Background. Although recent animal studies have shown that SMAD4/DPC4 gene alterations are essential for late- stage intestinal tumorigenesis, the role of SMAD4/DPC4 gene alterations in primary human colorectal carcin...Background. Although recent animal studies have shown that SMAD4/DPC4 gene alterations are essential for late- stage intestinal tumorigenesis, the role of SMAD4/DPC4 gene alterations in primary human colorectal carcinomas is not fully understood. Therefore, we attempted to clarify the role of the SMAD4/DPC4 gene during tumor progression of colorectal carcinoma. Methods. Differences in allelic imbalance (AI) and mutations of the SMAD4/DPC4 gene between diploid and aneuploid populations were analyzed for 30 sporadic DNA multiploid colorectal carcinomas (used as a tumor progression model and defined as the coexistence of diploid and aneuploid cells within the same tumor). The crypt isolation technique was coupled with DNA cytometric sorting and a polymerase chain reaction assay. In addition, hypermethylation of the promoter region was examined to clarify whether inactivation of gene expression occurred. Results. Although a SMAD4/DPC4 gene AI was detected in only 5 of 27 informative diploid populations, 25 of 27 aneuploid populations had a SMAD4/DPC4 gene AI. Mutation of the SMAD4/DPC4 gene was detected in only one aneuploid population of multiploid colorectal carcinomas, but not in the corresponding diploid population. In total, 20 available multiploid carcinomas were selected for methylation analysis, and no evidence of hypermethylation of the promoter region was found. Conclusions. We suggest that, although mutation of the SMAD4/DPC4 gene and hypermethylation of the promoter region are infrequent events in colorectal tumorigenesis, AI at the SMAD4/DPC4 gene locus may play a key role in the progression of colorectal carcinomas.展开更多
Objective.To d etermine whether the non-expression of DPC4protein only occurs late in the dev el-opment of colorectal carcinoma.Methods.In this study,we examined the ex pression of DPC4protein in formalin-fixed archiv...Objective.To d etermine whether the non-expression of DPC4protein only occurs late in the dev el-opment of colorectal carcinoma.Methods.In this study,we examined the ex pression of DPC4protein in formalin-fixed archival specimens from102colorec tal neoplasm with immunohistochemical analysis.Those specimens were classi-fie d into5stages:stageⅠ;stageⅡ(intramucosal carcinoma ,8cases);stageⅢ(primary invasive carcinoma without infiltration of the l ymph nodes,11cases);stageⅣ(primary invasive carcinoma with infiltration of the lymph nodes,25cases);and stageⅤ(carcinoma metastasized to dis-ta nt tissue,22cases).Results.The frequency of non-expression of DPC4prote ins were5.5%in stage I,12.5%in stage II;9% in stage III;36%in stage IV;32%in stag e V.The frequency of negative expression of DPC4protein were analyzed by÷ 2 test for stage II and III versus stage IV and V and there was statistically significant difference.At same time ,there was statistically signifi-cant differencefor adenoma versus carcinoma .Conclusions.The frequency of non-expression of DPC4protein increases as the stage of colorectal carcinoma advances and the non-expressio n of DPC4protein is likely to be a late event in the sequential pathogenesis o f colorectal carcinoma.The non-expression DPC4protein in colorectal neoplasm may sug-gest its malignant characteristic,which will help us to increase the insight on colorectal carcinoma.展开更多
文摘Background. Although recent animal studies have shown that SMAD4/DPC4 gene alterations are essential for late- stage intestinal tumorigenesis, the role of SMAD4/DPC4 gene alterations in primary human colorectal carcinomas is not fully understood. Therefore, we attempted to clarify the role of the SMAD4/DPC4 gene during tumor progression of colorectal carcinoma. Methods. Differences in allelic imbalance (AI) and mutations of the SMAD4/DPC4 gene between diploid and aneuploid populations were analyzed for 30 sporadic DNA multiploid colorectal carcinomas (used as a tumor progression model and defined as the coexistence of diploid and aneuploid cells within the same tumor). The crypt isolation technique was coupled with DNA cytometric sorting and a polymerase chain reaction assay. In addition, hypermethylation of the promoter region was examined to clarify whether inactivation of gene expression occurred. Results. Although a SMAD4/DPC4 gene AI was detected in only 5 of 27 informative diploid populations, 25 of 27 aneuploid populations had a SMAD4/DPC4 gene AI. Mutation of the SMAD4/DPC4 gene was detected in only one aneuploid population of multiploid colorectal carcinomas, but not in the corresponding diploid population. In total, 20 available multiploid carcinomas were selected for methylation analysis, and no evidence of hypermethylation of the promoter region was found. Conclusions. We suggest that, although mutation of the SMAD4/DPC4 gene and hypermethylation of the promoter region are infrequent events in colorectal tumorigenesis, AI at the SMAD4/DPC4 gene locus may play a key role in the progression of colorectal carcinomas.
文摘Objective.To d etermine whether the non-expression of DPC4protein only occurs late in the dev el-opment of colorectal carcinoma.Methods.In this study,we examined the ex pression of DPC4protein in formalin-fixed archival specimens from102colorec tal neoplasm with immunohistochemical analysis.Those specimens were classi-fie d into5stages:stageⅠ;stageⅡ(intramucosal carcinoma ,8cases);stageⅢ(primary invasive carcinoma without infiltration of the l ymph nodes,11cases);stageⅣ(primary invasive carcinoma with infiltration of the lymph nodes,25cases);and stageⅤ(carcinoma metastasized to dis-ta nt tissue,22cases).Results.The frequency of non-expression of DPC4prote ins were5.5%in stage I,12.5%in stage II;9% in stage III;36%in stage IV;32%in stag e V.The frequency of negative expression of DPC4protein were analyzed by÷ 2 test for stage II and III versus stage IV and V and there was statistically significant difference.At same time ,there was statistically signifi-cant differencefor adenoma versus carcinoma .Conclusions.The frequency of non-expression of DPC4protein increases as the stage of colorectal carcinoma advances and the non-expressio n of DPC4protein is likely to be a late event in the sequential pathogenesis o f colorectal carcinoma.The non-expression DPC4protein in colorectal neoplasm may sug-gest its malignant characteristic,which will help us to increase the insight on colorectal carcinoma.
