Genetic alterations associated with progression from pancreatic intraepithelial neoplasia to invasive pancreatic tumor

Stephen J. Murphy, Steven Hart, Joema Felipe Lima, Benjamin R. Kipp, Mitchell Klebig, Jennifer L. Winters, Csilla Szabo, Lizhi Zhang, Bruce W. Eckloff, Gloria M Petersen, Steven E. Scherer, Richard A. Gibbs, Robert R Mc Williams, George Vasmatzis, Fergus J Couch

Research output: Contribution to journalArticle

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Abstract

Background & Aims Increasing grade of pancreatic intraepithelial neoplasia (PanIN) has been associated with progression to pancreatic ductal adenocarcinoma (PDAC). However, the mechanisms that control progression from PanINs to PDAC are not well understood. We investigated the genetic alterations involved in this process. Methods Genomic DNA samples from laser-capture microdissected PDACs and adjacent PanIN2 and PanIN3 lesions from 10 patients with pancreatic cancer were analyzed by exome sequencing. Results Similar numbers of somatic mutations were identified in PanINs and tumors, but the mutational load varied greatly among cases. Ten of the 15 isolated PanINs shared more than 50% of somatic mutations with associated tumors. Mutations common to tumors and clonally related PanIN2 and PanIN3 lesions were identified as genes that could promote carcinogenesis. KRAS and TP53 frequently were altered in PanINs and tumors, but few other recurrently modified genes were detected. Mutations in DNA damage response genes were prevalent in all samples. Genes that encode proteins involved in gap junctions, the actin cytoskeleton, the mitogen-activated protein kinase signaling pathway, axon guidance, and cell-cycle regulation were among the earliest targets of mutagenesis in PanINs that progressed to PDAC. Conclusions Early stage PanIN2 lesions appear to contain many of the somatic gene alterations required for PDAC development.

Original languageEnglish (US)
JournalGastroenterology
Volume145
Issue number5
DOIs
StatePublished - Nov 2013

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Adenocarcinoma
Mutation
Genes
Neoplasms
Exome
Gap Junctions
Mitogen-Activated Protein Kinases
Tumor Burden
Actin Cytoskeleton
Pancreatic Neoplasms
Mutagenesis
DNA Damage
Cell Cycle
Carcinogenesis
Lasers
DNA
Proteins

Keywords

  • LCM
  • Pancreas
  • Tumorigenesis
  • Whole-Genome Amplification

ASJC Scopus subject areas

  • Gastroenterology

Cite this

Genetic alterations associated with progression from pancreatic intraepithelial neoplasia to invasive pancreatic tumor. / Murphy, Stephen J.; Hart, Steven; Lima, Joema Felipe; Kipp, Benjamin R.; Klebig, Mitchell; Winters, Jennifer L.; Szabo, Csilla; Zhang, Lizhi; Eckloff, Bruce W.; Petersen, Gloria M; Scherer, Steven E.; Gibbs, Richard A.; Mc Williams, Robert R; Vasmatzis, George; Couch, Fergus J.

In: Gastroenterology, Vol. 145, No. 5, 11.2013.

Research output: Contribution to journalArticle

Murphy, Stephen J. ; Hart, Steven ; Lima, Joema Felipe ; Kipp, Benjamin R. ; Klebig, Mitchell ; Winters, Jennifer L. ; Szabo, Csilla ; Zhang, Lizhi ; Eckloff, Bruce W. ; Petersen, Gloria M ; Scherer, Steven E. ; Gibbs, Richard A. ; Mc Williams, Robert R ; Vasmatzis, George ; Couch, Fergus J. / Genetic alterations associated with progression from pancreatic intraepithelial neoplasia to invasive pancreatic tumor. In: Gastroenterology. 2013 ; Vol. 145, No. 5.
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AU - Hart, Steven

AU - Lima, Joema Felipe

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AU - Winters, Jennifer L.

AU - Szabo, Csilla

AU - Zhang, Lizhi

AU - Eckloff, Bruce W.

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AU - Scherer, Steven E.

AU - Gibbs, Richard A.

AU - Mc Williams, Robert R

AU - Vasmatzis, George

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N2 - Background & Aims Increasing grade of pancreatic intraepithelial neoplasia (PanIN) has been associated with progression to pancreatic ductal adenocarcinoma (PDAC). However, the mechanisms that control progression from PanINs to PDAC are not well understood. We investigated the genetic alterations involved in this process. Methods Genomic DNA samples from laser-capture microdissected PDACs and adjacent PanIN2 and PanIN3 lesions from 10 patients with pancreatic cancer were analyzed by exome sequencing. Results Similar numbers of somatic mutations were identified in PanINs and tumors, but the mutational load varied greatly among cases. Ten of the 15 isolated PanINs shared more than 50% of somatic mutations with associated tumors. Mutations common to tumors and clonally related PanIN2 and PanIN3 lesions were identified as genes that could promote carcinogenesis. KRAS and TP53 frequently were altered in PanINs and tumors, but few other recurrently modified genes were detected. Mutations in DNA damage response genes were prevalent in all samples. Genes that encode proteins involved in gap junctions, the actin cytoskeleton, the mitogen-activated protein kinase signaling pathway, axon guidance, and cell-cycle regulation were among the earliest targets of mutagenesis in PanINs that progressed to PDAC. Conclusions Early stage PanIN2 lesions appear to contain many of the somatic gene alterations required for PDAC development.

AB - Background & Aims Increasing grade of pancreatic intraepithelial neoplasia (PanIN) has been associated with progression to pancreatic ductal adenocarcinoma (PDAC). However, the mechanisms that control progression from PanINs to PDAC are not well understood. We investigated the genetic alterations involved in this process. Methods Genomic DNA samples from laser-capture microdissected PDACs and adjacent PanIN2 and PanIN3 lesions from 10 patients with pancreatic cancer were analyzed by exome sequencing. Results Similar numbers of somatic mutations were identified in PanINs and tumors, but the mutational load varied greatly among cases. Ten of the 15 isolated PanINs shared more than 50% of somatic mutations with associated tumors. Mutations common to tumors and clonally related PanIN2 and PanIN3 lesions were identified as genes that could promote carcinogenesis. KRAS and TP53 frequently were altered in PanINs and tumors, but few other recurrently modified genes were detected. Mutations in DNA damage response genes were prevalent in all samples. Genes that encode proteins involved in gap junctions, the actin cytoskeleton, the mitogen-activated protein kinase signaling pathway, axon guidance, and cell-cycle regulation were among the earliest targets of mutagenesis in PanINs that progressed to PDAC. Conclusions Early stage PanIN2 lesions appear to contain many of the somatic gene alterations required for PDAC development.

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