Chronic pancreatitis

Weiss, Frank Ulrich; Skube, Mariya E.; Lerch, Markus M.

doi:10.1097/mog.0000000000000461

Cited by 28 publications

(11 citation statements)

References 59 publications

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“…Genetic factors are among the main factors associated with chronic pancreatitis . Hereditary pancreatitis is often accompanied by germline variations in the PRSS , SPINK1 , and CFTR genes .…”

Section: Discussionmentioning

confidence: 99%

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Prevalence of Germline Sequence Variations Among Patients With Pancreatic Cancer in China

Yin

Wei

et al. 2022

JAMA Netw Open

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IMPORTANCE A higher incidence of pancreatic cancer has been reported in the Chinese population compared with the White population, but genetic differences are unknown to date. Large-sample germline testing for both familial and sporadic pancreatic cancers has been conducted predominantly in White populations, whereas similar studies in Chinese populations are limited. OBJECTIVETo assess the prevalence of germline sequence variations in patients with pancreatic diseases in China. DESIGN, SETTING, AND PARTICIPANTS This genetic association study was a case series that included genetic data from patients with pancreatic ductal adenocarcinoma (PDAC) or non-PDAC pancreatic diseases seen at The First Affiliated Hospital of Nanjing Medical University in Nanjing, China, between January 2006 and December 2017 (Nanjing cohort). Comparator group data were obtained for a US cohort from Johns Hopkins Hospital (JHH), a population from East Asia from the Exome Aggregation Consortium (ExAC) database, and the larger population from China from the ChinaMAP database. Data were updated and analyzed in July 2021. MAIN OUTCOMES AND MEASURES Next-generation sequencing technology was used to examine the prevalence of deleterious variations in 59 genes of the included Chinese patients with DNA extracted from peripheral blood samples. The Fisher exact test was used to assess differences among the frequencies of germline variations in the study patients vs the comparator groups. RESULTS A total of 1009 patients with PDAC (627 [62.1%] male; mean [SD] age, 62.8 [10.2] years)and 885 with non-PDAC diseases (477 [53.9%] male; mean [SD] age, 52.0 [15.9] years) from the Nanjing cohort were included for genetic analysis; all were Han Chinese individuals. Pathogenic variations were detected in 63 patients with PDAC (6.2%; 95% CI, 4.7%-7.7%). Variations in BRCA2 (odds ratio [OR], 3.2; 95% CI, 1.4-7.7; P = .008) and PALB2 (OR, 5.2; 95% CI, 1.6-17.0; P = .007) were significantly associated with pancreatic risk in the Nanjing cohort. Pathogenic variants of genes associated with homologous recombination DNA damage repair, including ATM, BRCA1/2, PALB2, BRIP1, FANCA, FANCC, RAD51D, and XRCC2, were found in 34 patients with PDAC (3.4%). No Ashkenazi Jewish-specific BRCA2 variation (p.Ser1982fs) was detected. The odds ratio of a SPINK1 variation in patients with PDAC was 3.2 (95% CI, 1.8-5.7; P < .001) in the Nanjing cohort compared with the ExAC cohort. Variations in the pancreatic secretory enzyme genes CPA1 and CPB1 were not detected in the Nanjing cohort. CONCLUSIONS AND RELEVANCEIn this genetic association study, sporadic pancreatic cancer was associated with pathogenic germline variations in a cohort from China. These findings provide insights into the genetic background of pancreatic cancer in the Han Chinese population with PDAC.

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Section: Discussionmentioning

confidence: 99%

“…Additional largesample studies of pancreatic cystic tumors are needed to investigate the prevalence of germline variations and their associations with patient outcomes. Genetic factors are among the main factors associated with chronic pancreatitis 28. Hereditary pancreatitis is often accompanied by germline variations in the PRSS, SPINK1, and CFTR genes 29.…”

mentioning

confidence: 99%

Prevalence of Germline Sequence Variations Among Patients With Pancreatic Cancer in China

Yin

Wei

et al. 2022

JAMA Netw Open

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“…Specific genetic variants are tied to aberrant biologic pathways: trypsin regulation, unfolded protein response, oxidative stress, ductal dysfunction, and abnormal cell signaling. 3,56 These pathogenic pathways are potential targets for novel therapies. Early genetic testing can help identify likely disease-causing pathways in an individual patient so that directed therapies can be developed to mitigate the effects of the underlying pathology rather than just providing symptomatic relief of a progressive, destructive disease.…”

Section: Genetics and Opportunities For Gene Interventionmentioning

confidence: 99%

Accelerating the Drug Delivery Pipeline for Acute and Chronic Pancreatitis

et al. 2018

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Recurrent acute pancreatitis (RAP) is a complex clinical syndrome with significant morbidity, unpredictable outcomes and limited treatment options. The National Institute of Diabetes and Digestive and Kidney Disease sponsored a workshop on July 25, 2018 in Pittsburgh, PA to address research gaps impeding development of effective therapies for pancreatitis. The RAP working group identified challenges to clinical progress using existing definitions, risk assessment, diagnostic and severity criteria, disease trajectories, outcomes and research methods. RAP includes all the risk of acute pancreatitis (AP) and often progresses to chronic pancreatitis (CP) with variable complications of chronic pain, exocrine insufficiency, diabetes and pancreatic cancer. However, the great variability among individuals with RAP requites better precision in defining the risks, individual episodes and their frequency, pathogenic pathways and specific outcome measures for each of the systems affected by pancreatic inflammation. Because of disease complexity, few patients are similar enough for traditional studies and methods to conduct clinical trials with small sample sizes are required. The need for genetic testing, biomarker development and better imaging methods was highlighted. Adaptive and N-of-one study designs, better endpoints and outcome measures including patient reported outcomes should considered early in developing future therapeutic trial design and include all stakeholders.

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“…While acute and chronic pancreatitis were previously viewed as separated diseases, today they are regarded as a continuum, with nearly 30% of the patients exhibiting overlapping phenotypes that manifest as recurrent pancreatitis. 1 Chronic pancreatitis (CP) develops from recurrent episodes of acute pancreatitis that lead to fibrosis, exocrine pancreatic insufficiency and diabetes. While initial triggers for pancreatitis are diverse, almost all of them result in premature activation of trypsin and subsequently other proteases in pancreatic acinar cells.…”

Section: Introductionmentioning

confidence: 99%

A Hypothesized Mechanism for Chronic Pancreatitis Caused by the N34S Mutation of Serine Protease Inhibitor Kazal-Type 1 Based on Conformational Studies

Kulke¹,

Nagel²,

Schulig³

et al. 2021

JIR

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Purpose: Although strongly related, the pathophysiological effect of the N34S mutation in the serine protease inhibitor Kazal type 1 (SPINK1) in chronic pancreatitis is still unknown. In this study, we investigate the conformational space of the human cationic trypsin-serine protease inhibitor complex. Methods: Simulations with molecular dynamics, replica exchange, and transition pathway methods are used. Results: Two main binding states of the inhibitor to the complex were found, which explicitly relate the influence of the mutation site to conformational changes in the active site of trypsin. Conclusion: Based on our result, a hypothesis is formulated that explains the development of chronic pancreatitis through accelerated digestion of the mutant by trypsin.

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Chronic pancreatitis

Cited by 28 publications

References 59 publications

Prevalence of Germline Sequence Variations Among Patients With Pancreatic Cancer in China

Prevalence of Germline Sequence Variations Among Patients With Pancreatic Cancer in China

Accelerating the Drug Delivery Pipeline for Acute and Chronic Pancreatitis

A Hypothesized Mechanism for Chronic Pancreatitis Caused by the N34S Mutation of Serine Protease Inhibitor Kazal-Type 1 Based on Conformational Studies

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