Background & Aims: The role of the mismatch repair gene PMS2 in hereditary nonpolyposis colorectal carcinoma (HNPCC) is not fully clarified. To date, only 7 different heterozygous truncating PMS2 mutations have be...Background & Aims: The role of the mismatch repair gene PMS2 in hereditary nonpolyposis colorectal carcinoma (HNPCC) is not fully clarified. To date, only 7 different heterozygous truncating PMS2 mutations have been reported in HNPCC-suspected families. Our aim was to further assess the role of PMS2 in HNPCC. Methods: We performed Southern blot analysis in 112 patients from MLH1- , MSH2- , and MSH6- negative HNPCC-like families. A subgroup (n = 38) of these patients was analyzed by denaturing gradient gel electrophoresis (DGGE). In a second study group consisting of 775 index patients with familial colorectal cancer,we performed immunohistochemistry using antibodies against MLH1,MSH2, MSH6, and PMS2 proteins. In 8 of 775 tumors, only loss of PMS2 expression was found. In these cases, we performed Southern blot analysis and DGGE. Segregation analysis was performed in the families with a (possibly) deleterious mutation. Results: Seven novel mutations were identified: 4 genomic rearrangements and 3 truncating point mutations. Three of these 7 families fulfill the Amsterdam II criteria. The pattern of inheritance is autosomal dominant with a milder phenotype compared with families with pathogenic MLH1 or MSH2 mutations. Microsatellite instability and immunohistochemical analysis performed in HNPCC-related tumors from proven carriers showed a microsatellite instability high phenotype and loss of PMS2 protein expression in all tumors. Conclusions: We show that heterozygous truncatingmutations in PMS2 do play a role in a small subset of HNPCC-like families. PMS2 mutation analysis is indicated in patients diagnosed with a colorectal tumor with Absent staining for the PMS2 protein.展开更多
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
文摘Background & Aims: The role of the mismatch repair gene PMS2 in hereditary nonpolyposis colorectal carcinoma (HNPCC) is not fully clarified. To date, only 7 different heterozygous truncating PMS2 mutations have been reported in HNPCC-suspected families. Our aim was to further assess the role of PMS2 in HNPCC. Methods: We performed Southern blot analysis in 112 patients from MLH1- , MSH2- , and MSH6- negative HNPCC-like families. A subgroup (n = 38) of these patients was analyzed by denaturing gradient gel electrophoresis (DGGE). In a second study group consisting of 775 index patients with familial colorectal cancer,we performed immunohistochemistry using antibodies against MLH1,MSH2, MSH6, and PMS2 proteins. In 8 of 775 tumors, only loss of PMS2 expression was found. In these cases, we performed Southern blot analysis and DGGE. Segregation analysis was performed in the families with a (possibly) deleterious mutation. Results: Seven novel mutations were identified: 4 genomic rearrangements and 3 truncating point mutations. Three of these 7 families fulfill the Amsterdam II criteria. The pattern of inheritance is autosomal dominant with a milder phenotype compared with families with pathogenic MLH1 or MSH2 mutations. Microsatellite instability and immunohistochemical analysis performed in HNPCC-related tumors from proven carriers showed a microsatellite instability high phenotype and loss of PMS2 protein expression in all tumors. Conclusions: We show that heterozygous truncatingmutations in PMS2 do play a role in a small subset of HNPCC-like families. PMS2 mutation analysis is indicated in patients diagnosed with a colorectal tumor with Absent staining for the PMS2 protein.
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.
