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Multicenter Study
. 2017 May;242(1):16-23.
doi: 10.1002/path.4884. Epub 2017 Mar 30.

Genetic Analyses of Isolated High-Grade Pancreatic Intraepithelial Neoplasia (HG-PanIN) Reveal Paucity of Alterations in TP53 and SMAD4

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Free PMC article
Multicenter Study

Genetic Analyses of Isolated High-Grade Pancreatic Intraepithelial Neoplasia (HG-PanIN) Reveal Paucity of Alterations in TP53 and SMAD4

Waki Hosoda et al. J Pathol. .
Free PMC article

Abstract

High-grade pancreatic intraepithelial neoplasia (HG-PanIN) is the major precursor of pancreatic ductal adenocarcinoma (PDAC) and is an ideal target for early detection. To characterize pure HG-PanIN, we analysed 23 isolated HG-PanIN lesions occurring in the absence of PDAC. Whole-exome sequencing of five of these HG-PanIN lesions revealed a median of 33 somatic mutations per lesion, with a total of 318 mutated genes. Targeted next-generation sequencing of 17 HG-PanIN lesions identified KRAS mutations in 94% of the lesions. CDKN2A alterations occurred in six HG-PanIN lesions, and RNF43 alterations in five. Mutations in TP53, GNAS, ARID1A, PIK3CA, and TGFBR2 were limited to one or two HG-PanINs. No non-synonymous mutations in SMAD4 were detected. Immunohistochemistry for p53 and SMAD4 proteins in 18 HG-PanINs confirmed the paucity of alterations in these genes, with aberrant p53 labelling noted only in three lesions, two of which were found to be wild type in sequencing analyses. Sixteen adjacent LG-PanIN lesions from ten patients were also sequenced using targeted sequencing. LG-PanIN harboured KRAS mutations in 94% of the lesions; mutations in CDKN2A, TP53, and SMAD4 were not identified. These results suggest that inactivation of TP53 and SMAD4 are late genetic alterations, predominantly occurring in invasive PDAC. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Keywords: HG-PanIN; SMAD4; TP53; cancerization; pancreas; pancreatic ductal adenocarcinoma; pancreatic intraepithelial neoplasia; targeted next-generation sequencing; whole-exome sequencing.

Conflict of interest statement

Conflict of interest statement: LDW is a paid consultant for Personal Genome Diagnostics.

Figures

Figure 1
Figure 1
A representative isolated HG-PanIN. (A) The atypical proliferation spreads along the pancreatic duct. (B) Atypical cells showed cytological features of high-grade atypia, including irregular nuclear stratification, coarse chromatin, and prominent nucleoli.

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