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Mutational profiling of kinases in human tumours of pancreatic origin identifies candidate cancer genes in ductal and ampulla of vater carcinomas.

ABSTRACT: BACKGROUND: Protein kinases are key regulators of cellular processes (such as proliferation, apoptosis and invasion) that are often deregulated in human cancers. Accordingly, kinase genes have been the first to be systematically analyzed in human tumors leading to the discovery that many oncogenes correspond to mutated kinases. In most cases the genetic alterations translate in constitutively active kinase proteins, which are amenable of therapeutic targeting. Tumours of the pancreas are aggressive neoplasms for which no effective therapeutic strategy is currently available. METHODOLOGY/PRINCIPAL FINDINGS: We conducted a DNA-sequence analysis of a selected set of 35 kinase genes in a panel of 52 pancreatic exocrine neoplasms, including 36 pancreatic ductal adenocarcinoma, and 16 ampulla of Vater cancer. Among other changes we found somatic mutations in ATM, EGFR, EPHA3, EPHB2, and KIT, none of which was previously described in cancers. CONCLUSIONS/SIGNIFICANCE: Although the alterations identified require further experimental evaluation, the localization within defined protein domains indicates functional relevance for most of them. Some of the mutated genes, including the tyrosine kinases EPHA3 and EPHB2, are clearly amenable to pharmacological intervention and could represent novel therapeutic targets for these incurable cancers.

SUBMITTER: Corbo V

PROVIDER: S-EPMC2935892 | biostudies-literature | 2010

REPOSITORIES: biostudies-literature

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Mutational profiling of kinases in human tumours of pancreatic origin identifies candidate cancer genes in ductal and ampulla of vater carcinomas.

Corbo Vincenzo V Ritelli Rossana R Barbi Stefano S Funel Niccola N Campani Daniela D Bardelli Alberto A Scarpa Aldo A

PloS one 20100908 9

<h4>Background</h4>Protein kinases are key regulators of cellular processes (such as proliferation, apoptosis and invasion) that are often deregulated in human cancers. Accordingly, kinase genes have been the first to be systematically analyzed in human tumors leading to the discovery that many oncogenes correspond to mutated kinases. In most cases the genetic alterations translate in constitutively active kinase proteins, which are amenable of therapeutic targeting. Tumours of the pancreas are ...[more]

PMID: 20838624

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Project description:Tumors of the pancreas, the ampulla of Vater, and the extrahepatic and intrahepatic bile ducts have significant histological similarities due to the common embryonic origin of the pancreatobiliary system. This obviates the need for discovery of biomarkers with diagnostic and prognostic value for these tumors. Mucins, especially MUC-1, -2, -4 and -5AC, are important candidates for developing into such reliable biomarkers. Increased expression of MUC1 occurs in pancreatic ductal adenocarcinomas and is associated with increased degrees of dysplasia in pancreatic intraepithelial neoplasia (PanIN). Positive expression of MUC2 in intraductal papillary mucinus neoplasms (IPMN) of the intestinal type indicates high potential progression to invasive carcinoma with de novo expression of MUC1, while absence of MUC2 expression in IPMNs of gastric type implies low potential to malignant evolution. De novo MUC4 expression correlates to the severity of dysplasia in PanIN and is associated with a poor prognosis in patients with pancreatic ductal adenocarcinomas. In biliary intraepithelial neoplasia (BilIN), increased expression of MUC1 is associated with higher degrees of dysplasia. Intrahepatic cholangiocarcinomas (ICC) are characterized by increased expression of all glycoforms of MUC1. Positive MUC2 expression in intraductal papillary neoplasm of the bile ducts (IPNB) of the intestinal type indicates high malignant potential with de novo expression of MUC1 in the invasive element. Absent MUC2 expression in any degree of BilIN may prove useful in differentiating them from IPNB. De novo expression of MUC4 is associated with poor prognosis in patients with ICC or carcinoma of the extrahepatic bile ducts (EHBDC). High de novo expression of MUC5AC is found in all degrees of BilIN and all types of IPNB and ICC. The MUC5AC is useful in the detection of neoplastic lesions of the bile duct at an early stage. Increased expression of mucin MUC1 in carcinoma of the ampulla of Vater associated with unfavorable behavior of the tumor, such as lymph node metastasis, infiltration of the pancreas and duodenum, advanced TNM classification and worse prognosis. Patients with intra-ampullary papillary-tubular neoplasm (IAPN) of the pancreatobiliary immunophenotype did not show MUC2, while those of the intestinal immunophenotype are MUC2 positive. The expression of MUC4 is associated with poor prognosis in patients with carcinoma of the ampulla of Vater favoring metastasis and making them resistant to apoptosis. Moreover, it appears that MUC4 positivity correlates with recurrence of the tumor. Expression of MUC5AC is associated with the invasive potential of the tumor.

Project description:LESSONS LEARNED:Panitumumab has no clinical activity in metastatic RAS wild-type small bowel adenocarcinoma (SBA) and ampullary adenocarcinoma (AAC), possibly due to the foregut and midgut derivation of small bowel and ampulla.These results, along with findings from genomic characterization of SBA, suggest that SBA represents a unique intestinal malignancy and treatments should not be habitually extrapolated from colorectal cancer.Further studies evaluating the benefit of targeted therapies exclusively in SBA and AAC are warranted. BACKGROUND:Given the benefit of epidermal growth factor receptor (EGFR) monoclonal antibodies in colorectal cancer (CRC), we sought to evaluate the efficacy of panitumumab in metastatic RAS wild-type small bowel adenocarcinoma (SBA) and ampullary adenocarcinoma (AAC). METHODS:We conducted a single-center, open-label, single-arm, Bayesian phase II trial. The primary objective was response rate (RR). Panitumumab was administered at a dose of 6 mg/kg intravenously (IV) every 14 days. RESULTS:Nine patients (male/female 7:2, median age: 61 years [range: 40-74], Eastern Cooperative Oncology Group [ECOG] performance status 0/1: 2/7) were enrolled from September 2013 to October 2015. One patient had AAC (pancreaticobiliary subtype) and eight patients had SBA (three duodenal, five jejunal/ileal). Acneiform rash was the most common toxicity. The study was stopped early due to futility with no responses, stable disease (SD) in two patients, and progression of disease (PD) in seven patients. Median progression-free survival (PFS) and overall survival (OS) were 2.4 and 5.7 months, respectively. No patients had extended RAS mutations (exons 2/3/4), but two patients had BRAF G469A and one patient had PIK3CA H1074R mutations. CONCLUSION:Panitumumab had no clinically meaningful activity in patients with metastatic RAS wild-type SBA and AAC. Our findings may relate to the primarily midgut and foregut derivation of the small bowel and ampulla.

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Mutational profiling of kinases in human tumours of pancreatic origin identifies candidate cancer genes in ductal and ampulla of vater carcinomas.

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Mutational profiling of kinases in human tumours of pancreatic origin identifies candidate cancer genes in ductal and ampulla of vater carcinomas.

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