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Gastrointestinal Stromal Tumor and Leiomyosarcoma Are All Related to Interstitial Cells of Cajal

Author: LiangYuMei
Tutor: LiXiangHong;LvYouYong
School: PLA Postgraduate Medical School
Course: Pathology and Pathophysiology
Keywords: gastrointestinal stromal tumors leimyosarcoma miRNA interstitial cells of Cajal
CLC: R735
Type: PhD thesis
Year: 2008
Downloads: 192
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Abstract


Object Up to date,one of the most tangled two aspects in gastrointestinal stromal tumor(GIST)research is to differentiate GISTs from their mimics especially leiomyosarcoma.The other one is to predict the biological behavior precisely.To solve these two problems,based on the CD117 positive GISTs,possible CD117 negative GISTs and intra-abdominal leiomyosarcomas,we explored the relationship between GIST and leiomyosarcoma.At the same time,the survival was also analyzed based on the follow-up data.Materials and Methods A total of 256 cases of CD117 positive GIST,51 cases of possible CD117 negative GIST,61 cases of leiomyosarcoma,6 cases of uterus leiomyosarcoma,and 8 cases of leiomyosarcoma arising from superficial tissue or limb extreme were collected from the archive of Chinese PLA General Hospital pathology department from 1996 to 2006.The mutation in KIT exon 11,9,13 and 17 or in PDGFRA exon 12 and 18 were detected directly sequenceing.The Tyr721 in KIT were measured to analyze KIT expression and phosphorylation by ab721 and phosphorylated ab721(pab721).Significant genes of GIST and leiomyosarcoma were obtained from miRNA gene expression array.The expression status of these genes was detected by in situ hybridization with LNA probes on tissue microarray.The primary culture of GIST also established to investigate the expression of SMA,SM22 and desmin.There were 9 GI leiomyomas,24 cases of uterus leiomyoma,24 cases of smooth muscle of GI tract, 10cases of Schwannoma,10 cases of neurofibroma were selected as positive and negative control.Based on the follow-up data,the clinicopathological factors including anatomic location,risk assessment,DNA mutation,miRNA expression,KIT expression and activated Revel and the activation mTOR,S6K were analyzed by Kaplan-Meier and multivariate COX hazard ratio mode. Results There were 245 cases were followed up in the 256 cases of CD117 positive GIST,the three-year and 5-year disease free survival(DFS)was(62.97±7.18)%and (52.28±8.06)%respectively.166 cases were directly sequenced and 71.68%of these cases harbored mutation.The most frequent mutation is the deletion affecting codon 557 and codon 558 in KIT exon 11.44 cases of possible CD117 negative cases and 19 cases of leimyosarcoma were followed up.The 3-year DFS for these patients was (60.73±15.58)%and(25.84±21.68)%respectively.46.34%of the possible CD117 negative cases and 33.33%of the leimyosarcoma harbored mutation.In addition,there were 3 cases of uterus leimyosarcoma and 2 cases of superficial leimyosarcoma harbored mutation.69.68%of the CD117 positive cases were immunoactivated with ab721 and 75.33%with phosphorylated ab721.ab721 was positive in 70.45%of the possible CD117 negative cases and in 47.45%of leimyosarcoma.For phosphorylated ab721,there were 78.43%of the possible CD117 negative cases and 52.54%of the leimyosarcoma were immunoactivated.The expression status of ab721 and phosphorylated ab721 was significantly correlated with mutation(P=0.009).In the 6 cases uterus leimyosarcoma 2 were positive for ab721,3 were positive for phosphorylated ab721.3 cases of superficial tissue or limb extreme leimyosarcoma were positive for ab721 and 4 cases were positive for phosphorylated ab721.The miRNA gene expression microarray revealed that miRNA-1 and miRNA-133 had the potential ability to differentiated GIST from leimyosarcoma,yet tested by in situ hybridization,miRNA-1 and miRNA-133 were expressed in GIST,leimyosarcoma and myogenetic tissues.In CD117 positive cases,45.04%were miRNA-1 positive,59.18% and 77.58%for the possible CD117 negative cases and leimyosarcoma respectively.For miRNA-133a,the frequency was 49.04%,38%,46.55%respectively.For miRNA-133a, the frequency were 40.27%,56%,72.88%respectively in those 3 series of tumors.The primary culture of GIST showed that the expression of myogentic markers were followed the variation of KIT expression.Multivariate COX hazard ratio model testified that the robust prognostic indicators for CD117 positive GIST were risk assessment(P=0.11),phosphorylated status of KIT ((P=0.12)and the anatomic location(P=0.006),and for the possible CD117 negative cases and leimyosarcoma,phosphorylated AKT(thr308)was the independently prognostic factor(P=0.044).Conclution1.Maybe,there have no true leimyosarcoma in the intra-abdominal cavity.Just like GIST,they can harbor the mutation of KIT or PDGFRA,the phosphorylation of KIT.2.The detection of ab721 and phosphorylated ab721 will facilitate the diagnosis of GIST and the target therapy of imatinib and sunitinib.3.The biological behavior of GIST can be predicted by the combined analysis of risk assessment,KIT phosphorylated status and anatomic location.4.GIST may not just limit in the intra-abdominal cavity but with a much more wide distribution.

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