DPC-4 (Smad-4) and K-ras gene mutations in biliary tract epithelium in children with anomalous pancreaticobiliary ductal union

Shimotake, Takashi; Aoi, Shigeyoshi; Tomiyama, Hideki; Iwai, Naoharu

doi:10.1016/jpsu.2003.50185

Cited by 34 publications

(19 citation statements)

References 13 publications

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“…5,104 Carcinogenesis is thought to occur via multistep genetic events where early K-ras and p53 mutations are seen in more than 60% of CC-related carcinomas 79,106-108 followed by a late occurring DPC-4 gene inactivation. 107 Most reported cases of malignant transformation are cholangiocarcinoma; however, gallbladder carcinoma is identified in 10% to 25% of CC-related malignancies 5,10,24,27,54 (Table 1). The presence of an APBDU is thought to play a role in carcinogenesis and hepatocellular damage due to reflux of pancreatic contents into the bile duct.…”

Section: Pathologic Characteristicsmentioning

confidence: 99%

Choledochal Cysts: Presentation, Clinical Differentiation, and Management

Soares

Arnaoutakis

Kamel

et al. 2014

Journal of the American College of Surgeons

244

285

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Section: Pathologic Characteristicsmentioning

confidence: 99%

Choledochal Cysts: Presentation, Clinical Differentiation, and Management

Soares

Arnaoutakis

Kamel

et al. 2014

Journal of the American College of Surgeons

244

285

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“…Both dilated and undilated non-cancerous parts of the bile duct in patients with an APBDJ exhibit k-ras and p53 mutations, reflecting the high risk of malignant change in the biliary epithelium 66,67 . Kras mutations develop at an early stage in hyperplasia and metaplasia, whereas DPC-4 (Smad4) mutations occur at a later stage, when adenocarcinoma is evident 68 . A role for microsatellite instability in carcinogenesis has been proposed 69 .…”

Section: Malignancymentioning

confidence: 99%

Bile duct cysts in adults

Søreide

Kørner

Havnen

et al. 2004

British Journal of Surgery

180

191

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An increasing rate of occurrence of bile duct cyst is reported in adults. Type IV cysts are more frequent in adults than children. Presentation tends to be non-specific abdominal discomfort. Related hepatobiliary or pancreatic disease frequently precedes recognition, and may complicate the postoperative course. Surgical treatment aims to relieve complications deriving from the cysts and to reduce the significant risk of malignant change within the biliary tree. Complete cyst resection, cholecystectomy and Roux-en-Y hepaticojejunostomy reconstruction is standard. Controversy exists about the role of hepatic resection in type IV and V cysts, and the role of minimally invasive and laparoscopic treatment. In general, the outcome is good and a near-zero mortality rate has been reported in institutional series over the past decade.

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“…Mutations in KRAS have been identified in gallbladder dysplasia and carcinoma in the setting of abnormal junction of the pancreatic and bile ducts [2][3][4]. Activation of the mitogen-activated protein kinase or the phosphoinositide 3-kinase signaling pathways via mutation in one of many involved genes appears to be important in the pathogenesis of GBC associated with cholelithiasis [4][5][6][7][8][9][10][11][12][13].…”

Section: Introductionmentioning

confidence: 99%

Microsatellite instability in gallbladder carcinoma

et al. 2015

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The genetic abnormalities involved in the pathogenesis of gallbladder carcinoma (GBC) remain unclear. Microsatellite instability (MSI) has been described in many carcinomas, but little is known about the significance of mismatch repair in gallbladder carcinogenesis. Additionally, methylation status of long interspersed element-1 (LINE-1), a surrogate marker of global DNA methylation, has defined distinct subsets of other cancer types but has not been explored in GBC. Immunohistochemical expression of MSH2, MSH6, MLH1, and PMS2 and LINE-1 mRNA in situ hybridization was evaluated in 67 primary and 15 metastatic GBCs from 77 patients. Amplification of human epidermal growth factor receptor 2 (HER2) was evaluated by fluorescence in situ hybridization. Genotyping for 24 genes involved in carcinogenesis was performed using a multiplex PCR-based platform. MSI was present in 6 of 77 GBCs (7.8 %). Loss of MSH2/MSH6 was detected in five cases and loss of MLH1/PMS2 in one case. MSI status was not associated with Lynch syndrome, tumor grade, extracellular mucin, or tumor-infiltrating lymphocytes. There was no significant difference in mean overall survival of patients with and without MSI. Strong LINE-1 staining was identified in none of the GBC with MSI and in 36 of 69 (52 %) of those without MSI (p = 0.005), suggesting that LINE-1 in the former cohort was hypermethylated. All MSI tumors were negative for HER2 amplification, and TP53 and NRAS mutations were only found in GBC without MSI. MSI was identified in a minority of GBC cases. The strong correlation between global DNA methylation as measured by LINE-1 and loss of mismatch repair proteins suggests that methylation may account for the loss of these proteins. These hypermethylated tumors appear to represent a genetically unique cohort of gallbladder neoplasms, and the data suggests that demethylating agents may have a therapeutic value in this class of tumors.

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DPC-4 (Smad-4) and K-ras gene mutations in biliary tract epithelium in children with anomalous pancreaticobiliary ductal union

Cited by 34 publications

References 13 publications

Choledochal Cysts: Presentation, Clinical Differentiation, and Management

Choledochal Cysts: Presentation, Clinical Differentiation, and Management

Bile duct cysts in adults

Microsatellite instability in gallbladder carcinoma

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