Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0030305 (pancreatitis)
 16,014 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Our understanding of the molecular genetics of pancreatic cancer has advanced spectacularly over the last 5 years so that this tumour type is now one of the best characterised of all malignancies. A small proportion of cases results from inherited predisposition due to germline transmission of a mutated CDKN2 or BRCA2 gene, while patients with familial pancreatitis due to a mutated cationic trypsinogen gene have a greatly increased risk of developing pancreatic cancer. The majority of cases are sporadic and are characterised at the molecular level by several key genetic abnormalities. The most frequent of these is point mutation of the dominant oncogene KRAS, a lesion which occurs as an early and possibly initiating event in tumourigenesis. Inactivating mutations of the tumour suppressor genes TP53, CDKN2 and SMAD4 are also frequently observed and this constellation of genetic defects sets pancreatic cancer apart from other types of cancer, a feature which could have important implications for molecular diagnosis. Genetic intervention for cancer prevention and therapy is becoming a clinical reality and several approaches are being pursued for pancreatic cancer. As well as tumour suppressor gene replacement and oncogene blockade, strategies with a potential bystander effect are showing promise. These include genetic prodrug activation therapy using selective expression of suicide genes and genetic immunomodulation with cytokines and tumour-associated antigens.
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PMID:Molecular advances in pancreatic cancer. 943 1

Biliopancreatic malignancy is one of the leading causes of cancer death in the Western world. Defining at risk groups has been difficult. Diabetes mellitus and pancreatitis increase the risk of pancreatic carcinoma, and inflammatory bowel disease and associated sclerosing colangitis increase the risk of biliary tract malignancy. Pancreatic carcinoma has also been described in pedigrees with inherited cancer predisposition. Extensive molecular profiling of pancreatic carcinomas has been accomplished over the past few years, but similar knowledge in other biliopancreatic malignancies is lacking. In almost all pancreas cancers at least one alteration will occur out of a combination of K-ras mutations and inactivation of the tumor suppressor genes p16/MTS1/ink4a, p53 and DPC4/Smad4. Mutations of K-ras and p16 have been described in hyperplastic and dysplastic pancreatic ductal lesions believed to be the non-malignant precursors of pancreatic carcinoma. Detection of K-ras mutations in clinical samples (biliopancreatic secretions, stool, duodenal aspirates, and blood) identical to ones present in primary pancreatic cancers and/or their precursor ductal lesions has been reported in pilot studies. Recently detection of 18q deletions (at the DPC4 locus) in pancreatic secretions from early pancreatic cancers was also reported. These advances raise the possibility that within well defined at risk groups it will be possible to use a combined set of molecular markers to screen clinical samples and detect early pancreatic cancer or even pre-malignant lesions. The fulfillment of this promise will depend on proving the role of molecular screening in decreasing morbidity and mortality, which will require well designed clinical studies.
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PMID:Biliopancreatic malignancy: screening the at risk patient with molecular markers. 1043 11

Pancreatic intraepithelial neoplasia (PanIN) is thought to be a precursor lesion of infiltrating pancreatic ductal adenocarcinoma (IPA). DPC4 is a tumor-suppressor gene on chromosome 18q21.1 and is inactivated in approximately 55% of IPAs. Recently, immunohistochemical labeling using a monoclonal antibody to the Dpc4 protein has been shown to mirror DPC4 genetic status in invasive adenocarcinomas of the pancreas. In the present study, we examined the role of Dpc4 loss in neoplastic progression and recurrence. Two cases in which a PanIN clinically progressed to an invasive adenocarcinoma and a third of a patient with IPA of the head of the pancreas who later developed invasive adenocarcinoma in the tail of the pancreas were studied using Dpc4 immunolabeling. The first patient underwent pancreatic resection, which revealed PanIN-3 that lacked Dpc4 expression, and the patient developed an invasive pancreatic ductal carcinoma 10 years later that shared this loss of expression. The second patient had a pancreaticoduodenectomy for recurrent pancreatitis, and the resected pancreas contained PanIN-3 with intact Dpc4 expression. Seventeen months later, the patient developed an invasive adenocarcinoma of the distal pancreas that also had intact Dpc4 expression. In the third case, the patient underwent pancreaticoduodenectomy for an invasive ductal adenocarcinoma with negative margins. This carcinoma lacked Dpc4 expression. Three years later, resection of the pancreatic tail showed a second invasive adenocarcinoma. The cancer in the tail of the gland showed intact Dpc4 expression, suggesting it represented a second primary tumor, not a recurrence. We conclude that Dpc4 expression in PanIN can be predictive of Dpc4 expression in the subsequent invasive ductal adenocarcinoma. Additionally, Dpc4 expression can be used to differentiate recurrent or persistent adenocarcinoma from a second primary adenocarcinoma.
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PMID:Pancreatic intraepithelial neoplasia and infiltrating adenocarcinoma: analysis of progression and recurrence by DPC4 immunohistochemical labeling. 1143 19

Members of the TGF-beta superfamily of cytokines have been implicated in pancreatic cancer, pancreatitis and in regulation and differentiation of pancreatic endocrine and exocrine cells. Different TGF-beta members signal through phosphorylation of different signal transduction proteins, which eventually form oligomers with SMAD 4 and translocate to the nucleus. Reverse transcriptase-polymerase chain reaction showed that SMADs 1, 2 and 4 are expressed in pancreatic islets. Immunostaining revealed that SMAD 1 and 4 predominantly were expressed by islet insulin and glucagon cells. Since SMAD 1 is known to transduce signals from receptors binding bone morphogenetic protein (BMP) these results indicate a previously unknown role of BMP-like ligands in islet function.
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PMID:Expression of SMAD signal transduction molecules in the pancreas. 1168 56

This paper overviewed risk factors of pancreatic cancer. Both genetic and environmental factors may be playing significant roles in the development of pancreatic cancer. Cigarette smoking has been established as a major risk factor for pancreatic cancer, based on findings from almost all epidemiological studies. Long-term smoking cessation may reduce the risk. The evidence that alcohol drinking and coffee consumption increase the risk is not sufficient, although an association with higher level of consumption remains a possibility. Diabetes mellitus, long-standing diabetes in particular, may be a risk factor for pancreatic cancer. Individuals with hereditary pancreatitis or non-hereditary chronic pancreatitis are possibly at increased risk of pancreatic cancer. Higher intake of meat and fat may be associated with an increased risk, while consumption of fruits/vegetables appears to have a protective effect. Individuals with mutations or deletion in such genes as K-ras, p16, p53, DPC4, and BRCA2 increased the risk of developing pancreatic cancer. Cigarette smoking may play a role in the development of these mutations.
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PMID:An Epidemiological Overview of Environmental and Genetic Risk Factors of Pancreatic Cancer. 1271 18

The genetic basis for invasive and preoneoplastic neoplasms of the exocrine and endocrine pancreas has been the subject of a number of investigations in recent years. The purpose of this paper was to briefly review and summarize the pertinent findings. High frequency changes associated with pancreatic adenocarcinomas include mutations of the k-ras oncogene, and inactivating alterations of the p53, p16, and DPC4 tumor suppressor genes. Hereditary syndromes that have a known predisposition for pancreatic adenocarcinoma development include hereditary pancreatitis, familial atypical multiple mole melanoma (FAMM) syndrome, Peutz-Jeghers syndrome, familial breast cancer (BRCA-2), hereditary nonpolyposis colorectal cancer syndrome (HNPCC), and Li-Fraumeni syndrome. The underlying genetic defects have been identified and are currently being studied. Germline mutations of the men-1 gene are responsible for the MEN-1 syndrome, known to be associated with pancreatic endocrine tumors. It appears that somatic mutations of the gene are present in at least a subset of sporadic tumors. In addition, alterations in the Rb/p16 pathway appear to be commonly associated with pancreatic endocrine tumors. Further characterization of pancreatic tumors will result in a better understanding of the cellular pathways involved in pancreatic tumorigenesis and holds promise to identify targets for novel diagnostic and therapeutic strategies.
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PMID:The genetics of pancreatic cancer. 1294 33

Connective tissue growth factor (CTGF/CCN2) is thought to play a role in normal wound repair and bone remodeling, but also promotes fibrosis in several disease processes including diabetic nephropathy, sclerodoma and pancreatitis. A contribution to desmoplasia associated with pancreatic cancer progression has also been proposed. CTGF is induced by TGFbeta in diverse cell types, but TGFbeta receptor mediated signaling is impaired in pancreatic cancers and cell lines, usually due to DPC4/Smad4 mutations which arise during the later stages of intraepithelial neoplastic progression. Therefore, in order to define signaling pathways that mediate basal and TGFbeta-induced CTGF expression in normal and transformed cells, we compared CTGF gene regulation in pancreatic cancer cells and fibroblasts by measuring the effects of small molecule inhibitors and dominant negative mutants of signaling proteins on CTGF promoter reporter activity, message, and protein expression. We determined that the previously identified TEF-1 cis element is essential for CTGF promoter reporter activity in pancreatic cancer cell lines. Whereas p38 mediated CTGF induction by TGFbeta in fibroblasts, MEK/ERK signaling mediated TGFbeta-induced CTGF expression in pancreatic cancer cells and was also responsible for basal CTGF expression in pancreatic cancer cell lines with defective Smad signaling. Since activating Ras mutations occur in the earliest stages of pancreatic cancer, CTGF may be induced independent of Smad4 in pancreatic cancer cells.
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PMID:Expression of connective tissue growth factor in pancreatic cancer cell lines. 1778 99

There has been substantial recent progress in our ability to image and sample the pancreas leading to the improved recognition of benign and premalignant conditions of the pancreas such as autoimmune pancreatitis (AIP) and mucinous lesions (mucinous cystic neoplasms [MCN] and intraductal papillary mucinous neoplasms [IPMN]), respectively. Clinically relevant and difficult situations that continue to be faced in this context include differentiating MCN and IPMN from nonmucinous pancreatic cysts, the early detection of malignant degeneration in MCN and IPMN, and accurate differentiation between pancreatic cancer and inflammatory masses, especially AIP. These challenges arise primarily due to the less than perfect sensitivity for malignancy utilizing cytological samples obtained via EUS and ERCP. Aspirates from pancreatic cysts are often paucicellular further limiting the accuracy of cytology. One approach to improve the diagnostic yield from these very small samples is through the use of molecular techniques. Because the development of pancreatic cancer and malignant degeneration in MCN and IPMN is associated with well studied genetic insults including oncogene activation (eg, k-ras), tumor suppressor gene losses (eg, p53, p16, and DPC4), and genome maintenance gene mutations (eg, BRCA2 and telomerase), detecting these molecular abnormalities may aid in improving our diagnostic accuracy. A number of studies have shown the utility of testing clinical samples from pancreatic lesions and bile duct strictures for these molecular markers of malignancy to differentiate between cancer and inflammation. The information from these studies will be discussed with emphasis on how to use this information in clinical practice.
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PMID:Differentiating neoplastic from benign lesions of the pancreas: translational techniques. 1989

We review the current situation concerning molecular biological analysis in respect of pancreatic cancer, using specimens obtained by endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA). K-ras, p53, p16, DPC4/SMAD4, telomerase activity are used for discrimination between tumor-forming pancreatitis and pancreatic cancer. Examination of heat shock protein (HSP) 27, ribonucleotide reductase, and other factors are examined in order to test the sensitivity to Gemcitabin. Comparative genomic hybridization analysis for pancreatic cancer specimens obtained by EUS-FNA was reported to be useful for evaluate the biological characteristics of pancreatic cancer before treatment. It is expected that the genetic diagnosis using EUS-FNA specimens will not only positively contribute to improving the diagnostic performance, but it will also provide valuable information for carrying out tailor-made treatment.
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PMID:Genetic diagnosis of pancreatic cancer using specimens obtained by EUS-FNA. 2153

Autoimmune pancreatitis (AIP) often manifests as a mass lesion causing obstructive jaundice, clinically mimicking pancreatic carcinoma. A diagnosis of AIP may obviate the need for surgical resection, as most patients respond to steroid treatment. However, it is not clear whether these 2 conditions can coexist. In this study, 105 specimens resected for pancreatic ductal adenocarcinoma (PDAC) that also have changes of chronic pancreatitis were examined for features considered to be characteristic of AIP. Of 105 cases of PDAC with changes of chronic pancreatitis, 10 (9.5%) exhibited histologic features of AIP, including exuberant fibrosis, lymphoplasmacytic infiltration, obliterative phlebitis, or granulocytic epithelial lesions. Of these 10 cases, 7 had more than 20 immunoglobulin G4+ plasma cells per high-power field. Of these 7 cases, 5 were analyzed for Kirsten rat sarcoma viral oncogene mutation and SMAD4 expression. Three cases showed K-ras mutation and/or loss of SMAD4 expression in benign AIP-like areas. These findings suggest 2 possibilities: first, AIP-like lesions may occur in a small but significant portion of PDAC cases; second, some PDACs may arise in a background of AIP. Therefore, caution is necessary when making a diagnosis of AIP by needle biopsy of a mass lesion, and patients with a tentative AIP diagnosis should be closely followed up clinically.
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PMID:Pancreatic ductal adenocarcinoma with autoimmune pancreatitis-like histologic and immunohistochemical features. 2445 81


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