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

• Published in: The Journal of pathology Vol. 242; no. 1; pp. 16 - 23
• Main Authors: Hosoda, Waki, Chianchiano, Peter, Griffin, James F, Pittman, Meredith E, Brosens, Lodewijk AA, Noë, Michaël, Yu, Jun, Shindo, Koji, Suenaga, Masaya, Rezaee, Neda, Yonescu, Raluca, Ning, Yi, Albores‐Saavedra, Jorge, Yoshizawa, Naohiko, Harada, Kenichi, Yoshizawa, Akihiko, Hanada, Keiji, Yonehara, Shuji, Shimizu, Michio, Uehara, Takeshi, Samra, Jaswinder S, Gill, Anthony J, Wolfgang, Christopher L, Goggins, Michael G, Hruban, Ralph H, Wood, Laura D
• Format: Journal Article
• Language: English
• Published: Chichester, UK John Wiley & Sons, Ltd 01.05.2017; Wiley Subscription Services, Inc
• Subjects: cancerization; Carcinoma in Situ - genetics; Carcinoma in Situ - metabolism; Carcinoma in Situ - pathology; Genes, p53 - genetics; Genome, Human - genetics; HG‐PanIN; High-Throughput Nucleotide Sequencing - methods; Humans; Mutation; Neoplasm Grading; Neoplasm Proteins - genetics; Neoplasm Proteins - metabolism; pancreas; pancreatic ductal adenocarcinoma; pancreatic intraepithelial neoplasia; Pancreatic Neoplasms - genetics; Pancreatic Neoplasms - metabolism; Pancreatic Neoplasms - pathology; SMAD4; Smad4 Protein - genetics; Smad4 Protein - metabolism; targeted next‐generation sequencing; TP53; Tumor Suppressor Protein p53 - metabolism; whole‐exome sequencing; SMAD4; cancerization; targeted next-generation sequencing; pancreas; HG-PanIN; pancreatic intraepithelial neoplasia; TP53; whole-exome sequencing; pancreatic ductal adenocarcinoma
• ISSN: 0022-3417; 1096-9896
• DOI: 10.1002/path.4884

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.