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
Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Department of Surgery, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
J Pathol. 2017 May;242(1):16-23. doi: 10.1002/path.4884. Epub 2017 Mar 30.
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.
高级别胰腺上皮内瘤变（HG-PanIN）是胰腺导管腺癌（PDAC）的主要前体，是早期检测的理想靶点。为了表征纯HG-PanIN，我们分析了23例在无PDAC情况下发生的孤立HG-PanIN病变。对其中5例HG-PanIN病变进行全外显子测序，结果显示每个病变的体细胞突变中位数为33个，共有318个突变基因。对17例HG-PanIN病变进行靶向二代测序，发现94%的病变存在KRAS突变。6例HG-PanIN病变发生CDKN2A改变，5例发生RNF43改变。TP53、GNAS、ARID1A、PIK3CA和TGFBR2的突变仅限于一两个HG-PanIN。未检测到SMAD4的非同义突变。对18例HG-PanIN进行p53和SMAD4蛋白免疫组化，证实这些基因的改变很少，仅在3个病变中发现异常p53标记，其中2个在测序分析中为野生型。还对来自10例患者的16个相邻低级别胰腺上皮内瘤变（LG-PanIN）病变进行了靶向测序。LG-PanIN中94%的病变存在KRAS突变；未发现CDKN2A、TP53和SMAD4的突变。这些结果表明，TP53和SMAD4的失活是晚期遗传改变，主要发生在浸润性PDAC中。版权所有© 2017英国和爱尔兰病理学会。由约翰·威利父子有限公司出版。
