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Pancreatic Neoplasms: HELP
Articles by Peter E. Chianchiano
Based on 7 articles published since 2010
(Why 7 articles?)
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Between 2010 and 2020, Peter Chianchiano wrote the following 7 articles about Pancreatic Neoplasms.
 
+ Citations + Abstracts
1 Article Genetic Analysis of Small Well-differentiated Pancreatic Neuroendocrine Tumors Identifies Subgroups With Differing Risks of Liver Metastases. 2020

Pea, Antonio / Yu, Jun / Marchionni, Luigi / Noe, Michael / Luchini, Claudio / Pulvirenti, Alessandra / de Wilde, Roeland F / Brosens, Lodewijk A / Rezaee, Neda / Javed, Ammar / Chianchiano, Peter / Gobbo, Stefano / Regi, Paolo / Salvia, Roberto / Bassi, Claudio / He, Jin / Weiss, Matthew J / Cameron, John L / Offerhaus, G Johan A / Hruban, Ralph H / Lawlor, Rita T / Scarpa, Aldo / Heaphy, Christopher M / Wood, Laura D / Wolfgang, Christopher L. ·Department of Surgery, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD. · Department of Surgery, The Pancreas Institute, Verona, Italy. · Department of Oncology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD. · Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD. · Department of Diagnostics and Public Health, Section of Pathology, University and Hospital Trust of Verona, Verona, Italy. · Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands. · Department of Pathology, Pederzoli Hospital, Peschiera, Italy. · Department of Surgery, Pederzoli Hospital, Peschiera, Italy. · ARC-Net Applied Research on Cancer Center, University and Hospital Trust of Verona, Verona, Italy. ·Ann Surg · Pubmed #30339629.

ABSTRACT: OBJECTIVE: The aim of this study was to investigate the key molecular alterations in small primary pancreatic neuroendocrine tumors (PanNETs) associated with the development of liver metastases. BACKGROUND: Well-differentiated PanNETs with small size are typically indolent; however, a limited subset metastasize to the liver. METHODS: A total of 87 small primary PanNETs (<3 cm), including 32 metastatic cases and 55 nonmetastatic cases after a 5-year follow-up, were immunolabeled for DAXX/ATRX and analyzed for alternative lengthening of telomeres (ALT) by Fluorescence In Situ Hybridization. A subset of these cases, 24 that metastasized and 24 that did not metastasize, were assessed by targeted next-generation sequencing and whole-genome copy number variation. RESULTS: In the entire cohort, high Ki-67 (OR 1.369; 95% CI 1.121-1.673; P = 0.002), N-stage (OR 4.568; 95% CI 1.458-14.312; P = 0.009), and ALT-positivity (OR 3.486; 95% CI 1.093-11.115; P = 0.035) were independently associated with liver metastases. In the subset assessed by next-generation sequencing and copy number variation analysis, 3 molecular subtypes with differing risks of liver metastases were identified. Group 1 (n = 15; 73% metastasized) was characterized by recurrent chromosomal gains, CN-LOH, DAXX mutations, and ALT-positivity. Group 2 (n = 19; 42% metastasized, including 5 G1 tumors) was characterized by limited copy number alterations and mutations. Group 3 (n = 14; 35% metastasized) were defined by chromosome 11 loss. CONCLUSIONS: We identified genomic patterns of small PanNETs associated with a different risk for liver metastases. Molecular alterations, such as DAXX mutations, chromosomal gains, and ALT, are associated with an increased risk of metastasis in small PanNETs. Therefore, targeted sequencing and/or ALT analysis may help in the clinical decisions for these small PanNETs.

2 Article Intraductal Papillary Mucinous Neoplasms Arise From Multiple Independent Clones, Each With Distinct Mutations. 2019

Fischer, Catherine G / Beleva Guthrie, Violeta / Braxton, Alicia M / Zheng, Lily / Wang, Pei / Song, Qianqian / Griffin, James F / Chianchiano, Peter E / Hosoda, Waki / Niknafs, Noushin / Springer, Simeon / Dal Molin, Marco / Masica, David / Scharpf, Robert B / Thompson, Elizabeth D / He, Jin / Wolfgang, Christopher L / Hruban, Ralph H / Roberts, Nicholas J / Lennon, Anne Marie / Jiao, Yuchen / Karchin, Rachel / Wood, Laura D. ·Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland. · Institute for Computational Medicine, Johns Hopkins University, Baltimore, Maryland; Department of Biomedical Engineering, Johns Hopkins University, Baltimore, Maryland. · Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland; Department of Molecular and Comparative Pathobiology, Johns Hopkins University School of Medicine, Baltimore, Maryland. · McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland. · State Key Lab of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. · Department of Surgery, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland. · Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland. · Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland; Ludwig Center for Cancer Genetics and Therapeutics, Johns Hopkins University School of Medicine, Baltimore, Maryland. · Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland; Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland. · Department of Medicine, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland. · Institute for Computational Medicine, Johns Hopkins University, Baltimore, Maryland; Department of Biomedical Engineering, Johns Hopkins University, Baltimore, Maryland; Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland. Electronic address: karchin@jhu.edu. · Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland; Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland. Electronic address: ldwood@jhmi.edu. ·Gastroenterology · Pubmed #31175866.

ABSTRACT: BACKGROUND & AIMS: Intraductal papillary mucinous neoplasms (IPMNs) are lesions that can progress to invasive pancreatic cancer and constitute an important system for studies of pancreatic tumorigenesis. We performed comprehensive genomic analyses of entire IPMNs to determine the diversity of somatic mutations in genes that promote tumorigenesis. METHODS: We microdissected neoplastic tissues from 6-24 regions each of 20 resected IPMNs, resulting in 227 neoplastic samples that were analyzed by capture-based targeted sequencing. Somatic mutations in genes associated with pancreatic tumorigenesis were assessed across entire IPMN lesions, and the resulting data were supported by evolutionary modeling, whole-exome sequencing, and in situ detection of mutations. RESULTS: We found a high prevalence of heterogeneity among mutations in IPMNs. Heterogeneity in mutations in KRAS and GNAS was significantly more prevalent in IPMNs with low-grade dysplasia than in IPMNs with high-grade dysplasia (P < .02). Whole-exome sequencing confirmed that IPMNs contained multiple independent clones, each with distinct mutations, as originally indicated by targeted sequencing and evolutionary modeling. We also found evidence for convergent evolution of mutations in RNF43 and TP53, which are acquired during later stages of tumorigenesis. CONCLUSIONS: In an analysis of the heterogeneity of mutations throughout IPMNs, we found that early-stage IPMNs contain multiple independent clones, each with distinct mutations, indicating their polyclonal origin. These findings challenge the model in which pancreatic neoplasms arise from a single clone. Increasing our understanding of the mechanisms of IPMN polyclonality could lead to strategies to identify patients at increased risk for pancreatic cancer.

3 Article Single-cell sequencing defines genetic heterogeneity in pancreatic cancer precursor lesions. 2019

Kuboki, Yuko / Fischer, Catherine G / Beleva Guthrie, Violeta / Huang, Wenjie / Yu, Jun / Chianchiano, Peter / Hosoda, Waki / Zhang, Hao / Zheng, Lily / Shao, Xiaoshan / Thompson, Elizabeth D / Waters, Kevin / Poling, Justin / He, Jin / Weiss, Matthew J / Wolfgang, Christopher L / Goggins, Michael G / Hruban, Ralph H / Roberts, Nicholas J / Karchin, Rachel / Wood, Laura D. ·Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA. · Institute for Computational Medicine, Johns Hopkins University, Baltimore, MD, USA. · Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD, USA. · Department of Surgery, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA. · Department of Molecular Microbiology and Immunology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA. · McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA. · Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA. ·J Pathol · Pubmed #30430578.

ABSTRACT: Intraductal papillary mucinous neoplasms (IPMNs) are precursors to pancreatic cancer; however, little is known about genetic heterogeneity in these lesions. The objective of this study was to characterize genetic heterogeneity in IPMNs at the single-cell level. We isolated single cells from fresh tissue from ten IPMNs, followed by whole genome amplification and targeted next-generation sequencing of pancreatic driver genes. We then determined single-cell genotypes using a novel multi-sample mutation calling algorithm. Our analyses revealed that different mutations in the same driver gene frequently occur in the same IPMN. Two IPMNs had multiple mutations in the initiating driver gene KRAS that occurred in unique tumor clones, suggesting the possibility of polyclonal origin or an unidentified initiating event preceding this critical mutation. Multiple mutations in later-occurring driver genes were also common and were frequently localized to unique tumor clones, raising the possibility of convergent evolution of these genetic events in pancreatic tumorigenesis. Single-cell sequencing of IPMNs demonstrated genetic heterogeneity with respect to early and late occurring driver gene mutations, suggesting a more complex pattern of tumor evolution than previously appreciated in these lesions. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

4 Article PD-1, PD-L1, and CD163 in pancreatic undifferentiated carcinoma with osteoclast-like giant cells: expression patterns and clinical implications. 2018

Luchini, Claudio / Cros, Jerome / Pea, Antonio / Pilati, Camilla / Veronese, Nicola / Rusev, Borislav / Capelli, Paola / Mafficini, Andrea / Nottegar, Alessia / Brosens, Lodewijk A A / Noë, Michaël / Offerhaus, G Johan A / Chianchiano, Peter / Riva, Giulio / Piccoli, Paola / Parolini, Claudia / Malleo, Giuseppe / Lawlor, Rita T / Corbo, Vincenzo / Sperandio, Nicola / Barbareschi, Mattia / Fassan, Matteo / Cheng, Liang / Wood, Laura D / Scarpa, Aldo. ·Department of Diagnostics and Public Health, Section of Pathology, University of Verona, 37134 Verona, Italy. · Department of Pathology, Beaujon Hospital, 92110 Clichy, France; Paris-Diderot School of Medicine, Inflammation Research Center, 75013 Paris, France. · Department of Surgery, University and Hospital Trust of Verona, 37134 Verona, Italy. · Personalized Medicine, Pharmacogenomics, Therapeutic Optimization, Paris-Descartes University, 75006 Paris, France. · National Institute of Gastroenterology-Research Hospital, IRCCS "S. de Bellis," 70013, Castellana Grotte, Bari, Italy. · ARC-Net Research Center, University of Verona, 37134 Verona, Italy. · Department of Surgery, Section of Pathology, San Bortolo Hospital, 36100 Vicenza, Italy. · Department of Pathology, University Medical Center Utrecht, 3508 Utrecht, The Netherlands; Department of Pathology, Radboud University Medical Center, 6500, HB, Nijmegen, The Netherlands. · Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD 21211, USA. · Department of Pathology, University Medical Center Utrecht, 3508 Utrecht, The Netherlands. · Surgical Pathology Unit, Santa Chiara Hospital, 38122 Trento, Italy. · Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA. · Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD 21211, USA; Department of Oncology, Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD 21211, USA. Electronic address: ldwood@jhmi.edu. · Department of Diagnostics and Public Health, Section of Pathology, University of Verona, 37134 Verona, Italy; ARC-Net Research Center, University of Verona, 37134 Verona, Italy. Electronic address: aldo.scarpa@univr.it. ·Hum Pathol · Pubmed #30031096.

ABSTRACT: Undifferentiated carcinoma with osteoclast-like giant cells (UCOGC), a variant of pancreatic ductal adenocarcinoma (PDAC), has a striking genetic similarity to PDAC but a significantly improved overall survival. We hypothesize that this difference could be due to the immune response to the tumor, and as such, we investigated the expression of PD-1, PD-L1, and CD163 in a series of UCOGC. To this aim, 27 pancreatic UCOGCs (11 pure and 16 PDAC-associated), 5 extrapancreatic tumors with osteoclast-like giant cells and 10 pancreatic anaplastic carcinomas were immunostained using antibodies against PD-1, PD-L1, and CD163. In pancreatic UCOGCs, PD-L1 was expressed in neoplastic cells of 17 (63%) of 27 cases, more often in cases with an associated PDAC (P = .04). Expression of PD-L1 was associated with poor prognosis, confirmed by multivariate analysis: patients with PD-L1-positive UCOGCs had a risk of all-cause mortality that was 3 times higher than did patients with PD-L1-negative UCOGCs (hazard ratio, 3.397; 95% confidence interval, 1.023-18.375; P = .034). PD-L1 expression on tumor cells was also associated with aberrant P53 expression (P = .035). PD-1 was expressed on rare lymphocytes in 12 UCOGCs (44.4%), mainly located at the tumor periphery. CD163 was expressed on histiocytes, with a diffuse and strong staining pattern in all UCOGCs. Extrapancreatic tumors with osteoclast-like giant cells showed very similar staining patterns for the same proteins. Anaplastic carcinomas have some similarities to UCOGCs, but PD-L1 has no prognostic roles. Our results may have important implications for immunotherapeutic strategies in UCOGCs; these tumors may also represent a model for future therapeutic approaches against PDAC.

5 Article IPMNs with co-occurring invasive cancers: neighbours but not always relatives. 2018

Felsenstein, Matthäus / Noë, Michaël / Masica, David L / Hosoda, Waki / Chianchiano, Peter / Fischer, Catherine G / Lionheart, Gemma / Brosens, Lodewijk A A / Pea, Antonio / Yu, Jun / Gemenetzis, Georgios / Groot, Vincent P / Makary, Martin A / He, Jin / Weiss, Matthew J / Cameron, John L / Wolfgang, Christopher L / Hruban, Ralph H / Roberts, Nicholas J / Karchin, Rachel / Goggins, Michael G / Wood, Laura D. ·Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. · Department of Surgery, Charité-Universitätsmedizin Berlin, Berlin, Germany. · Institute for Computational Medicine, Johns Hopkins University, Baltimore, Maryland, USA. · Department of Biomedical Engineering, Johns Hopkins University, Baltimore, Maryland, USA. · Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands. · Department of Surgery, University and Hospital Trust of Verona, Verona, Italy. · Department of Surgery, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. · Department of Surgery, University Medical Center Utrecht, Utrecht, The Netherlands. · Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. ·Gut · Pubmed #29500184.

ABSTRACT: OBJECTIVE: Intraductal papillary mucinous neoplasms (IPMNs) are precursor lesions that can give rise to invasive pancreatic carcinoma. Although approximately 8% of patients with resected pancreatic ductal adenocarcinoma have a co-occurring IPMN, the precise genetic relationship between these two lesions has not been systematically investigated. DESIGN: We analysed all available patients with co-occurring IPMN and invasive intrapancreatic carcinoma over a 10-year period at a single institution. For each patient, we separately isolated DNA from the carcinoma, adjacent IPMN and distant IPMN and performed targeted next generation sequencing of a panel of pancreatic cancer driver genes. We then used the identified mutations to infer the relatedness of the IPMN and co-occurring invasive carcinoma in each patient. RESULTS: We analysed co-occurring IPMN and invasive carcinoma from 61 patients with IPMN/ductal adenocarcinoma as well as 13 patients with IPMN/colloid carcinoma and 7 patients with IPMN/carcinoma of the ampullary region. Of the patients with co-occurring IPMN and ductal adenocarcinoma, 51% were likely related. Surprisingly, 18% of co-occurring IPMN and ductal adenocarcinomas were likely independent, suggesting that the carcinoma arose from an independent precursor. By contrast, all colloid carcinomas were likely related to their associated IPMNs. In addition, these analyses showed striking genetic heterogeneity in IPMNs, even with respect to well-characterised driver genes. CONCLUSION: This study demonstrates a higher prevalence of likely independent co-occurring IPMN and ductal adenocarcinoma than previously appreciated. These findings have important implications for molecular risk stratification of patients with IPMN.

6 Article Pancreatic undifferentiated carcinoma with osteoclast-like giant cells is genetically similar to, but clinically distinct from, conventional ductal adenocarcinoma. 2017

Luchini, Claudio / Pea, Antonio / Lionheart, Gemma / Mafficini, Andrea / Nottegar, Alessia / Veronese, Nicola / Chianchiano, Peter / Brosens, Lodewijk Aa / Noë, Michaël / Offerhaus, G Johan A / Yonescu, Raluca / Ning, Yi / Malleo, Giuseppe / Riva, Giulio / Piccoli, Paola / Cataldo, Ivana / Capelli, Paola / Zamboni, Giuseppe / Scarpa, Aldo / Wood, Laura D. ·Department of Diagnostics and Public Health, Section of Pathology, University of Verona, Verona, Italy. · Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA. · Department of Surgery, University and Hospital Trust of Verona, Verona, Italy. · Department of Surgery, Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA. · ARC-Net Research Center, University of Verona, Verona, Italy. · National Research Council, Neuroscience Institute, Aging Branch, Padua, Italy. · Institute for Clinical Research and Education in Medicine (IREM), Padua, Italy. · Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands. · Department of Pathology, Radboud University Medical Center, Nijmegen, The Netherlands. · Sacro Cuore Don Calabria Hospital, Negrar, Verona, Italy. · Department of Oncology, Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA. ·J Pathol · Pubmed #28722124.

ABSTRACT: Undifferentiated carcinoma of the pancreas with osteoclast-like giant cells (UCOGC) is currently considered a morphologically and clinically distinct variant of pancreatic ductal adenocarcinoma (PDAC). In this study, we report clinical and pathological features of a series of 22 UCOGCs, including the whole exome sequencing of eight UCOGCs. We observed that 60% of the UCOGCs contained a well-defined epithelial component and that patients with pure UCOGC had a significantly better prognosis than did those with an UCOGC with an associated epithelial neoplasm. The genetic alterations in UCOGC are strikingly similar to those known to drive conventional PDAC, including activating mutations in the oncogene KRAS and inactivating mutations in the tumor suppressor genes CDKN2A, TP53, and SMAD4. These results further support the classification of UCOGC as a PDAC variant and suggest that somatic mutations are not the determinants of the unique phenotype of UCOGC. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

7 Article Genetic analyses of isolated high-grade pancreatic intraepithelial neoplasia (HG-PanIN) reveal paucity of alterations in TP53 and SMAD4. 2017

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. · Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, New York, USA. · Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands. · Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. · Department of Pathology, Medica Sur Clinic and Foundation, Mexico City, Mexico. · The First Department of Internal Medicine, Mie University School of Medicine, Tsu, Japan. · Department of Human Pathology, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Japan. · Department of Diagnostic Pathology, Kyoto University Hospital, Kyoto, Japan. · Center for Gastroendoscopy, Onomichi General Hospital, Onomichi, Japan. · Department of Pathology, Onomichi General Hospital, Onomich, Japan. · Diagnostic Pathology Center, Hakujikai Memorial Hospital, Tokyo, Japan. · Department of Laboratory Medicine, Shinshu University School of Medicine, Matsumoto, Japan. · Department of Gastrointestinal Surgery, Royal North Shore Hospital and Discipline of Surgery, University of Sydney, Sydney, Australia. · Cancer Diagnosis and Pathology Group, Kolling Institute of Medical Research Royal North Shore Hospital and University of Sydney, Sydney, Australia. · Department of Oncology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. · Department of Medicine, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. ·J Pathol · Pubmed #28188630.

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.