Diseases of the exocrine pancreas such as recurrent acute pancreatitis (RAP), chronic pancreatiti... more Diseases of the exocrine pancreas such as recurrent acute pancreatitis (RAP), chronic pancreatitis (CP) and pancreatic ductal adenocarcinoma (PDAC) represent syndromes defined according to traditional clinicopathologic criteria. The failure of traditional approaches to identify primary mechanisms underlying these progressive disorders illustrates a greater problem of failure of the germ theory of disease for complex disorders. Multiple genetic discoveries and new complex disease models force consideration of a new paradigm of ‘precision medicine’, requiring a new mechanistic definition of CP. Recognizing the advances in understanding complex gene and environment interactions, as well as the development of new strategies that limit or prevent the development of devastating end-stage diseases of the pancreas may lead to substantial improvements in patient care.
Hereditary pancreatitis is typically caused by the PRSS1 R122H or N29I mutations resulting in hig... more Hereditary pancreatitis is typically caused by the PRSS1 R122H or N29I mutations resulting in high penetrance (about 80%) autosomal dominant disorder that is usually reported in North America, Northern Europe and Northeast Asia, but not South America, Africa or India. Here we report a kindred from Venezuela, South America with the PRSS1 R122H variant. Only the proband, an 11-year old boy with severe chronic pancreatitis, and a maternal grandmother with pancreatitis at age 60 years (confirmed PRSS1 R122H), are symptomatic. Issues of mutation prevalence, non-penetrance, and disease recognition in various countries are discussed.
American Journal of Physiology-Gastrointestinal and Liver Physiology, 2004
Pancreatic inflammation appears to increase the risk of pancreatic cancer. This observation is st... more Pancreatic inflammation appears to increase the risk of pancreatic cancer. This observation is striking in the hereditary pancreatitis kindreds but also occurs in alcoholic, idiopathic, and tropical chronic pancreatitis and cystic fibrosis. However, the mutations associated with hereditary pancreatitis or cystic fibrosis are not found in sporadic pancreatic adenocarcinomas, suggesting that the effects are indirect by causing recurrent pancreatitis and chronic inflammation. The process of mutation accumulation and clonal expansion that is required for development of invasive pancreatic adenocarcinoma must therefore be accelerated in chronic pancreatitis to account for the high incidence of pancreatic cancer in these patients.
Context Hereditary pancreatitis is typically caused by the PRSS1 R122H or N29I mutations resultin... more Context Hereditary pancreatitis is typically caused by the PRSS1 R122H or N29I mutations resulting in high penetrance (about 80%) autosomal dominant disorder that is usually reported in North America, Northern Europe and Northeast Asia, but not South America, Africa or India. Case report Here we report a kindred from Venezuela, South America with the PRSS1 R122H variant. Only the proband, an 11-year old boy with severe chronic pancreatitis, and a maternal grandmother with pancreatitis at age 60 years (confirmed PRSS1 R122H), are symptomatic. Conclusions Issues of mutation prevalence, non-penetrance, and disease recognition in various countries are discussed.
Pancreatic cancer requires many genetic mutations. Combinations of underlying germline variants a... more Pancreatic cancer requires many genetic mutations. Combinations of underlying germline variants and environmental factors may increase the risk of cancer and accelerate the oncogenic process. We systematically reviewed, annotated, and classified previously reported pancreatic cancer-associated germline variants in established risk genes. Variants were scored using multiple criteria and binned by evidence for pathogenicity, then annotated with published functional studies and associated biological systems/pathways. Twenty-two previously identified pancreatic cancer risk genes and 337 germline variants were identified from 97 informative studies that met our inclusion criteria. Fifteen of these genes contained 66 variants predicted to be pathogenic (APC, ATM, BRCA1, BRCA2, CDKN2A, CFTR, CHEK2, MLH1, MSH2, NBN, PALB2, PALLD, PRSS1, SPINK1, TP53). Pancreatic cancer risk genes were organized into key biological mechanisms that promote pancreatic oncogenesis within an oncogenic model. Dev...
Hereditary pancreatitis is the early onset form of chronic pancreatitis that is carried in an aut... more Hereditary pancreatitis is the early onset form of chronic pancreatitis that is carried in an autosomal dominant pattern with variable penetrance. While 80% of hereditary pancreatitis has been shown to be due to a single mutation in the trypsinogen gene PRSS1, a number of hereditary pancreatitis families have no identified genetic cause for illness; thus no reliable screening options or clear therapy. To explore the use of massive parallel DNA sequencing technology to discover the etiology of pancreatitis in a family with idiopathic hereditary pancreatitis. Candidate gene screening and verification within a kindred. Prospective cohort study, university based. Kindred with idiopathic hereditary pancreatitis. None. Identification of DNA variants predicted to increase susceptibility to pancreatitis. Whole exome sequencing of two distantly related subjects with variant-specific confirmation in the subjects and other family members. We identified three deleterious genetic changes in the ...
Genetic risk for acute pancreatitis (AP), recurrent acute pancreatitis (RAP) and chronic pancreat... more Genetic risk for acute pancreatitis (AP), recurrent acute pancreatitis (RAP) and chronic pancreatitis (CP) are increasingly recognized. The exocrine pancreas is composed of both acinar cells and duct cells, with genetic factors associated with AP, RAP and CP linked to one cell type or the other. Increased susceptibility to pancreatitis occurs when the normal physiological mechanisms that allow the pancreas to respond to common stresses or injury are altered. Currently, most our knowledge about genetics focuses on three genes that play critical roles in pancreatic function (PRSS1, CFTR, SPINK1) such that isolated defects lead to disease. However, recent data suggest that more complex combination of genetic and environmental factors are also as important, or more important than Mendelian genetic risk. Understanding of complex interactions requires modeling of these factors so that the response to stresses or injury can be simulated and critical interactions understood. A simple duct c...
Growing evidence suggests that recurrent acute pancreatitis leads to chronic pancreatitis, but th... more Growing evidence suggests that recurrent acute pancreatitis leads to chronic pancreatitis, but this sequence is seldom reported in human subjects. The sentinel acute pancreatitis event hypothesis suggests that an initial episode of acute pancreatitis is the first step in a complicated series of events ultimately leading to chronic pancreatitis. To identify patients who evolved from recurrent acute pancreatitis to chronic pancreatitis. The Severity of Acute Pancreatitis Study (SAPS) database was reviewed. Four out of 102 enrolled patients fulfilled the above sequence of events: progression from a single self-limited episode of acute pancreatitis to recurrent attacks to chronic pancreatitis proven by CT scan. However, not all 102 enrolled patients were followed with CT scans; hence there may be more patients with progression. In all four patients, upon initial presentation, there was no evidence of chronic pancreatitis on the CT scan performed and no clear acute pancreatitis etiology ...
In chronic calcific pancreatitis of the tropics, etiology and relationship to developing diabetes... more In chronic calcific pancreatitis of the tropics, etiology and relationship to developing diabetes mellitus are unknown. Some consider these cases a straightforward secondary type of diabetes, while others suggest selective beta-cell impairment. Testing pancreatic function, we investigated whether selective beta-cell impairment triggers diabetes associated with tropical pancreatitis. At a Bangladeshi research institute, 8 chronic tropical pancreatitis and no diabetes mellitus subjects, 14 fibrocalculous pancreatic diabetics and 27 matched healthy controls underwent arginine (endocrine pancreatic function) and secretin (exocrine pancreatic function assessment) stimulation tests. All patients with clinically-diagnosed, chronic pancreatitis demonstrated pronounced exocrine pancreatic dysfunction with beta-cell functioning differing significantly between the two groups. Compared to controls, patients having tropical pancreatitis and no diabetes showed normal plasma C-peptide values at baseline and after arginine stimulation, while fibrocalculous pancreatic diabetics demonstrated a typical diabetic pattern for plasma C-peptide levels. In contrast, pancreatic alpha-cell functioning (glucagon response to arginine) was preserved in both pancreatitis groups. A preserved pancreatic alpha-cell function in diabetics with advanced chronic pancreatitis of the tropics supports the concept of two different pathogenic mechanisms, one eliciting chronic pancreatitis and the other selective pancreatic beta-cell impairment and subsequent diabetes mellitus.
The etiology of nonalcoholic chronic pancreatitis, occurring in tropical regions, is unknown. Alt... more The etiology of nonalcoholic chronic pancreatitis, occurring in tropical regions, is unknown. Although environmental factors may play a role in its pathogenesis, a specific genetic predisposition may be necessary. The genetic mutation responsible for hereditary pancreatitis was described recently. Unlike in patients with hereditary pancreatitis, we found a lack of the R117H mutation in the cationic trypsinogen gene in all patients with tropical pancreatitis from Bangladesh.
Diseases of the exocrine pancreas such as recurrent acute pancreatitis (RAP), chronic pancreatiti... more Diseases of the exocrine pancreas such as recurrent acute pancreatitis (RAP), chronic pancreatitis (CP) and pancreatic ductal adenocarcinoma (PDAC) represent syndromes defined according to traditional clinicopathologic criteria. The failure of traditional approaches to identify primary mechanisms underlying these progressive disorders illustrates a greater problem of failure of the germ theory of disease for complex disorders. Multiple genetic discoveries and new complex disease models force consideration of a new paradigm of ‘precision medicine’, requiring a new mechanistic definition of CP. Recognizing the advances in understanding complex gene and environment interactions, as well as the development of new strategies that limit or prevent the development of devastating end-stage diseases of the pancreas may lead to substantial improvements in patient care.
Hereditary pancreatitis is typically caused by the PRSS1 R122H or N29I mutations resulting in hig... more Hereditary pancreatitis is typically caused by the PRSS1 R122H or N29I mutations resulting in high penetrance (about 80%) autosomal dominant disorder that is usually reported in North America, Northern Europe and Northeast Asia, but not South America, Africa or India. Here we report a kindred from Venezuela, South America with the PRSS1 R122H variant. Only the proband, an 11-year old boy with severe chronic pancreatitis, and a maternal grandmother with pancreatitis at age 60 years (confirmed PRSS1 R122H), are symptomatic. Issues of mutation prevalence, non-penetrance, and disease recognition in various countries are discussed.
American Journal of Physiology-Gastrointestinal and Liver Physiology, 2004
Pancreatic inflammation appears to increase the risk of pancreatic cancer. This observation is st... more Pancreatic inflammation appears to increase the risk of pancreatic cancer. This observation is striking in the hereditary pancreatitis kindreds but also occurs in alcoholic, idiopathic, and tropical chronic pancreatitis and cystic fibrosis. However, the mutations associated with hereditary pancreatitis or cystic fibrosis are not found in sporadic pancreatic adenocarcinomas, suggesting that the effects are indirect by causing recurrent pancreatitis and chronic inflammation. The process of mutation accumulation and clonal expansion that is required for development of invasive pancreatic adenocarcinoma must therefore be accelerated in chronic pancreatitis to account for the high incidence of pancreatic cancer in these patients.
Context Hereditary pancreatitis is typically caused by the PRSS1 R122H or N29I mutations resultin... more Context Hereditary pancreatitis is typically caused by the PRSS1 R122H or N29I mutations resulting in high penetrance (about 80%) autosomal dominant disorder that is usually reported in North America, Northern Europe and Northeast Asia, but not South America, Africa or India. Case report Here we report a kindred from Venezuela, South America with the PRSS1 R122H variant. Only the proband, an 11-year old boy with severe chronic pancreatitis, and a maternal grandmother with pancreatitis at age 60 years (confirmed PRSS1 R122H), are symptomatic. Conclusions Issues of mutation prevalence, non-penetrance, and disease recognition in various countries are discussed.
Pancreatic cancer requires many genetic mutations. Combinations of underlying germline variants a... more Pancreatic cancer requires many genetic mutations. Combinations of underlying germline variants and environmental factors may increase the risk of cancer and accelerate the oncogenic process. We systematically reviewed, annotated, and classified previously reported pancreatic cancer-associated germline variants in established risk genes. Variants were scored using multiple criteria and binned by evidence for pathogenicity, then annotated with published functional studies and associated biological systems/pathways. Twenty-two previously identified pancreatic cancer risk genes and 337 germline variants were identified from 97 informative studies that met our inclusion criteria. Fifteen of these genes contained 66 variants predicted to be pathogenic (APC, ATM, BRCA1, BRCA2, CDKN2A, CFTR, CHEK2, MLH1, MSH2, NBN, PALB2, PALLD, PRSS1, SPINK1, TP53). Pancreatic cancer risk genes were organized into key biological mechanisms that promote pancreatic oncogenesis within an oncogenic model. Dev...
Hereditary pancreatitis is the early onset form of chronic pancreatitis that is carried in an aut... more Hereditary pancreatitis is the early onset form of chronic pancreatitis that is carried in an autosomal dominant pattern with variable penetrance. While 80% of hereditary pancreatitis has been shown to be due to a single mutation in the trypsinogen gene PRSS1, a number of hereditary pancreatitis families have no identified genetic cause for illness; thus no reliable screening options or clear therapy. To explore the use of massive parallel DNA sequencing technology to discover the etiology of pancreatitis in a family with idiopathic hereditary pancreatitis. Candidate gene screening and verification within a kindred. Prospective cohort study, university based. Kindred with idiopathic hereditary pancreatitis. None. Identification of DNA variants predicted to increase susceptibility to pancreatitis. Whole exome sequencing of two distantly related subjects with variant-specific confirmation in the subjects and other family members. We identified three deleterious genetic changes in the ...
Genetic risk for acute pancreatitis (AP), recurrent acute pancreatitis (RAP) and chronic pancreat... more Genetic risk for acute pancreatitis (AP), recurrent acute pancreatitis (RAP) and chronic pancreatitis (CP) are increasingly recognized. The exocrine pancreas is composed of both acinar cells and duct cells, with genetic factors associated with AP, RAP and CP linked to one cell type or the other. Increased susceptibility to pancreatitis occurs when the normal physiological mechanisms that allow the pancreas to respond to common stresses or injury are altered. Currently, most our knowledge about genetics focuses on three genes that play critical roles in pancreatic function (PRSS1, CFTR, SPINK1) such that isolated defects lead to disease. However, recent data suggest that more complex combination of genetic and environmental factors are also as important, or more important than Mendelian genetic risk. Understanding of complex interactions requires modeling of these factors so that the response to stresses or injury can be simulated and critical interactions understood. A simple duct c...
Growing evidence suggests that recurrent acute pancreatitis leads to chronic pancreatitis, but th... more Growing evidence suggests that recurrent acute pancreatitis leads to chronic pancreatitis, but this sequence is seldom reported in human subjects. The sentinel acute pancreatitis event hypothesis suggests that an initial episode of acute pancreatitis is the first step in a complicated series of events ultimately leading to chronic pancreatitis. To identify patients who evolved from recurrent acute pancreatitis to chronic pancreatitis. The Severity of Acute Pancreatitis Study (SAPS) database was reviewed. Four out of 102 enrolled patients fulfilled the above sequence of events: progression from a single self-limited episode of acute pancreatitis to recurrent attacks to chronic pancreatitis proven by CT scan. However, not all 102 enrolled patients were followed with CT scans; hence there may be more patients with progression. In all four patients, upon initial presentation, there was no evidence of chronic pancreatitis on the CT scan performed and no clear acute pancreatitis etiology ...
In chronic calcific pancreatitis of the tropics, etiology and relationship to developing diabetes... more In chronic calcific pancreatitis of the tropics, etiology and relationship to developing diabetes mellitus are unknown. Some consider these cases a straightforward secondary type of diabetes, while others suggest selective beta-cell impairment. Testing pancreatic function, we investigated whether selective beta-cell impairment triggers diabetes associated with tropical pancreatitis. At a Bangladeshi research institute, 8 chronic tropical pancreatitis and no diabetes mellitus subjects, 14 fibrocalculous pancreatic diabetics and 27 matched healthy controls underwent arginine (endocrine pancreatic function) and secretin (exocrine pancreatic function assessment) stimulation tests. All patients with clinically-diagnosed, chronic pancreatitis demonstrated pronounced exocrine pancreatic dysfunction with beta-cell functioning differing significantly between the two groups. Compared to controls, patients having tropical pancreatitis and no diabetes showed normal plasma C-peptide values at baseline and after arginine stimulation, while fibrocalculous pancreatic diabetics demonstrated a typical diabetic pattern for plasma C-peptide levels. In contrast, pancreatic alpha-cell functioning (glucagon response to arginine) was preserved in both pancreatitis groups. A preserved pancreatic alpha-cell function in diabetics with advanced chronic pancreatitis of the tropics supports the concept of two different pathogenic mechanisms, one eliciting chronic pancreatitis and the other selective pancreatic beta-cell impairment and subsequent diabetes mellitus.
The etiology of nonalcoholic chronic pancreatitis, occurring in tropical regions, is unknown. Alt... more The etiology of nonalcoholic chronic pancreatitis, occurring in tropical regions, is unknown. Although environmental factors may play a role in its pathogenesis, a specific genetic predisposition may be necessary. The genetic mutation responsible for hereditary pancreatitis was described recently. Unlike in patients with hereditary pancreatitis, we found a lack of the R117H mutation in the cationic trypsinogen gene in all patients with tropical pancreatitis from Bangladesh.
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