PURPOSE:Role and timing of frameshift mutations during carcinogenesis in hereditary nonpolyposis colorectal cancer have not been examined.This study was designed to clarify the relationship between frameshift mutation...PURPOSE:Role and timing of frameshift mutations during carcinogenesis in hereditary nonpolyposis colorectal cancer have not been examined.This study was designed to clarify the relationship between frameshift mutations and clinicopathologic features in colorectal cancer from patients with hereditary nonpolyposis colorectal cancer.METHODS:Thirty-one colorectal cancers from patients with hereditary nonpolyposis colorectal cancer at different clinicopathologic stages were analyzed for frameshift mutation in 18 genes.RESULTS:The frameshift mutations of the ACVR2 and PTHLH genes were found to have an extremely high frequency(94-100 percent)in all pathologic stages,and mutation of the MARCKS gene also was high(94 percent)in Dukes B and C cancers.These frequencies were higher than the frequency of TGF βRII gene inactivation(64-88 percent).Mutations of the hMSH3,TCF4,CASP5,RIZ,RAD50,and MBD4 genes were comparatively frequent(>35 percent)in all stages.Frequencies of inactivation of the MARCKS,BAX,IGF IIR,and PTEN genes were significantly higher in Dukes B and C cancers than in Dukes A cancer(P < 0.05).The number of accumulated frameshift mutations was larger in Dukes B and C cancers(9.4)than in Dukes A cancer(6.8)(P = 0.003).CONCLUSIONS:The present data suggest that the disruption of the transforming growth factor-βsuperfamily signaling pathway by the alteration of the ACVR2 and/or TGFβRII genes and the disruption of antiproliferative function by the PTHLH gene alteration contribute to the development of early colorectal cancer.Moreover,the further accumulation of alterations in the MARCKS,BAX,IGF IIR,and PTEN genes seem to be associated with progression from early to advanced colorectal cancer from patients with hereditary nonpolyposis colorectal cancer.展开更多
Background: Hereditary non-polyposis colorectal cancer (HNPCC) is clinically defined by familial clustering of colorectal cancer and other associated tumours. Methods: By thorough molecular and clinical evaluation of ...Background: Hereditary non-polyposis colorectal cancer (HNPCC) is clinically defined by familial clustering of colorectal cancer and other associated tumours. Methods: By thorough molecular and clinical evaluation of 41 families, two dif ferent groups were characterised: group 1, 25 families with truncating mutations in MLH1 or MSH2 (12 novel mutations); and group 2, 16 Amsterdam positive famili es without mutations in these genes and without microsatellite instability in th eir corresponding tumours. Results: Significant clinical differences between the se two groups were found. Firstly, earlier age of onset for all colorectal cancers (median 41 v 55 years; p < 0.001) and all tumours (median 4 3 v 56 years; p = 0.022) was observed, comparing groups 1 and 2. Secondly, 68%o f the index colorectal cancers were localised proximally of the splenic flexure in group 1 compared with 14%in group 2 (p < 0.010). Thirdly, more synchronous a nd metachronous colorectal (p = 0.017) and extracolorectal tumours (p < 0.001) w ere found in group 1. Fourthly, a higher colorectal adenoma/carcinoma ratio (p = 0.030) and a tendency towards more synchronousor metachronous adenomas in group 2 (p = 0.084) was observed, indicating a slower progression of adenomas to carc inomas. As three mutation negative tumours revealed chromosomal instability afte r comparative genomic hybridisation, these tumours may be caused by one or more highly penetrant disease alleles from the chromosomal instability pathway. Concl usion: These data show that HNPCC includes at least two entities with clinical a nd molecular differences. This will have implications for surveillance programme s and for cancer research.展开更多
目的 :考察遗传性非息肉病性结直肠癌 (HNPCC)家系 h ML H1 /h MSH2生殖系突变的情况。 方法 :选择 1 3个符合Amsterdam标准的 HNPCC家系中的先证者 ,利用 DNA测序检测 h ML H1 /h MSH2基因突变情况。对其中不携带 h ML H1 /h MSH2生殖...目的 :考察遗传性非息肉病性结直肠癌 (HNPCC)家系 h ML H1 /h MSH2生殖系突变的情况。 方法 :选择 1 3个符合Amsterdam标准的 HNPCC家系中的先证者 ,利用 DNA测序检测 h ML H1 /h MSH2基因突变情况。对其中不携带 h ML H1 /h MSH2生殖系突变的 HNPCC家系 ,利用免疫组化检测 h ML H1 /h MSH2基因表达、PCR- SSCP检测先证者肿瘤组织的微卫星不稳定性 (MSI)。 结果 :1 3个 HNPCC家系的先证者中有 3例检测不到 h ML H1 /h MSH2的生殖系突变。 3例无 h ML H1 /h MSH2突变的先证者中 ,肿瘤组织的微卫星不稳定检测均为 MSI- H,免疫组化检测 h ML H1 /h MSH2基因表达正常。结论 :3个严格符合 Amsterdam标准的 HNPCC家系中未发现 h ML H1 /h MSH2基因系突变 ,提示可能存在其他基因突变导致该 3个家系展开更多
文摘PURPOSE:Role and timing of frameshift mutations during carcinogenesis in hereditary nonpolyposis colorectal cancer have not been examined.This study was designed to clarify the relationship between frameshift mutations and clinicopathologic features in colorectal cancer from patients with hereditary nonpolyposis colorectal cancer.METHODS:Thirty-one colorectal cancers from patients with hereditary nonpolyposis colorectal cancer at different clinicopathologic stages were analyzed for frameshift mutation in 18 genes.RESULTS:The frameshift mutations of the ACVR2 and PTHLH genes were found to have an extremely high frequency(94-100 percent)in all pathologic stages,and mutation of the MARCKS gene also was high(94 percent)in Dukes B and C cancers.These frequencies were higher than the frequency of TGF βRII gene inactivation(64-88 percent).Mutations of the hMSH3,TCF4,CASP5,RIZ,RAD50,and MBD4 genes were comparatively frequent(>35 percent)in all stages.Frequencies of inactivation of the MARCKS,BAX,IGF IIR,and PTEN genes were significantly higher in Dukes B and C cancers than in Dukes A cancer(P < 0.05).The number of accumulated frameshift mutations was larger in Dukes B and C cancers(9.4)than in Dukes A cancer(6.8)(P = 0.003).CONCLUSIONS:The present data suggest that the disruption of the transforming growth factor-βsuperfamily signaling pathway by the alteration of the ACVR2 and/or TGFβRII genes and the disruption of antiproliferative function by the PTHLH gene alteration contribute to the development of early colorectal cancer.Moreover,the further accumulation of alterations in the MARCKS,BAX,IGF IIR,and PTEN genes seem to be associated with progression from early to advanced colorectal cancer from patients with hereditary nonpolyposis colorectal cancer.
文摘Background: Hereditary non-polyposis colorectal cancer (HNPCC) is clinically defined by familial clustering of colorectal cancer and other associated tumours. Methods: By thorough molecular and clinical evaluation of 41 families, two dif ferent groups were characterised: group 1, 25 families with truncating mutations in MLH1 or MSH2 (12 novel mutations); and group 2, 16 Amsterdam positive famili es without mutations in these genes and without microsatellite instability in th eir corresponding tumours. Results: Significant clinical differences between the se two groups were found. Firstly, earlier age of onset for all colorectal cancers (median 41 v 55 years; p < 0.001) and all tumours (median 4 3 v 56 years; p = 0.022) was observed, comparing groups 1 and 2. Secondly, 68%o f the index colorectal cancers were localised proximally of the splenic flexure in group 1 compared with 14%in group 2 (p < 0.010). Thirdly, more synchronous a nd metachronous colorectal (p = 0.017) and extracolorectal tumours (p < 0.001) w ere found in group 1. Fourthly, a higher colorectal adenoma/carcinoma ratio (p = 0.030) and a tendency towards more synchronousor metachronous adenomas in group 2 (p = 0.084) was observed, indicating a slower progression of adenomas to carc inomas. As three mutation negative tumours revealed chromosomal instability afte r comparative genomic hybridisation, these tumours may be caused by one or more highly penetrant disease alleles from the chromosomal instability pathway. Concl usion: These data show that HNPCC includes at least two entities with clinical a nd molecular differences. This will have implications for surveillance programme s and for cancer research.
文摘目的 :考察遗传性非息肉病性结直肠癌 (HNPCC)家系 h ML H1 /h MSH2生殖系突变的情况。 方法 :选择 1 3个符合Amsterdam标准的 HNPCC家系中的先证者 ,利用 DNA测序检测 h ML H1 /h MSH2基因突变情况。对其中不携带 h ML H1 /h MSH2生殖系突变的 HNPCC家系 ,利用免疫组化检测 h ML H1 /h MSH2基因表达、PCR- SSCP检测先证者肿瘤组织的微卫星不稳定性 (MSI)。 结果 :1 3个 HNPCC家系的先证者中有 3例检测不到 h ML H1 /h MSH2的生殖系突变。 3例无 h ML H1 /h MSH2突变的先证者中 ,肿瘤组织的微卫星不稳定检测均为 MSI- H,免疫组化检测 h ML H1 /h MSH2基因表达正常。结论 :3个严格符合 Amsterdam标准的 HNPCC家系中未发现 h ML H1 /h MSH2基因系突变 ,提示可能存在其他基因突变导致该 3个家系
