title: Genetic alterations associated with progression from pancreatic intraepithelial neoplasia to invasive pancreatic tumor.
abstract: OBJECTIVE
  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.
authors.affiliation: Department of Molecular Medicine, Mayo Clinic, Rochester, Minnesota.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Murphy
authors.forename: Steven N
authors.initials: SN
authors.lastname: Hart
authors.forename: Joema Felipe
authors.initials: JF
authors.lastname: Lima
authors.forename: Benjamin R
authors.initials: BR
authors.lastname: Kipp
authors.forename: Mitchell
authors.initials: M
authors.lastname: Klebig
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Winters
authors.forename: Csilla
authors.initials: C
authors.lastname: Szabo
authors.forename: Lizhi
authors.initials: L
authors.lastname: Zhang
authors.forename: Bruce W
authors.initials: BW
authors.lastname: Eckloff
authors.forename: Gloria M
authors.initials: GM
authors.lastname: Petersen
authors.forename: Steven E
authors.initials: SE
authors.lastname: Scherer
authors.forename: Richard A
authors.initials: RA
authors.lastname: Gibbs
authors.forename: Robert R
authors.initials: RR
authors.lastname: McWilliams
authors.forename: George
authors.initials: G
authors.lastname: Vasmatzis
authors.forename: Fergus J
authors.initials: FJ
authors.lastname: Couch
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics* / Q000473:pathology; D063646:Carcinogenesis / Q000235:genetics / Q000473:pathology; D002278:Carcinoma in Situ / Q000235:genetics* / Q000473:pathology; D004273:DNA, Neoplasm / Q000235:genetics; D018450:Disease Progression; D006801:Humans; D009154:Mutation / Q000235:genetics; D009361:Neoplasm Invasiveness / Q000235:genetics* / Q000473:pathology; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000473:pathology; D011518:Proto-Oncogene Proteins / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras); D012189:Retrospective Studies; D016159:Tumor Suppressor Protein p53 / Q000235:genetics; D018631:ras Proteins / Q000235:genetics
chemical_list: D004273:DNA, Neoplasm; C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins
keywords: AAF; ATM; LCM; P; PDAC; PanIN; Pancreas; PxT; SNV; T; Tumorigenesis; WGA; Whole-Genome Amplification; alternate allele frequency; ataxia telangiectasia mutated; laser capture microdissection; pancreatic ductal adenocarcinoma; pancreatic intraepithelial neoplasia; pancreatic intraepithelial neoplasia alone; single-nucleotide variant; tumor; tumors and adjacent pancreatic intraepithelial neoplasia; whole-genome amplification
references.citation: Bioinformatics. 2012 Feb 1;28(3):311-7
references.pmid: 22155872
references.citation: Breast Cancer Res Treat. 2010 Jun;121(3):555-63
references.pmid: 19669408
references.citation: BMC Cancer. 2010 Sep 22;10:503
references.pmid: 20860816
references.citation: Bioinformatics. 2012 Jan 15;28(2):277-8
references.pmid: 22088845
references.citation: Langenbecks Arch Surg. 2005 Apr;390(2):94-103
references.pmid: 15578211
references.citation: Ann Surg. 2000 Jul;232(1):73-80
references.pmid: 10862198
references.citation: Nat Rev Endocrinol. 2011 Aug 30;7(10):569-80
references.pmid: 21878896
references.citation: Biochem J. 2011 Nov 15;440(1):115-25
references.pmid: 21777200
references.citation: Annu Rev Genomics Hum Genet. 2006;7:61-80
references.pmid: 16824020
references.citation: Proc Natl Acad Sci U S A. 1997 Aug 19;94(17):9040-5
references.pmid: 9256431
references.citation: Sci Transl Med. 2011 Jul 20;3(92):92ra66
references.pmid: 21775669
references.citation: Pancreas. 2008 Aug;37(2):134-8
references.pmid: 18665072
references.citation: FEBS J. 2010 Apr;277(8):1790-804
references.pmid: 20236313
references.citation: Am J Surg Pathol. 2004 Aug;28(8):977-87
references.pmid: 15252303
references.citation: CA Cancer J Clin. 2009 Jul-Aug;59(4):225-49
references.pmid: 19474385
references.citation: Genome Res. 2010 Sep;20(9):1297-303
references.pmid: 20644199
references.citation: Hum Mutat. 2009 Feb;30(2):E451-9
references.pmid: 19058223
references.citation: Exp Cell Res. 2008 Apr 15;314(7):1519-28
references.pmid: 18313049
references.citation: FASEB J. 2012 Jul;26(7):2764-75
references.pmid: 22441987
references.citation: Int J Oncol. 2007 Dec;31(6):1491-500
references.pmid: 17982676
references.citation: Gut. 2006 Nov;55(11):1598-605
references.pmid: 16682430
references.citation: J Gastrointest Surg. 2000 Nov-Dec;4(6):567-79
references.pmid: 11307091
references.citation: Cancer Res. 2010 Jul 15;70(14):5901-11
references.pmid: 20570890
references.citation: Genome Biol. 2012 Sep 26;13(9):R52
references.pmid: 22951069
references.citation: Nature. 2012 Nov 15;491(7424):399-405
references.pmid: 23103869
references.citation: DNA Res. 2012 Oct;19(5):395-406
references.pmid: 22991452
references.citation: Genomics. 1989 Apr;4(3):367-75
references.pmid: 2541066
references.citation: PLoS One. 2012;7(10):e46887
references.pmid: 23056513
references.citation: Nat Rev Cancer. 2007 Dec;7(12):925-36
references.pmid: 18004398
references.citation: Clin Bull. 1978;8(3):91-9
references.pmid: 371858
references.citation: Nucleic Acids Res. 2010 Jun;38(11):3523-32
references.pmid: 20172960
references.citation: Cancer Discov. 2012 Jan;2(1):41-6
references.pmid: 22585167
references.citation: Cancer Cell. 2003 Dec;4(6):437-50
references.pmid: 14706336
references.citation: Science. 2008 Sep 26;321(5897):1801-6
references.pmid: 18772397