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Gastroenterology. 2013 Nov;145(5):1098-1109.e1. doi: 10.1053/j.gastro.2013.07.049. Epub 2013 Aug 2.

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

Author information

1
Department of Molecular Medicine, Mayo Clinic, Rochester, Minnesota.

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.

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

PMID:
23912084
PMCID:
PMC3926442
DOI:
10.1053/j.gastro.2013.07.049
[Indexed for MEDLINE]
Free PMC Article
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