Genetic analyses of isolated high-grade pancreatic intraepithelial neoplasia (HG-PanIN) reveal paucity of alterations in TP53 and SMAD4

被引：109

作者：

Hosoda, Waki ^{[1
]}

Chianchiano, Peter ^{[1
]}

Griffin, James F. ^{[2
]}

Pittman, Meredith E. ^{[3
]}

Brosens, Lodewijk A. A. ^{[4
]}

Noe, Michael ^{[1
]}

Yu, Jun ^{[1
]}

Shindo, Koji ^{[1
]}

Suenaga, Masaya ^{[1
]}

Rezaee, Neda ^{[2
]}

Yonescu, Raluca ^{[5
]}

Ning, Yi ^{[5
]}

Albores-Saavedra, Jorge ^{[6
]}

Yoshizawa, Naohiko ^{[7
]}

Harada, Kenichi ^{[8
]}

Yoshizawa, Akihiko ^{[9
]}

Hanada, Keiji ^{[10
]}

Yonehara, Shuji ^{[11
]}

Shimizu, Michio ^{[12
]}

Uehara, Takeshi ^{[13
]}

Samra, Jaswinder S. ^{[14
,15
]}

Gill, Anthony J. ^{[16
,17
]}

Wolfgang, Christopher L. ^{[2
,18
]}

Goggins, Michael G. ^{[1
,18
,19
]}

Hruban, Ralph H. ^{[1
,18
]}

Wood, Laura D. ^{[1
,18
]}

机构：

[1] Johns Hopkins Univ, Sch Med, Dept Pathol, Sol Goldman Pancreat Canc Res Ctr, Baltimore, MD 21205 USA

[2] Johns Hopkins Univ, Sch Med, Dept Surg, Sol Goldman Pancreat Canc Res Ctr, Baltimore, MD 21205 USA

[3] Weill Cornell Med, Pathol & Lab Med, New York, NY USA

[4] Univ Med Ctr Utrecht, Dept Pathol, Utrecht, Netherlands

[5] Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21205 USA

[6] Med Sur Clin & Fdn, Dept Pathol, Mexico City, DF, Mexico

[7] Mie Univ, Dept Internal Med 1, Sch Med, Tsu, Mie, Japan

[8] Kanazawa Univ, Dept Human Pathol, Grad Sch Med Sci, Kanazawa, Ishikawa, Japan

[9] Kyoto Univ Hosp, Dept Diagnost Pathol, Kyoto, Japan

[10] Onomichi Gen Hosp, Ctr Gastroendoscopy, Onomichi, Japan

[11] Onomichi Gen Hosp, Dept Pathol, Onomich, Japan

[12] Hakujikai Mem Hosp, Diagnost Pathol Ctr, Tokyo, Japan

[13] Shinshu Univ, Dept Lab Med, Sch Med, Matsumoto, Nagano, Japan

[14] Univ Sydney, Royal North Shore Hosp, Dept Gastrointestinal Surg, Sydney, NSW, Australia

[15] Univ Sydney, Discipline Surg, Sydney, NSW, Australia

[16] Royal North Shore Hosp, Canc Diag & Pathol Grp, Kolling Inst Med Res, Sydney, NSW, Australia

[17] Univ Sydney, Sydney, NSW, Australia

[18] Johns Hopkins Univ, Sch Med, Dept Oncol, Sol Goldman Pancreat Canc Res Ctr, Baltimore, MD 21205 USA

[19] Johns Hopkins Univ, Sch Med, Dept Med, Sol Goldman Pancreat Canc Res Ctr, Baltimore, MD 21205 USA

来源：

JOURNAL OF PATHOLOGY | 2017年 / 242卷 / 01期

关键词：

pancreas; pancreatic intraepithelial neoplasia; HG-PanIN; pancreatic ductal adenocarcinoma; whole-exome sequencing; targeted next-generation sequencing; TP53; SMAD4; cancerization; MUTATIONS; CANCER; INACTIVATION; PROGRESSION; PATHWAYS; LESIONS; JUICE;

D O I：

10.1002/path.4884

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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 (C) 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

引用

页码：16 / 23

页数：8

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