118(8):1937-40.
[31]Jones S, Emmerson P, Maynaard J, et al. Biallelic germline mutations in MYH predispose to multiple colorectal adenoma and somatic G:C＞T:A mutations.Hum Mol Genet, 2002,11(23):2961-67.