KRAS and guanine nucleotide-binding protein mutations in pancreatic juice collected from the duodenum of patients at high risk for neoplasia undergoing endoscopic ultrasound

James R. Eshleman, Alexis L. Norris, Yoshihiko Sadakari, Marija Debeljak, Michael Borges, Colleen Harrington, Elaine Lin, Aaron Brant, Thomas Barkley, J. Alejandro Almario, Mark Topazian, James Farrell, Sapna Syngal, Jeffrey H. Lee, Jun Yu, Ralph H. Hruban, Mitsuro Kanda, Marcia Irene Canto, Michael Goggins

Research output: Contribution to journalArticle

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Abstract

Background & Aims: Pancreatic imaging can identify neoplastic cysts but not microscopic neoplasms. Mutation analysis of pancreatic fluid after secretin stimulation might identify microscopic neoplasias in the pancreatic duct system. We determined the prevalence of mutations in KRAS and guanine nucleotide-binding protein α-stimulating genes in pancreatic juice from subjects undergoing endoscopic ultrasound for suspected pancreatic intraepithelial neoplasia, intraductal papillary mucinous neoplasms, or pancreatic adenocarcinoma. Methods: Secretin-stimulated juice samples were collected from the duodenum of 272 subjects enrolled in Cancer of the Pancreas Screening studies; 194 subjects were screened because of a family history of, or genetic predisposition to, pancreatic cancer, and 78 subjects were evaluated for pancreatic cancer (n= 30) or other disorders (controls: pancreatic cysts, pancreatitis, or normal pancreata, n= 48). Mutations were detected by digital high-resolution melt-curve analysis and pyrosequencing. The number of replicates containing a mutation determined the mutation score. Results: KRAS mutations were detected in pancreatic juice from larger percentages of subjects with pancreatic cancer (73%) or undergoing cancer screening (50%) than controls (19%) (P= .0005). A greater proportion of patients with pancreatic cancer had at least 1 KRAS mutation detected 3 or more times (47%) than screened subjects (21%) or controls (6%, P= .002). Among screened subjects, mutations in KRAS (but not guanine nucleotide-binding protein α-stimulating) were found in similar percentages of patients with or without pancreatic cysts. However, a greater proportion of patients older than age 50 years had KRAS mutations (54.6%) than younger patients (36.3%) (P= .032); the older subjects also had more mutations in KRAS (P= .02). Conclusions: Mutations in KRAS are detected in pancreatic juice from the duodenum of 73% of patients with pancreatic cancer, and 50% of asymptomatic individuals with a high risk for pancreatic cancer. However, KRAS mutations were detected in pancreatic juice from 19% of controls. Mutations detected in individuals without pancreatic abnormalities, based on imaging analyses, likely arise from small pancreatic intraepithelial neoplasia lesions. ClinicalTrials.gov no: NCT00438906 and NCT00714701.

Original languageEnglish (US)
Pages (from-to)963-969
Number of pages7
JournalClinical Gastroenterology and Hepatology
Volume13
Issue number5
DOIs
StatePublished - Jan 1 2015

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Pancreatic Juice
Guanine Nucleotides
Duodenum
Carrier Proteins
Mutation
Pancreatic Neoplasms
Neoplasms
Pancreatic Cyst
Secretin
Early Detection of Cancer
Pancreatic Ducts
Genetic Predisposition to Disease
Pancreatitis
Cysts
Pancreas

Keywords

  • Early detection
  • EUS
  • Screening

ASJC Scopus subject areas

  • Hepatology
  • Gastroenterology

Cite this

KRAS and guanine nucleotide-binding protein mutations in pancreatic juice collected from the duodenum of patients at high risk for neoplasia undergoing endoscopic ultrasound. / Eshleman, James R.; Norris, Alexis L.; Sadakari, Yoshihiko; Debeljak, Marija; Borges, Michael; Harrington, Colleen; Lin, Elaine; Brant, Aaron; Barkley, Thomas; Almario, J. Alejandro; Topazian, Mark; Farrell, James; Syngal, Sapna; Lee, Jeffrey H.; Yu, Jun; Hruban, Ralph H.; Kanda, Mitsuro; Canto, Marcia Irene; Goggins, Michael.

In: Clinical Gastroenterology and Hepatology, Vol. 13, No. 5, 01.01.2015, p. 963-969.

Research output: Contribution to journalArticle

Eshleman, JR, Norris, AL, Sadakari, Y, Debeljak, M, Borges, M, Harrington, C, Lin, E, Brant, A, Barkley, T, Almario, JA, Topazian, M, Farrell, J, Syngal, S, Lee, JH, Yu, J, Hruban, RH, Kanda, M, Canto, MI & Goggins, M 2015, 'KRAS and guanine nucleotide-binding protein mutations in pancreatic juice collected from the duodenum of patients at high risk for neoplasia undergoing endoscopic ultrasound', Clinical Gastroenterology and Hepatology, vol. 13, no. 5, pp. 963-969. https://doi.org/10.1016/j.cgh.2014.11.028
Eshleman, James R. ; Norris, Alexis L. ; Sadakari, Yoshihiko ; Debeljak, Marija ; Borges, Michael ; Harrington, Colleen ; Lin, Elaine ; Brant, Aaron ; Barkley, Thomas ; Almario, J. Alejandro ; Topazian, Mark ; Farrell, James ; Syngal, Sapna ; Lee, Jeffrey H. ; Yu, Jun ; Hruban, Ralph H. ; Kanda, Mitsuro ; Canto, Marcia Irene ; Goggins, Michael. / KRAS and guanine nucleotide-binding protein mutations in pancreatic juice collected from the duodenum of patients at high risk for neoplasia undergoing endoscopic ultrasound. In: Clinical Gastroenterology and Hepatology. 2015 ; Vol. 13, No. 5. pp. 963-969.
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abstract = "Background & Aims: Pancreatic imaging can identify neoplastic cysts but not microscopic neoplasms. Mutation analysis of pancreatic fluid after secretin stimulation might identify microscopic neoplasias in the pancreatic duct system. We determined the prevalence of mutations in KRAS and guanine nucleotide-binding protein α-stimulating genes in pancreatic juice from subjects undergoing endoscopic ultrasound for suspected pancreatic intraepithelial neoplasia, intraductal papillary mucinous neoplasms, or pancreatic adenocarcinoma. Methods: Secretin-stimulated juice samples were collected from the duodenum of 272 subjects enrolled in Cancer of the Pancreas Screening studies; 194 subjects were screened because of a family history of, or genetic predisposition to, pancreatic cancer, and 78 subjects were evaluated for pancreatic cancer (n= 30) or other disorders (controls: pancreatic cysts, pancreatitis, or normal pancreata, n= 48). Mutations were detected by digital high-resolution melt-curve analysis and pyrosequencing. The number of replicates containing a mutation determined the mutation score. Results: KRAS mutations were detected in pancreatic juice from larger percentages of subjects with pancreatic cancer (73{\%}) or undergoing cancer screening (50{\%}) than controls (19{\%}) (P= .0005). A greater proportion of patients with pancreatic cancer had at least 1 KRAS mutation detected 3 or more times (47{\%}) than screened subjects (21{\%}) or controls (6{\%}, P= .002). Among screened subjects, mutations in KRAS (but not guanine nucleotide-binding protein α-stimulating) were found in similar percentages of patients with or without pancreatic cysts. However, a greater proportion of patients older than age 50 years had KRAS mutations (54.6{\%}) than younger patients (36.3{\%}) (P= .032); the older subjects also had more mutations in KRAS (P= .02). Conclusions: Mutations in KRAS are detected in pancreatic juice from the duodenum of 73{\%} of patients with pancreatic cancer, and 50{\%} of asymptomatic individuals with a high risk for pancreatic cancer. However, KRAS mutations were detected in pancreatic juice from 19{\%} of controls. Mutations detected in individuals without pancreatic abnormalities, based on imaging analyses, likely arise from small pancreatic intraepithelial neoplasia lesions. ClinicalTrials.gov no: NCT00438906 and NCT00714701.",
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T1 - KRAS and guanine nucleotide-binding protein mutations in pancreatic juice collected from the duodenum of patients at high risk for neoplasia undergoing endoscopic ultrasound

AU - Eshleman, James R.

AU - Norris, Alexis L.

AU - Sadakari, Yoshihiko

AU - Debeljak, Marija

AU - Borges, Michael

AU - Harrington, Colleen

AU - Lin, Elaine

AU - Brant, Aaron

AU - Barkley, Thomas

AU - Almario, J. Alejandro

AU - Topazian, Mark

AU - Farrell, James

AU - Syngal, Sapna

AU - Lee, Jeffrey H.

AU - Yu, Jun

AU - Hruban, Ralph H.

AU - Kanda, Mitsuro

AU - Canto, Marcia Irene

AU - Goggins, Michael

PY - 2015/1/1

Y1 - 2015/1/1

N2 - Background & Aims: Pancreatic imaging can identify neoplastic cysts but not microscopic neoplasms. Mutation analysis of pancreatic fluid after secretin stimulation might identify microscopic neoplasias in the pancreatic duct system. We determined the prevalence of mutations in KRAS and guanine nucleotide-binding protein α-stimulating genes in pancreatic juice from subjects undergoing endoscopic ultrasound for suspected pancreatic intraepithelial neoplasia, intraductal papillary mucinous neoplasms, or pancreatic adenocarcinoma. Methods: Secretin-stimulated juice samples were collected from the duodenum of 272 subjects enrolled in Cancer of the Pancreas Screening studies; 194 subjects were screened because of a family history of, or genetic predisposition to, pancreatic cancer, and 78 subjects were evaluated for pancreatic cancer (n= 30) or other disorders (controls: pancreatic cysts, pancreatitis, or normal pancreata, n= 48). Mutations were detected by digital high-resolution melt-curve analysis and pyrosequencing. The number of replicates containing a mutation determined the mutation score. Results: KRAS mutations were detected in pancreatic juice from larger percentages of subjects with pancreatic cancer (73%) or undergoing cancer screening (50%) than controls (19%) (P= .0005). A greater proportion of patients with pancreatic cancer had at least 1 KRAS mutation detected 3 or more times (47%) than screened subjects (21%) or controls (6%, P= .002). Among screened subjects, mutations in KRAS (but not guanine nucleotide-binding protein α-stimulating) were found in similar percentages of patients with or without pancreatic cysts. However, a greater proportion of patients older than age 50 years had KRAS mutations (54.6%) than younger patients (36.3%) (P= .032); the older subjects also had more mutations in KRAS (P= .02). Conclusions: Mutations in KRAS are detected in pancreatic juice from the duodenum of 73% of patients with pancreatic cancer, and 50% of asymptomatic individuals with a high risk for pancreatic cancer. However, KRAS mutations were detected in pancreatic juice from 19% of controls. Mutations detected in individuals without pancreatic abnormalities, based on imaging analyses, likely arise from small pancreatic intraepithelial neoplasia lesions. ClinicalTrials.gov no: NCT00438906 and NCT00714701.

AB - Background & Aims: Pancreatic imaging can identify neoplastic cysts but not microscopic neoplasms. Mutation analysis of pancreatic fluid after secretin stimulation might identify microscopic neoplasias in the pancreatic duct system. We determined the prevalence of mutations in KRAS and guanine nucleotide-binding protein α-stimulating genes in pancreatic juice from subjects undergoing endoscopic ultrasound for suspected pancreatic intraepithelial neoplasia, intraductal papillary mucinous neoplasms, or pancreatic adenocarcinoma. Methods: Secretin-stimulated juice samples were collected from the duodenum of 272 subjects enrolled in Cancer of the Pancreas Screening studies; 194 subjects were screened because of a family history of, or genetic predisposition to, pancreatic cancer, and 78 subjects were evaluated for pancreatic cancer (n= 30) or other disorders (controls: pancreatic cysts, pancreatitis, or normal pancreata, n= 48). Mutations were detected by digital high-resolution melt-curve analysis and pyrosequencing. The number of replicates containing a mutation determined the mutation score. Results: KRAS mutations were detected in pancreatic juice from larger percentages of subjects with pancreatic cancer (73%) or undergoing cancer screening (50%) than controls (19%) (P= .0005). A greater proportion of patients with pancreatic cancer had at least 1 KRAS mutation detected 3 or more times (47%) than screened subjects (21%) or controls (6%, P= .002). Among screened subjects, mutations in KRAS (but not guanine nucleotide-binding protein α-stimulating) were found in similar percentages of patients with or without pancreatic cysts. However, a greater proportion of patients older than age 50 years had KRAS mutations (54.6%) than younger patients (36.3%) (P= .032); the older subjects also had more mutations in KRAS (P= .02). Conclusions: Mutations in KRAS are detected in pancreatic juice from the duodenum of 73% of patients with pancreatic cancer, and 50% of asymptomatic individuals with a high risk for pancreatic cancer. However, KRAS mutations were detected in pancreatic juice from 19% of controls. Mutations detected in individuals without pancreatic abnormalities, based on imaging analyses, likely arise from small pancreatic intraepithelial neoplasia lesions. ClinicalTrials.gov no: NCT00438906 and NCT00714701.

KW - Early detection

KW - EUS

KW - Screening

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