Dataset Information

GNAS codon 201 mutations are uncommon in intraductal papillary neoplasms of the bile duct.

ABSTRACT:

Background

Activating point mutations of GNAS at codon 201 have been detected in approximately two thirds of intraductal papillary mucinous neoplasms (IPMNs) of the pancreas. Intraductal papillary neoplasms of the bile ducts (IPNBs) morphologically resemble pancreatic IPMNs. This study sought to assess the mutational status of GNAS at codon 201 in IPNBs.

Methods

Thirty-four patients were included. DNA from microdissected IPNBs was subjected to a polymerase chain reaction and ligation method for the detection of GNAS mutations at codon 201 and of KRAS mutations at codon 12. Mutational status was compared with clinical and pathologic data.

Results

The IPNBs had a median diameter of 3.5 cm and were located intrahepatically (n= 6), extrahepatically (n= 13), both intra- and extrahepatically (n= 4) or in the gallbladder (intracystic papillary neoplasms, n= 11). Most exhibited pancreatobiliary differentiation (n= 20), high-grade dysplasia (n= 26) and an associated adenocarcinoma (n= 20). Analysis of GNAS codon 201 identified only one mutant sample in a multifocal intestinal subtype intrahepatic IPNB with high-grade dysplasia. Six lesions harboured a KRAS codon 12 mutation.

Conclusions

GNAS codon 201 mutations are uncommon in IPNBs, by contrast with pancreatic IPMNs. More comprehensive molecular profiling is needed to uncover the pathways involved in IPNB development.

SUBMITTER: Matthaei H

PROVIDER: S-EPMC3461374 | biostudies-literature | 2012 Oct

REPOSITORIES: biostudies-literature

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Publications

GNAS codon 201 mutations are uncommon in intraductal papillary neoplasms of the bile duct.

Matthaei Hanno H Wu Jian J Dal Molin Marco M Debeljak Marija M Lingohr Philipp P Katabi Nora N Klimstra David S DS Adsay N Volkan NV Eshleman James R JR Schulick Richard D RD Kinzler Kenneth W KW Vogelstein Bert B Hruban Ralph H RH Maitra Anirban A

HPB : the official journal of the International Hepato Pancreato Biliary Association 20120618 10

<h4>Background</h4>Activating point mutations of GNAS at codon 201 have been detected in approximately two thirds of intraductal papillary mucinous neoplasms (IPMNs) of the pancreas. Intraductal papillary neoplasms of the bile ducts (IPNBs) morphologically resemble pancreatic IPMNs. This study sought to assess the mutational status of GNAS at codon 201 in IPNBs.<h4>Methods</h4>Thirty-four patients were included. DNA from microdissected IPNBs was subjected to a polymerase chain reaction and ligat ...[more]

PMID: 22954004

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Project description:BackgroundIntraductal papillary mucinous neoplasm of the bile duct (IPMN-B) is considered an uncommon tumor, and there is limited understanding of IPMN-B. This study aimed to investigate the prognosis and influential factors of the IPMN-B from 58 cases.MethodsThe clinical data of 58 patients with pathologically confirmed IPMN-B admitted to our hospital from January 1, 2012 to August 2017 were collected and analyzed. The patients were followed up by outpatient or telephone until January 1, 2019. SPSS 19.0 software was applied for data analysis. Survival analysis was performed using Kaplan-Meier method and parallel Log-rank test. Prognostic factors were analyzed by univariate analysis and multiple Cox regression model.ResultsAmong of all the patients, 26 cases were benign tumors and 32 cases were malignant tumors. The preoperative tumor markers CA242 and CEA of malignant IPNM-B patients were significantly higher than those in benign tumors (P < 0.05). Survival analysis showed that patients with malignant tumors had a worse prognosis. The median survival time of malignant IPMN-B patients was 40.6 ± 3.0 months, yet median survival time of benign IPMN-B patients was not reached (P = 0.19). The one-year survival rate and three-year survival rate of benign IPMN-B were 84% and 74% respectively. The one-year survival rate and three-year survival rate of malignant IPMN-B were 88% and 64% respectively. Univariate analysis showed that combined lymph node metastasis, surgical method, and differentiation degree could affect patients' prognosis (P < 0.05). Multivariate analysis showed differentiation degree was an independent risk factor affecting prognosis (OR = 0.06, 95% confidence interval: 0.007∼0.486, P < 0.05).ConclusionThe levels of CEA and CA242 were helpful to identify benign and malignant of IPNM-B. Moreover, radical surgical resection could prolong patients' survival. Finally, differentiation degree was an independent risk factor affecting malignant IPNM-B prognosis.

Project description:Intraductal Papillary Mucinous Neoplasms (IPMNs) of the pancreas are cyst-like precursor lesions that give rise to 25% of pancreatic ductal adenocarcinomas (PDAC). While ~90% of cases are diagnosed before cancer forms, metrics and markers by which to determine if an IPMN will progress are currently lacking. Overall, 96% of IPMNs harbor KRAS (~80%) and/or GNAS (~66%) driver mutations and IPMN may be classified as either gastric, intestinal, or pancreatobiliary type. Recently, we identified a shared program of pyloric type metaplasia between pancreatic and gastric injury. Here, we combined immunostaining, RNA-sequencing, molecular biology, and analysis of patient samples to identify major drivers of this program in IPMN. Methods Single cell RNA-sequencing datasets of human IPMN were assayed for markers of pyloric-type metaplasia. 37 IPMN patient samples were immunostained using MxIHC for MUC5AC, CD44v9, and AQP5. KrasG12D and GnasR201C expression was modified in IPMN cell lines to identify transcriptomic programs driven by each oncogene, and in combination. Gene sets were compared to murine and human gastric cell types. Transcriptomic drivers were identified and manipulated in vitro. Candidate driver expression was evaluated by immunostaining of patient IPMN and graded. Results Analysis of published bulk and scRNA-seq IPMN datasets revealed expression of previously described markers of pyloric type metaplasia. Marker expression was confirmed in patient samples. Manipulation of KrasG12D and GnasR201C expression in IPMN cell lines identified the relative contributions of each oncogene to this gastric phenotype. Regulon analysis suggests that transcription factors SPDEF, CREB3L1, and CREB3L4 amplify this program in response to GnasR201C expression. All transcription factors were expressed in patient IPMN samples. Conclusions In response to oncogenic mutation(s), IPMN form in the pancreas and express markers of pyloric type metaplasia. KrasG12D and GnasR201C expression drive this program through independent and synergistic mechanisms that result in amplified expression of mucins and gastrokines, consistent with the phenotype identified in vivo.

Dataset Information

GNAS codon 201 mutations are uncommon in intraductal papillary neoplasms of the bile duct.

Background

Methods

Results

Conclusions

Publications

GNAS codon 201 mutations are uncommon in intraductal papillary neoplasms of the bile duct.

Similar Datasets

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