TY - JOUR
T1 - Genetic analyses of isolated high-grade pancreatic intraepithelial neoplasia (HG-PanIN) reveal paucity of alterations in TP53 and SMAD4
AU - Hosoda, Waki
AU - Chianchiano, Peter
AU - Griffin, James F.
AU - Pittman, Meredith E.
AU - Brosens, Lodewijk A.A.
AU - Noë, Michaël
AU - Yu, Jun
AU - Shindo, Koji
AU - Suenaga, Masaya
AU - Rezaee, Neda
AU - Yonescu, Raluca
AU - Ning, Yi
AU - Albores-Saavedra, Jorge
AU - Yoshizawa, Naohiko
AU - Harada, Kenichi
AU - Yoshizawa, Akihiko
AU - Hanada, Keiji
AU - Yonehara, Shuji
AU - Shimizu, Michio
AU - Uehara, Takeshi
AU - Samra, Jaswinder S.
AU - Gill, Anthony J.
AU - Wolfgang, Christopher L.
AU - Goggins, Michael G.
AU - Hruban, Ralph H.
AU - Wood, Laura D.
N1 - Funding Information:
We thank Dr James R Eshleman and Marija Debeljak for helpful discussions in data analysis of targeted sequencing. We acknowledge the following sources of funding: NIH/NCI P50 CA62924; NIH/NIDDK K08 DK107781; Sol Goldman Pancreatic Cancer Research Center; Buffone Family Gastrointestinal Cancer Research Fund; Kaya Tuncer Career Development Award in Gastrointestinal Cancer Prevention; AGA-Bernard Lee Schwartz Foundation Research Scholar Award in Pancreatic Cancer; Sidney Kimmel Foundation for Cancer Research Kimmel Scholar Award; AACR-Incyte Corporation Career Development Award for Pancreatic Cancer Research; Rolfe Pancreatic Cancer Foundation; Joseph C Monastra Foundation; The Gerald O Mann Charitable Foundation (Harriet and Allan Wulfstat, Trustees); Sigma Beta Sorority; Tampa Bay Fisheries Inc; Union for International Cancer Control (UICC) Yamagiwa-Yoshida Memorial International Cancer Study Grants; the Nijbakker-Morra Stichting; the Lisa Waller Hayes Foundation; and the Dutch Digestive Foundation (MLDS CDG 14-02).
Publisher Copyright:
Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
PY - 2017/5
Y1 - 2017/5
N2 - 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.
AB - 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.
KW - HG-PanIN
KW - SMAD4
KW - TP53
KW - cancerization
KW - pancreas
KW - pancreatic ductal adenocarcinoma
KW - pancreatic intraepithelial neoplasia
KW - targeted next-generation sequencing
KW - whole-exome sequencing
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U2 - 10.1002/path.4884
DO - 10.1002/path.4884
M3 - Article
C2 - 28188630
AN - SCOPUS:85017359383
SN - 0022-3417
VL - 242
SP - 16
EP - 23
JO - Journal of Pathology
JF - Journal of Pathology
IS - 1
ER -