Genetic Risk Factors for Pancreatic Disorders

Whitcomb, David C.

doi:10.1053/j.gastro.2013.01.069

Cited by 259 publications

(187 citation statements)

References 122 publications

Supporting

Mentioning

182

Contrasting

Unclassified

Order By: Relevance

“…Such genes were selected among the genes annotated in the "Pancreatic Secretion Pathway" (map04972), available in the KEGG database (22). The 70 genes selected were classified into six groups according to the activity of the encoded protein or their role in the pathogenesis of pancreatitis: (i) genes encoding proteins potentially involved in premature intrapancreatic activation of trypsin (CFTR, PRSS1, PRSS2, SPINK1, CTRC, CTSB, KRT8 and CASR) (23)(24)(25)(26)(27)(28)(29)(30); (ii) CF modifier genes the risk increases for patients with residual pancreatic function (about 10% of cases). However, also excluding all such causes, about one-third of recurrent/ chronic pancreatitis remains idiopathic, and this number is higher in children, who seldom report the classical risk factors observed in adults (8).…”

Section: Miseq Panel Genesmentioning

confidence: 99%

Extensive Molecular Analysis Suggested the Strong Genetic Heterogeneity of Idiopathic Chronic Pancreatitis

Sofia

Sacco

Surace

et al. 2016

Mol Med

View full text Add to dashboard Cite

Genetic features of chronic pancreatitis (CP) have been investigated extensively, mainly by testing genes associated to the trypsinogen activation pathway. However, different molecular pathways involving other genes may be implicated in CP pathogenesis. A total of 80 patients with idiopathic chronic pancreatitis (ICP) were investigated using a Next-Generation Sequencing (NGS) approach with a panel of 70 genes related to six different pancreatic pathways: premature activation of trypsinogen, modifier genes of cystic fibrosis phenotype, pancreatic secretion and ion homeostasis, calcium signaling and zymogen granules (ZG) exocytosis, autophagy and autoimmune pancreatitis-related genes. We detected mutations in 34 out of 70 genes examined; of the 80 patients, 64 (80.0%) were positive for mutations in one or more genes and 16 (20.0%) had no mutations. Mutations in CFTR were detected in 32 of the 80 patients (40.0%) and 22 of them exhibited at least one mutation in genes of other pancreatic pathways. Of the remaining 48 patients, 13/80 (16.3%) had mutations in genes involved in premature activation of trypsinogen and 19/80 (23.8%) had mutations only in genes of the other pathways: 38 (59.3%) of the 64 patients positive for mutations showed variants in two or more genes. Our data, although to be extended with functional analysis of novel mutations, suggest a high rate of genetic heterogeneity in CP and that trans-heterozygosity may predispose to the ICP phenotype. online address: http://www.molmed.org

show abstract

Section: Miseq Panel Genesmentioning

confidence: 99%

Extensive Molecular Analysis Suggested the Strong Genetic Heterogeneity of Idiopathic Chronic Pancreatitis

Sofia

Sacco

Surace

et al. 2016

Mol Med

View full text Add to dashboard Cite

show abstract

“…3 We and others have also reported similar findings using different strains of Tet2-mutant mice. [4][5][6][7] These observations led us to speculate that enhanced HSC function of Tet2-mutant mice sets a critical background for malignant transformation, and such dysregulated HSCs are the cell of origin for myeloid malignancies. However, leukemic stem cells (LSCs) of myeloid leukemia have been shown to emerge from committed progenitors, such as common myeloid progenitors (CMPs) or granulocyte-monocyte progenitors with enhanced selfrenewal capacity conferred by leukemia-associated oncogenes.…”

Section: To the Editormentioning

confidence: 99%

“…Other mechanisms postulated for the observed toxicity include circulating unconjugated monomethylauristatin E, the presence of isolated CD30-positive malignant cells in the pancreas of some patients, or host factors such as mutations predisposing patients to the development of acute or chronic pancreatitis. 7 BV offers a promising therapeutic advance for the treatment of CD30-positive lymphomas, with limited toxicity. This series demonstrates an uncommon, previously unreported, and potentially life-threatening adverse event.…”

mentioning

confidence: 99%

Pancreatitis in patients treated with brentuximab vedotin: a previously unrecognized serious adverse event

Gandhi

Evens

Fenske

et al. 2014

Blood

View full text Add to dashboard Cite

Pancreatitis in patients treated with brentuximab vedotin: a previously unrecognized serious adverse event Brentuximab vedotin (BV) is a novel anti-CD30 antibody drug conjugate that gained accelerated regulatory approval 1 after studies demonstrating impressive efficacy in relapsed Hodgkin lymphoma and anaplastic large cell lymphoma.2-4 The cytotoxic component is monomethylauristatin E, a potent inhibitor of microtubule assembly. Although abdominal pain has been reported in up to 18% of patients treated with BV, pancreatitis is a previously unidentified serious adverse event (while this report was under review, an additional case of BV-associated pancreatitis was reported in which the patient was successfully retreated 5

show abstract

“…The main goals in the clinical management of AP are adequate fluid resuscitation and the prevention of MOF (6,7). Both genetic and environmental factors affect the development and severity of pancreatitis (8). Although the pathogenic mechanisms remain largely unknown, increasing evidence suggests that damageassociated molecular pattern molecules (DAMPs) play a central role in the pathogenesis of AP.…”

Section: Introductionmentioning

confidence: 99%

Cell Death and DAMPs in Acute Pancreatitis

Kang

Lotze

Zeh

et al. 2014

Mol Med

129

View full text Add to dashboard Cite

The pancreas is a dual-purpose gland with exocrine and endocrine functions. The exocrine pancreas produces digestive proteases in inactive proenzyme form, namely zymogens. The pancreas is normally able to protect itself from zymogen activation by synthesis of protease inhibitors such as pancreatic secretory trypsin inhibitor and serine protease inhibitor (for example, SPINK1/Spink3). By contrast, pancreatic autodigestion and subsequent AP is initiated once these defenses are impaired. In studies of rodent models (for example, repetitive cerulein or L-arginine injections, choline-deficient ethionine supplementation [CDE] diet, perfusion of taurocholate into the biliary or pancreatic duct and surgical ligation or infusion of pancreatic duct models), some essential pathogenic AP events have been identified (see Figure 1) (15,16).The development of AP involves a complex cascade of events (17), which start with injury or disruption of the pan- Cell Death and DAMPs in Acute PancreatitisRui Kang, Michael T Lotze, Herbert J Zeh, Timothy R Billiar, and Daolin Tang Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America Cell death and inflammation are key pathologic responses of acute pancreatitis (AP), the leading cause of hospital admissions for gastrointestinal disorders. It is becoming increasingly clear that damage-associated molecular pattern molecules (DAMPs) play an important role in the pathogenesis of AP by linking local tissue damage to systemic inflammation syndrome. Endogenous DAMPs released from dead, dying or injured cells initiate and extend sterile inflammation via specific pattern recognition receptors. Inhibition of the release and activity of DAMPs (for example, high mobility group box 1, DNA, histones and adenosine triphosphate) provides significant protection against experimental AP . Moreover, increased serum levels of DAMPs in patients with AP correlate with disease severity. These findings provide novel insight into the mechanism, diagnosis and management of AP . DAMPs might be an attractive therapeutic target in AP.

show abstract

Genetic Risk Factors for Pancreatic Disorders

Cited by 259 publications

References 122 publications

Extensive Molecular Analysis Suggested the Strong Genetic Heterogeneity of Idiopathic Chronic Pancreatitis

Extensive Molecular Analysis Suggested the Strong Genetic Heterogeneity of Idiopathic Chronic Pancreatitis

Pancreatitis in patients treated with brentuximab vedotin: a previously unrecognized serious adverse event

Cell Death and DAMPs in Acute Pancreatitis

Contact Info

Product

Resources

About