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Zen Y, Akita M. Neoplastic Progression in Intraductal Papillary Neoplasm of the Bile Duct. Arch Pathol Lab Med 2024; 148:989-996. [PMID: 36800543 DOI: 10.5858/arpa.2022-0407-ra] [Citation(s) in RCA: 9] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/09/2022] [Indexed: 02/19/2023]
Abstract
CONTEXT.— Intraductal papillary neoplasm of the bile duct (IPNB) is classified into types 1 and 2 based on criteria proposed in 2019. Recent studies investigated the clinicopathologic and molecular features of IPNB, which contributed to a more detailed understanding of this undercharacterized neoplasm. OBJECTIVE.— To summarize driver gene mutations, radiologic tumor evolution, and a potentially unique pattern of tumor progression in IPNB. DATA SOURCES.— Data were derived from a literature review and personal clinical and research experiences. CONCLUSIONS.— In contrast to de novo cholangiocarcinoma, type 1 IPNB often has mutations in APC, CTNNB1, STK11, and GNAS. These molecular features are shared with intraductal papillary mucinous neoplasm of the pancreas; however, the frequencies of individual gene abnormalities differ between these 2 neoplasms. A radiologic review of sequential images suggested that type 1 IPNB is a slow-growing neoplasm, with an ∼1-cm increase in size every 2 to 3 years, and remains in a noninvasive state for many years. A similar papillary neoplasm may develop in the biliary tree years after the complete surgical resection of IPNB. The second neoplasm has the same genetic abnormalities as the first neoplasm, indicating intrabiliary implantation rather than multifocal lesions. In contrast to type 1 IPNB, most cases of type 2 IPNB have invasive malignancy at the initial presentation. Type 2 IPNB shares many clinicopathologic and molecular features with de novo cholangiocarcinoma, questioning the distinctness of this tumor entity. The molecular mechanisms underlying malignant transformation in IPNB warrant further study.
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Affiliation(s)
- Yoh Zen
- From the Institute of Liver Studies, King's College Hospital, London, UK (Zen)
| | - Masayuki Akita
- the Department of Hepato-Biliary-Pancreatic Surgery, Kobe University Graduate School of Medicine, Kobe, Japan (Akita)
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2
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Wang T, Askan G, Ozcan K, Rana S, Zehir A, Bhanot UK, Yantiss RK, Rao DS, Wahl SJ, Bagci P, Balci S, Balachandran V, Jarnagin WR, Adsay NV, Klimstra DS, Basturk O. Tumoral Intraductal Neoplasms of the Bile Ducts Comprise Morphologically and Genetically Distinct Entities. Arch Pathol Lab Med 2023; 147:1390-1401. [PMID: 36821179 DOI: 10.5858/arpa.2022-0343-oa] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/16/2022] [Indexed: 02/24/2023]
Abstract
CONTEXT.— Tumoral (grossly visible) intraductal neoplasms of the bile ducts are still being characterized. OBJECTIVE.— To investigate their morphologic, immunohistochemical, and molecular features. DESIGN.— Forty-one cases were classified as gastric-, intestinal-, pancreatobiliary-type intraductal papillary neoplasm (IPN), intraductal oncocytic papillary neoplasm (IOPN), or intraductal tubulopapillary neoplasm (ITPN) on the basis of histology. All neoplasms were subjected to targeted next-generation sequencing. RESULTS.— The mean age at diagnosis was 69 years (42-81 years); male to female ratio was 1.3. Most neoplasms (n = 23, 56%) were extrahepatic/large (mean size, 4.6 cm). The majority (n = 32, 78%) contained high-grade dysplasia, and 68% (n = 28) revealed invasion. All gastric-type IPNs (n = 9) and most ITPNs/IOPNs showed consistent colabeling for CK7/MUC6, which was less common among others (P = .004). Intestinal-type IPNs (n = 5) showed higher rates of CK20 expression than others (P < .001). Overall, the most commonly mutated genes included TP53 and APC, while copy number variants affected ELF3 and CDKN2A/B. All gastric-type IPNs contained an alteration affecting the Wnt signaling pathway; 7 of 9 (78%) showed aberrations in the MAPK pathway. Mutations in APC and KRAS were common in gastric-type IPNs as compared with others (P = .01 for both). SMAD4 was more frequently mutated in intestinal-type IPNs (P = .02). Pancreatobiliary-type IPNs (n = 14) exhibited frequent alterations in tumor suppressor genes including TP53, CDKN2A/B, and ARID2 (P = .04, P = .01 and P = .002, respectively). Of 6 IOPNs analyzed, 3 (50%) revealed ATP1B1-PRKACB fusion. ITPNs (n = 6) showed relatively few recurrent genetic aberrations. Follow-up information was available for 38 patients (median, 58.5 months). The ratio of disease-related deaths was higher for the cases with invasion (56% versus 10%). CONCLUSIONS.— Tumoral intraductal neoplasms of the bile ducts, similar to their counterparts in the pancreas, are morphologically and genetically heterogeneous.
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Affiliation(s)
- Tao Wang
- From the Department of Pathology and Laboratory Medicine (Wang, Askan, Ozcan, Rana, Zehir, Bhanot, Rao, Klimstra, Basturk), Memorial Sloan Kettering Cancer Center, New York, New York
| | - Gokce Askan
- From the Department of Pathology and Laboratory Medicine (Wang, Askan, Ozcan, Rana, Zehir, Bhanot, Rao, Klimstra, Basturk), Memorial Sloan Kettering Cancer Center, New York, New York
| | - Kerem Ozcan
- From the Department of Pathology and Laboratory Medicine (Wang, Askan, Ozcan, Rana, Zehir, Bhanot, Rao, Klimstra, Basturk), Memorial Sloan Kettering Cancer Center, New York, New York
| | - Satshil Rana
- From the Department of Pathology and Laboratory Medicine (Wang, Askan, Ozcan, Rana, Zehir, Bhanot, Rao, Klimstra, Basturk), Memorial Sloan Kettering Cancer Center, New York, New York
| | - Ahmet Zehir
- From the Department of Pathology and Laboratory Medicine (Wang, Askan, Ozcan, Rana, Zehir, Bhanot, Rao, Klimstra, Basturk), Memorial Sloan Kettering Cancer Center, New York, New York
| | - Umeshkumar K Bhanot
- From the Department of Pathology and Laboratory Medicine (Wang, Askan, Ozcan, Rana, Zehir, Bhanot, Rao, Klimstra, Basturk), Memorial Sloan Kettering Cancer Center, New York, New York
| | - Rhonda K Yantiss
- Department of Pathology, Weill Cornell Medicine, New York, New York (Yantiss)
| | - Deepthi S Rao
- From the Department of Pathology and Laboratory Medicine (Wang, Askan, Ozcan, Rana, Zehir, Bhanot, Rao, Klimstra, Basturk), Memorial Sloan Kettering Cancer Center, New York, New York
| | - Samuel J Wahl
- Department of Pathology, Lenox Hill Hospital, New York, New York (Wahl)
| | - Pelin Bagci
- Department of Pathology, Marmara University Hospital, Istanbul, Turkey (Bagci)
| | - Serdar Balci
- Department of Pathology, Memorial Healthcare Group, Istanbul, Turkey (Balci)
| | - Vinod Balachandran
- The Department of Surgery (Balachandran, Jarnagin), Memorial Sloan Kettering Cancer Center, New York, New York
| | - William R Jarnagin
- The Department of Surgery (Balachandran, Jarnagin), Memorial Sloan Kettering Cancer Center, New York, New York
| | - N Volkan Adsay
- The Department of Pathology, Koç University Hospital and Koç University Research Center for Translational Medicine (KUTTAM), Istanbul, Turkey (Adsay)
| | - David S Klimstra
- From the Department of Pathology and Laboratory Medicine (Wang, Askan, Ozcan, Rana, Zehir, Bhanot, Rao, Klimstra, Basturk), Memorial Sloan Kettering Cancer Center, New York, New York
| | - Olca Basturk
- From the Department of Pathology and Laboratory Medicine (Wang, Askan, Ozcan, Rana, Zehir, Bhanot, Rao, Klimstra, Basturk), Memorial Sloan Kettering Cancer Center, New York, New York
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3
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Manzano-Núñez F, Prates Tiago Aguilar L, Sempoux C, Lemaigre FP. Biliary Tract Cancer: Molecular Biology of Precursor Lesions. Semin Liver Dis 2023; 43:472-484. [PMID: 37944999 DOI: 10.1055/a-2207-9834] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/12/2023]
Abstract
Biliary tract cancer is a devastating malignancy of the bile ducts and gallbladder with a dismal prognosis. The study of precancerous lesions has received considerable attention and led to a histopathological classification which, in some respects, remains an evolving field. Consequently, increasing efforts have been devoted to characterizing the molecular pathogenesis of the precursor lesions, with the aim of better understanding the mechanisms of tumor progression, and with the ultimate goal of meeting the challenges of early diagnosis and treatment. This review delves into the molecular mechanisms that initiate and promote the development of precursor lesions of intra- and extrahepatic cholangiocarcinoma and of gallbladder carcinoma. It addresses the genomic, epigenomic, and transcriptomic landscape of these precursors and provides an overview of animal and organoid models used to study them. In conclusion, this review summarizes the known molecular features of precancerous lesions in biliary tract cancer and highlights our fragmentary knowledge of the molecular pathogenesis of tumor initiation.
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Affiliation(s)
| | | | - Christine Sempoux
- Institute of Pathology, Lausanne University Hospital CHUV, University of Lausanne, Lausanne, Switzerland
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Mocchegiani F, Vincenzi P, Conte G, Nicolini D, Rossi R, Cacciaguerra AB, Vivarelli M. Intraductal papillary neoplasm of the bile duct: The new frontier of biliary pathology. World J Gastroenterol 2023; 29:5361-5373. [PMID: 37900587 PMCID: PMC10600795 DOI: 10.3748/wjg.v29.i38.5361] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/31/2023] [Revised: 08/07/2023] [Accepted: 08/31/2023] [Indexed: 10/12/2023] Open
Abstract
Intraductal papillary neoplasms of the bile duct (IPNBs) represent a rare variant of biliary tumors characterized by a papillary growth within the bile duct lumen. Since their first description in 2001, several classifications have been proposed, mainly based on histopathological, radiological and clinical features, although no specific guidelines addressing their management have been developed. Bile duct neoplasms generally develop through a multistep process, involving different precursor pathways, ranging from the initial lesion, detectable only microscopically, i.e. biliary intraepithelial neoplasia, to the distinctive grades of IPNB until the final stage represented by invasive cholangiocarcinoma. Complex and advanced investigations, mainly relying on magnetic resonance imaging (MRI) and cholangioscopy, are required to reach a correct diagnosis and to define an adequate bile duct mapping, which supports proper treatment. The recently introduced subclassifications of types 1 and 2 highlight the histopathological and clinical aspects of IPNB, as well as their natural evolution with a particular focus on prognosis and survival. Aggressive surgical resection, including hepatectomy, pancreaticoduodenectomy or both, represents the treatment of choice, yielding optimal results in terms of survival, although several endoscopic approaches have been described. IPNBs are newly recognized preinvasive neoplasms of the bile duct with high malignant potential. The novel subclassification of types 1 and 2 defines the histological and clinical aspects, prognosis and survival. Diagnosis is mainly based on MRI and cholangioscopy. Surgical resection represents the mainstay of treatment, although endoscopic resection is currently applied to nonsurgically fit patients. New frontiers in genetic research have identified the processes underlying the carcinogenesis of IPNB, to identify targeted therapies.
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Affiliation(s)
- Federico Mocchegiani
- Department of Experimental and Clinical Medicine, Polytechnic University of Marche, Ancona 60126, Italy
| | - Paolo Vincenzi
- Department of Gastroenterology and Transplant, United Hospital of Marche, Ancona 60126, Italy
| | - Grazia Conte
- Department of Gastroenterology and Transplant, United Hospital of Marche, Ancona 60126, Italy
| | - Daniele Nicolini
- Department of Gastroenterology and Transplant, United Hospital of Marche, Ancona 60126, Italy
| | - Roberta Rossi
- Department of Gastroenterology and Transplant, United Hospital of Marche, Ancona 60126, Italy
| | | | - Marco Vivarelli
- Department of Experimental and Clinical Medicine, Polytechnic University of Marche, Ancona 60126, Italy
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5
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Xue Y, Basturk O. Intraductal neoplasms of the pancreatobiliary tract: navigating the alphabet. Histopathology 2023; 83:499-508. [PMID: 37455382 DOI: 10.1111/his.15003] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2023] [Revised: 06/02/2023] [Accepted: 06/19/2023] [Indexed: 07/18/2023]
Abstract
Cancers of the pancreatobiliary tract are diseases with unfavourable prognoses. In the last couple of decades, two types of lesions have been described as precursors that precede pancreatobiliary cancers. These include incidental microscopic (flat) lesions known as pancreatic intra-epithelial neoplasia and biliary intra-epithelial neoplasia, and grossly visible, mass-forming lesions (tumoral intra-epithelial neoplasia) including intraductal papillary mucinous neoplasms, intraductal oncocytic papillary neoplasms, intraductal tubulopapillary neoplasms, intraductal papillary neoplasms of the bile duct and intracholecystic papillary neoplasms. Early detection and adequate treatment of these precursor lesions, especially the second group, have the potential to prevent pancreatobiliary cancer or at least improve its prognosis. In this review, we discuss their histopathology and recent updates on molecular profiling of these intraductal neoplasms of the pancreatobiliary tract.
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Affiliation(s)
- Yue Xue
- Department of Pathology and Laboratory Medicine, Northwestern University, Chicago, IL, USA
| | - Olca Basturk
- Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
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6
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Kamp EJCA, Dinjens WNM, van Velthuysen MLF, de Jonge PJF, Bruno MJ, Peppelenbosch MP, de Vries AC. Next-generation sequencing mutation analysis on biliary brush cytology for differentiation of benign and malignant strictures in primary sclerosing cholangitis. Gastrointest Endosc 2023; 97:456-465.e6. [PMID: 36252869 DOI: 10.1016/j.gie.2022.10.014] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/30/2022] [Revised: 10/10/2022] [Accepted: 10/10/2022] [Indexed: 01/29/2023]
Abstract
BACKGROUND AND AIMS Differentiation of benign and malignant biliary tract strictures on brush material remains highly challenging but is essential for adequate clinical management of patients with primary sclerosing cholangitis (PSC). In this case-control study, biliary brush cytology samples from PSC patients with cholangiocarcinoma (PSC-CCA) were compared with samples from PSC patients without CCA (PSC-control subjects) using next-generation sequencing (NGS). METHODS Cells on archived slides were dissected for DNA extraction. NGS was performed using a gene panel containing 242 hotspots in 14 genes. Repeated brush samples from the same patient were analyzed to study the consistency of NGS results. In PSC-CCA cases that underwent surgical resection, molecular aberrations in brush samples were compared with NGS data from subsequent resection specimens. RESULTS Forty patients (20 PSC-CCA and 20 PSC-control subjects) were included. The gene panel detected 22 mutations in 15 of 20 PSC-CCA brush samples, including mutations in TP53 (8 brush samples), K-ras (5), G-nas (3), ERBB2 (1), APC (1), PIK3CA (1), and SMAD4 (1). One G-nas and 3 K-ras mutations were found in 3 of 20 PSC-control brush samples. The sensitivity of the NGS panel was 75% (95% confidence interval, 62%-80%) and specificity 85% (95% confidence interval, 64%-95%). Repeated brush samples showed identical mutations in 6 of 9 cases. Three repeated brush samples demonstrated additional mutations as compared with the first brush sample. In 6 of 7 patients, mutations in brush samples were identical to mutations in subsequent resection specimens. CONCLUSIONS NGS mutation analysis of PSC brush cytology detects oncogenic mutations with high sensitivity and specificity and seems to constitute a valuable adjunct to cytologic assessment of brush samples.
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Affiliation(s)
- Eline J C A Kamp
- Department of Gastroenterology and Hepatology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands
| | - Winand N M Dinjens
- Department of Pathology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands
| | | | - Pieter Jan F de Jonge
- Department of Gastroenterology and Hepatology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands
| | - Marco J Bruno
- Department of Gastroenterology and Hepatology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands
| | - Maikel P Peppelenbosch
- Department of Gastroenterology and Hepatology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands
| | - Annemarie C de Vries
- Department of Gastroenterology and Hepatology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands
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7
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Ozcan K, Klimstra DS. A Review of Mucinous Cystic and Intraductal Neoplasms of the Pancreatobiliary Tract. Arch Pathol Lab Med 2022; 146:298-311. [PMID: 35192699 DOI: 10.5858/arpa.2021-0399-ra] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/24/2021] [Indexed: 11/06/2022]
Abstract
CONTEXT.— Although most pancreatic and bile duct neoplasms are solid, mucinous cystic neoplasms and intraductal neoplasms have been increasingly recognized even when clinically silent, thanks to the increased use of sensitive imaging techniques. Cystic and intraductal neoplasms of the pancreas are often resectable and curable and constitute about 5% of all pancreatic neoplasms. Owing to their preinvasive nature and different biology, recognition of these entities remains a major priority. Mucinous cystic neoplasms are histologically and clinically distinct from other cystic pancreatic neoplasms. Pancreatic intraductal neoplasms encompass 3 major entities: intraductal papillary mucinous neoplasm, intraductal oncocytic papillary neoplasm, and intraductal tubulopapillary neoplasm. Intraductal papillary neoplasms of bile ducts are also preinvasive mass-forming neoplasms with both similarities and differences with their pancreatic counterparts. All of these pancreatobiliary neoplasms have diverse and distinctive clinicopathologic, genetic, and prognostic variations. OBJECTIVE.— To review the clinical, pathologic, and molecular features of mucinous cystic and intraductal neoplasms of the pancreatobiliary tract. DATA SOURCES.— Literature review, diagnostic manuals, and guidelines. CONCLUSIONS.— This review will briefly describe well-known clinical and pathologic features and will focus on selected recently described aspects of morphology, grading, classification, and genomic alterations of cystic and intraductal neoplasms of the pancreatobiliary tract.
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Affiliation(s)
- Kerem Ozcan
- From the Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York
| | - David S Klimstra
- From the Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York
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8
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Sakihama K, Koga Y, Yamamoto T, Shimada Y, Yamada Y, Kawata J, Shindo K, Nakamura M, Oda Y. RNF43 as a predictor of malignant transformation of pancreatic mucinous cystic neoplasm. Virchows Arch 2022; 480:1189-1199. [PMID: 35066614 DOI: 10.1007/s00428-022-03277-9] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2021] [Revised: 12/23/2021] [Accepted: 01/12/2022] [Indexed: 11/26/2022]
Abstract
Mucinous cystic neoplasm (MCN) of the pancreas rarely progresses to invasive carcinoma, but few studies have analyzed genomic alterations involved in its malignant transformation. The relationships of ring finger protein 43 (RNF43) mutations with cytological atypia, RNF43 protein expression, and Wnt signaling proteins in MCN remain unclear. This study included 106 MCN cases, classified into 89 low-grade dysplasia (LG), 9 high-grade dysplasia (HG), and 8 invasive carcinoma (INV). We analyzed HG/INV and LG lesions of 9 HG/INV cases and LG lesions of 9 LG cases using targeted sequencing and confirmed the protein expression of RNF43 and β-catenin. The frequency of RNF43 mutations was significantly higher in HG/INV cases than in LG cases. Furthermore, HG/INV lesions (56%) and LG lesions (33%) of HG/INV cases possessed RNF43 mutation, whereas no such mutation was detected in any LG cases. The expression of RNF43 was reduced in 71% of HG/INV cases and significantly correlated with histological grade and aberrant expression of β-catenin. In 3 of 5 RNF43-mutated cases, the expression of RNF43 was reduced, but there was no significant correlation between RNF43 mutation and protein expression. MCNs frequently harbored KRAS mutations, at rates of 100% in HG/INV lesions and 50% in LG lesions of HG/INV and LG cases. There was no significant difference in mutation frequency in LG lesions between HG/INV and LG cases. These results suggest that RNF43 mutations may be involved in and predictive of malignant transformation from an early stage of MCN.
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Affiliation(s)
- Kukiko Sakihama
- Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashiku, Fukuoka, 812-8582, Japan
- Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Yutaka Koga
- Department of Pathology, National Hospital Organization Kyushu Cancer Center, Fukuoka, Japan
| | - Takeo Yamamoto
- Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashiku, Fukuoka, 812-8582, Japan
- Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Yuki Shimada
- Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashiku, Fukuoka, 812-8582, Japan
- Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Yutaka Yamada
- Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashiku, Fukuoka, 812-8582, Japan
- Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Jun Kawata
- Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashiku, Fukuoka, 812-8582, Japan
- Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Koji Shindo
- Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Masafumi Nakamura
- Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Yoshinao Oda
- Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashiku, Fukuoka, 812-8582, Japan.
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Sohn SH, Sul HJ, Kim B, Kim HS, Kim BJ, Lim H, Kang HS, Soh JS, Kim KC, Cho JW, Seo J, Koh Y, Zang DY. RNF43 and PWWP2B inhibit cancer cell proliferation and are predictive or prognostic biomarker for FDA-approved drugs in patients with advanced gastric cancer. J Cancer 2021; 12:4616-4625. [PMID: 34149925 PMCID: PMC8210561 DOI: 10.7150/jca.56014] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2020] [Accepted: 05/19/2021] [Indexed: 12/19/2022] Open
Abstract
Background: Abnormal regulation of genes has been closely related to gastric cancer. The characterization of gastric cancer has necessitated the development of new therapeutics as well as the identification of prognostic markers to predict the response to novel drugs. In our study, we used RNA sequencing analyses to show that on gastric cancer tissues to identification of gastric cancer prognostic markers. We specifically chose to study RNF43 because it inhibits gastric cancer-related Wnt/β-catenin signaling by interacting with Wnt receptors. PWWP2B was chosen because it is a gene which is downregulated in gastric cancer. Methods: Utilizing RNA sequencing analysis, we evaluated the mRNA expression profile in gastric cancer patients. Also, we used HAP1 cells which is a human near-haploid cell line derived from the male chronic myelogenous leukemia cell line KBM-7. These cell line has one copy of each gene, ensuring the edited allele will not be masked by additional alleles. We investigated the screening of 1,449 FDA-approved drugs in HAP1, HAP1 RNF43 KO and HAP1 PWWP2B KO cells. RNA sequencing data reveals that RNF43 and PWWP2B expression were down-regulated in recurrence gastric cancer patients. Next, we investigated the anti-cancer effects of selected drugs in RNF43 and PWWP2B down-regulated MKN45 gastric cancer cells and xenograft model. Results: Among these FDA-approved drugs, three drugs (docetaxel trihydrate, pelitinib and uprosertib) showed strong inhibitory effects in RNF43 KO cells and PWWP2B KO cells. In MKN45 xenograft model, tumor volumes were significantly reduced in the docetaxel trihydrate, uprosertib or pelitinib-treated group. Our data demonstrated that RNF43 and PWWP2B are a biomarker that predict recurrence of gastric cancer. Conclusions: Our findings suggest that docetaxel trihydrate, uprosertib and pelitinib could be used as novel therapeutic agents for the prevention and treatment of gastric cancer with a decrease in RNF43 and PWWP2B expression.
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Affiliation(s)
- Sung-Hwa Sohn
- Hallym Translational Research Institute, Hallym University Sacred Heart Hospital, Anyang, 14066, Republic of Korea
| | - Hee Jung Sul
- Hallym Translational Research Institute, Hallym University Sacred Heart Hospital, Anyang, 14066, Republic of Korea
| | - Bohyun Kim
- Hallym Translational Research Institute, Hallym University Sacred Heart Hospital, Anyang, 14066, Republic of Korea
| | - Hyeong Su Kim
- Department of Internal Medicine, Hallym University Medical Center, Hallym University College of Medicine, Anyang-si, Gyeonggi-do 14068, Republic of Korea
| | - Bum Jun Kim
- Department of Internal Medicine, Hallym University Medical Center, Hallym University College of Medicine, Anyang-si, Gyeonggi-do 14068, Republic of Korea
| | - Hyun Lim
- Department of Internal Medicine, Hallym University Medical Center, Hallym University College of Medicine, Anyang-si, Gyeonggi-do 14068, Republic of Korea
| | - Ho Suk Kang
- Department of Internal Medicine, Hallym University Medical Center, Hallym University College of Medicine, Anyang-si, Gyeonggi-do 14068, Republic of Korea
| | - Jae Seung Soh
- Department of Internal Medicine, Hallym University Medical Center, Hallym University College of Medicine, Anyang-si, Gyeonggi-do 14068, Republic of Korea
| | - Kab Choong Kim
- Department of Surgery, Hallym University Medical Center, Hallym University Kangnam Sacred Hospital, Singil-ro Yeongdeungpo-gu, Seoul, 07441, Republic of Korea
| | - Ji Woong Cho
- Department of Surgery, Hallym University Medical Center, Hallym University Kangnam Sacred Hospital, Singil-ro Yeongdeungpo-gu, Seoul, 07441, Republic of Korea
| | - Jinwon Seo
- Department of Pathology, Hallym University Medical Center, Hallym University College of Medicine, Anyang-si, Gyeonggi-do 14068, Republic of Korea
| | - Youngho Koh
- Department of Bio-medical Gerontology, Ilsong Institute of Life Sciences, Hallym University, Anyang, Gyeonggi-do, Republic of Korea
| | - Dae Young Zang
- Hallym Translational Research Institute, Hallym University Sacred Heart Hospital, Anyang, 14066, Republic of Korea.,Department of Internal Medicine, Hallym University Medical Center, Hallym University College of Medicine, Anyang-si, Gyeonggi-do 14068, Republic of Korea
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10
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Reappraisal of pathological features of intraductal papillary neoplasm of bile duct with respect to the type 1 and 2 subclassifications. Hum Pathol 2021; 111:21-35. [PMID: 33508254 DOI: 10.1016/j.humpath.2021.01.002] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/28/2020] [Revised: 01/13/2021] [Accepted: 01/13/2021] [Indexed: 12/14/2022]
Abstract
The pathological spectrum of intraductal papillary neoplasm of bile duct (IPNB) remains to be clarified. A total of 186 IPNBs were pathologically examined using the type 1 and 2 subclassifications proposed by Japanese and Korean biliary pathologists incorporating a two-tiered grading system (low-grade and high-grade dysplasia), with reference to four subtypes (intestinal [i], gastric [g], pancreatobiliary [pb], and concocytic [o] subtype). IPNBs were classifiable into type 1 composed of low-grade dysplasia and 'high-grade dysplasia with regular structures' (69 IPNBs), and type 2 of 'high grade dysplasia with irregular structures and complicated lesions' (117 IPNBs). Type 1 was more common in the intrahepatic bile duct (78%), whereas type 2 was frequently located in the extrahepatic bile duct (58%). Mucin hypersecretion was more common in type 1 (61%) than in type 2 (37%). IPNBs were classifiable into the four subtypes: 86 iPNBs, 40 gIPNBs, 31 pbIPNBs, and 29 oIPNBs. The four subtypes were histologically evaluable with reference to the type 1 and 2 subclassifications. iIPNB and pbIPNBs were frequently classified as type 2, whereas types 1 and 2 were observed at similar rates in gIPNB and oIPNB. Stromal invasion was almost absent in type 1, irrespective of subtype, but was found in 66 of 117 type 2 IPNBs (P < .01), and postoperative outcome was favorable in IPNBs without invasion compared with IPNBs with invasion (P < .05). The type 1 and 2 subclassifications with reference to the four subtypes may provide useful information for understanding IPNB.
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Intraductal Papillary Neoplasm of Bile Duct: Updated Clinicopathological Characteristics and Molecular and Genetic Alterations. J Clin Med 2020; 9:jcm9123991. [PMID: 33317146 PMCID: PMC7763595 DOI: 10.3390/jcm9123991] [Citation(s) in RCA: 55] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2020] [Revised: 12/03/2020] [Accepted: 12/07/2020] [Indexed: 02/06/2023] Open
Abstract
Intraductal papillary neoplasm of the bile duct (IPNB), a pre-invasive neoplasm of the bile duct, is being established pathologically as a precursor lesion of invasive cholangiocarcinoma (CCA), and at the time of surgical resection, approximately half of IPNBs show stromal invasion (IPNB associated with invasive carcinoma). IPNB can involve any part of the biliary tree. IPNB shows grossly visible, exophytic growth in a dilated bile duct lumen, with histologically villous/papillary neoplastic epithelia with tubular components covering fine fibrovascular stalks. Interestingly, IPNB can be classified into four subtypes (intestinal, gastric, pancreatobiliary and oncocytic), similar to intraductal papillary mucinous neoplasm of the pancreas (IPMN). IPNBs are classified into low-grade and high-grade based on lining epithelial features. The new subclassification of IPNB into types 1 (low-grade dysplasia and high-grade dysplasia with regular architecture) and 2 (high-grade dysplasia with irregular architecture) proposed by the Japan–Korea pathologist group may be useful in the clinical field. The outcome of post-operative IPNBs is more favorable in type 1 than type 2. Recent genetic studies using next-generation sequencing have demonstrated the existence of several groups of mutations of genes: (i) IPNB showing mutations in KRAS, GNAS and RNF43 belonged to type 1, particularly the intestinal subtype, similar to the mutation patterns of IPMN; (ii) IPNB showing mutations in CTNNB1 and lacking mutations in KRAS, GNAS and RNF43 belonged to the pancreatobiliary subtype but differed from IPMN. IPNB showing mutation of TP53, SMAD4 and PIK3CA might reflect complicated and other features characterizing type 2. The recent recognition of IPNBs may facilitate further clinical and basic studies of CCA with respect to the pre-invasive and early invasive stages.
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12
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Kleeman SO, Leedham SJ. Not All Wnt Activation Is Equal: Ligand-Dependent versus Ligand-Independent Wnt Activation in Colorectal Cancer. Cancers (Basel) 2020; 12:E3355. [PMID: 33202731 PMCID: PMC7697568 DOI: 10.3390/cancers12113355] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2020] [Revised: 11/11/2020] [Accepted: 11/12/2020] [Indexed: 02/08/2023] Open
Abstract
Wnt signaling is ubiquitously activated in colorectal tumors and driver mutations are identified in genes such as APC, CTNNB1, RNF43 and R-spondin (RSPO2/3). Adenomatous polyposis coli (APC) and CTNNB1 mutations lead to downstream constitutive activation (ligand-independent), while RNF43 and RSPO mutations require exogenous Wnt ligand to activate signaling (ligand-dependent). Here, we present evidence that these mutations are not equivalent and that ligand-dependent and ligand-independent tumors differ in terms of underlying Wnt biology, molecular pathogenesis, morphology and prognosis. These non-overlapping characteristics can be harnessed to develop biomarkers and targeted treatments for ligand-dependent tumors, including porcupine inhibitors, anti-RSPO3 antibodies and asparaginase. There is emerging evidence that these therapies may synergize with immunotherapy in ligand-dependent tumors. In summary, we propose that ligand-dependent tumors are an underappreciated separate disease entity in colorectal cancer.
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Affiliation(s)
- Sam O. Kleeman
- Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA;
- Intestinal Stem Cell Biology Lab, Wellcome Trust Centre Human Genetics, University of Oxford, Oxford OX3 7BN, UK
| | - Simon J. Leedham
- Intestinal Stem Cell Biology Lab, Wellcome Trust Centre Human Genetics, University of Oxford, Oxford OX3 7BN, UK
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13
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RNF43 Mutations in IPMN Cases: A Potential Prognostic Factor. Gastroenterol Res Pract 2020; 2020:1457452. [PMID: 32934653 PMCID: PMC7479465 DOI: 10.1155/2020/1457452] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/01/2020] [Accepted: 06/29/2020] [Indexed: 12/15/2022] Open
Abstract
An intraductal papillary mucinous neoplasm (IPMN) is a common pancreatic precursor lesion, and it often harbors mutations in KRAS, GNAS, and RNF43. To clarify the molecular profiles of IPMNs, we conducted mutation analysis of KRAS, GNAS, and RNF43 in 61 IPMN formalin-fixed, paraffin-embedded (FFPE) specimens. The mutation rates of codons 12, 13, and 61 in KRAS and codon 201 in GNAS were detected by Sanger sequencing. Next-generation sequencing was performed on RNF43, and the results were further verified by Sanger sequencing. We identified KRAS and GNAS mutations in 35 (57%) and 40 (66%) IPMN cases, respectively. GNAS mutations were significantly correlated with the morphologic subtype (P < 0.001) and were more prevalent in the intestinal subtype (93%) than in the gastric (55%) and pancreatobiliary subtypes (44%) but were absent in the oncocytic subtype. RNF43 mutations were found in 5 cases (8%), all of which occurred in high-grade dysplasia and invasive lesions (2/5 and 3/5). All 5 cases harboring RNF43 mutations also exhibited GNAS mutations. RNF43 mutations were associated with a worse prognosis in invasive IPMN patients (P = 0.002), while KRAS and GNAS mutations did not affect the prognosis of patients.
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14
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Yanai Y, Saito T, Hayashi T, Akazawa Y, Yatagai N, Tsuyama S, Tomita S, Hirai S, Ogura K, Matsumoto T, Wada R, Yao T. Molecular and clinicopathological features of appendiceal mucinous neoplasms. Virchows Arch 2020; 478:413-426. [PMID: 32821969 DOI: 10.1007/s00428-020-02906-5] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2019] [Revised: 07/27/2020] [Accepted: 08/10/2020] [Indexed: 12/14/2022]
Abstract
Appendiceal mucinous tumors (AMTs) include low-grade mucinous appendiceal neoplasms (LAMNs), high-grade mucinous appendiceal neoplasms (HAMNs), and mucinous adenocarcinomas (MACs). We collected 51 AMT samples (LAMN: 34, HAMN: 8, MAC: 9). Three of the eight HAMN cases contained LAMN components, and four out of nine MAC cases contained LAMN and/or HAMN components within the tumor. A next-generation sequencing (NGS) cancer hotspot panel was used to analyze 11 pure LAMN, 4 HAMN, and 3 MAC cases. The results revealed KRAS and GNAS as the most frequently mutated genes. Sanger sequencing was then performed to detect KRAS, GNAS, and TP53 mutations in the remaining 31 cases and RNF43 mutations in all cases. KRAS/GNAS and TP53 mutations occurred exclusively in pure LAMNs; however, five LAMN cases had mutations in both KRAS and GNAS. RNF43 mutations almost exclusively occurred with KRAS/GNAS mutations in pure LAMNs. In MAC and HAMN, KRAS/GNAS mutation status was nearly preserved between lower-grade areas. Most of the detected RNF43 mutations was missense type. RNF43 mutations were detected in both components of MAC with lower-grade area; however, RNF43 mutations detected in these two lesions were entirely different. RNF43 mutations were detected in only one of the eight HAMN patients, which was the sole case without pseudomyxoma peritonei (PMP). None of the four MAC patients with RNF43 mutation showed PMP. These findings suggest that RNF43 mutations occur at a later stage of MAC development and do not associate with PMP. Furthermore, a gradual transition from LAMN to MAC via HAMN could be considered.
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Affiliation(s)
- Yuka Yanai
- Department of Human Pathology, Graduate School of Medicine, Juntendo University, 2-1-1 Hongo, Bunkyo-Ku, Tokyo, 113-8421, Japan
| | - Tsuyoshi Saito
- Department of Human Pathology, Graduate School of Medicine, Juntendo University, 2-1-1 Hongo, Bunkyo-Ku, Tokyo, 113-8421, Japan. .,Intractable Disease Research Center, Graduate School of Medicine, Juntendo University, Tokyo, 113-8421, Japan.
| | - Takuo Hayashi
- Department of Human Pathology, Graduate School of Medicine, Juntendo University, 2-1-1 Hongo, Bunkyo-Ku, Tokyo, 113-8421, Japan
| | - Yoichi Akazawa
- Department of Gastroenterology, Graduate School of Medicine, Juntendo University, Tokyo, 113-8421, Japan
| | - Noboru Yatagai
- Department of Gastroenterology, Graduate School of Medicine, Juntendo University, Tokyo, 113-8421, Japan
| | - Sho Tsuyama
- Department of Human Pathology, Graduate School of Medicine, Juntendo University, 2-1-1 Hongo, Bunkyo-Ku, Tokyo, 113-8421, Japan
| | - Shigeki Tomita
- Department of Pathology, Juntendo University Urayasu Hospital, Urayasu, Chiba, 279-0021, Japan
| | - Shu Hirai
- Department of Pathology, Juntendo University Tokyo Koto Geriatric Medical center, Tokyo, 136-0075, Japan
| | - Kanako Ogura
- Department of Pathology, Juntendo University Nerima Hospital, Tokyo, 177-8521, Japan
| | - Toshiharu Matsumoto
- Department of Pathology, Juntendo University Nerima Hospital, Tokyo, 177-8521, Japan
| | - Ryo Wada
- Department of Pathology, Juntendo University Shizuoka Hospital, Shizuoka, 410-2295, Japan
| | - Takashi Yao
- Department of Human Pathology, Graduate School of Medicine, Juntendo University, 2-1-1 Hongo, Bunkyo-Ku, Tokyo, 113-8421, Japan
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15
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Aoki Y, Mizuma M, Hata T, Aoki T, Omori Y, Ono Y, Mizukami Y, Unno M, Furukawa T. Intraductal papillary neoplasms of the bile duct consist of two distinct types specifically associated with clinicopathological features and molecular phenotypes. J Pathol 2020; 251:38-48. [PMID: 32100878 DOI: 10.1002/path.5398] [Citation(s) in RCA: 41] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2019] [Revised: 01/13/2020] [Accepted: 02/11/2020] [Indexed: 12/16/2022]
Abstract
Intraductal papillary neoplasm of the bile duct (IPNB) is a grossly visible papillary biliary neoplasm with morphological variations and occasional invasion. Recently a new classification of IPNB into type 1 and type 2 was proposed in which the type 1 IPNBs consist of fine papillary neoplastic glands and the type 2 IPNBs consist of complex branching glands, seldom with foci of solid-tubular components. However, clinicopathological and molecular characteristics of these types of IPNBs are yet to be identified. We aimed to uncover clinicopathological and molecular characteristics of the types of IPNBs. Thirty-six IPNBs were studied retrospectively. Clinicopathological features as well as molecular alterations of 31 genes were evaluated by means of targeted next-generation sequencing and immunohistochemical examination of expression of mucin and cancer-associated molecules. The 36 IPNBs were classified into 22 of type 1 and 14 of type 2. The type 1 IPNBs were associated with a non-invasive phenotype, intestinal and oncocytic subtypes, development in the intrahepatic bile duct, overt mucin production, and a relatively good prognosis. The type 2 IPNBs were associated with an invasive phenotype, the pancreatobiliary subtype, development within the extrahepatic bile duct, and worse prognosis compared with the type 1 IPNBs. In the molecular analysis, recurrent mutations were found in TP53 (34.3%), KRAS (31.4%), STK11 (25.7%), CTNNB1 (17.1%), APC (14.3%), SMAD4 (14.3%), GNAS (11.4%), PBRM1 (11.4%), ELF3 (8.6%), KMT2C (8.6%), NF1 (8.6%), PIK3CA (8.6%), ARID1A (5.7%), ARID2 (5.7%), BAP1 (5.7%), BRAF (5.7%), EPHA6 (5.7%), ERBB2 (5.7%), ERBB3 (5.7%), KMT2D (5.7%), and RNF43 (5.7%). Mutations in KRAS and GNAS were enriched in the type 1 IPNBs, whereas mutations in TP53, SMAD4, and KMT2C were enriched in the type 2 IPNBs. These results indicate that IPNBs consist of two distinct types of neoplasms specifically associated with clinicopathological features and molecular phenotypes. © 2020 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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Affiliation(s)
- Yasutaka Aoki
- Department of Surgery, Tohoku University Graduate School of Medicine, Sendai, Japan.,Department of Investigative Pathology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Masamichi Mizuma
- Department of Surgery, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Tatsuo Hata
- Department of Surgery, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Takeshi Aoki
- Department of Surgery, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Yuko Omori
- Department of Investigative Pathology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Yusuke Ono
- Institute of Biomedical Research, Sapporo Higashi Tokushukai Hospital, Sapporo, Japan
| | - Yusuke Mizukami
- Institute of Biomedical Research, Sapporo Higashi Tokushukai Hospital, Sapporo, Japan.,Department of Medicine, Asahikawa Medical University, Asahikawa, Japan
| | - Michiaki Unno
- Department of Surgery, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Toru Furukawa
- Department of Investigative Pathology, Tohoku University Graduate School of Medicine, Sendai, Japan
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16
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Li S, Lavrijsen M, Bakker A, Magierowski M, Magierowska K, Liu P, Wang W, Peppelenbosch MP, Smits R. Commonly observed RNF43 mutations retain functionality in attenuating Wnt/β-catenin signaling and unlikely confer Wnt-dependency onto colorectal cancers. Oncogene 2020; 39:3458-3472. [PMID: 32103169 DOI: 10.1038/s41388-020-1232-5] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2019] [Revised: 02/14/2020] [Accepted: 02/17/2020] [Indexed: 02/08/2023]
Abstract
Cancer-associated RNF43 mutations lead to activation of β-catenin signaling through aberrantly increasing Wnt-receptor levels at the membrane. Importantly, inactivating RNF43 mutations have been suggested to render cancer cells sensitive to Wnt-based therapeutics. However, the extent to which RNF43 mutations lead to impaired regulation of Wnt/β-catenin signaling has been poorly investigated. Here, we observed that tumors with a functional mismatch repair system show a predominant 5'-location of truncating RNF43 mutations, suggesting C-terminal truncations such as the most commonly reported p.G659fs mutation, do not affect β-catenin signaling. In accordance, expressing C-terminal truncation mutants and wild-type RNF43, showed equal effects on β-catenin signaling, Wnt-receptor turnover, and DVL-binding. We confirmed these observations at endogenous levels by CRISPR-Cas9-mediated knockout of G659fs RNF43 expression in KM12 cells and generating comparable mutations in HEK293T cells. We could not confirm previous reports linking RNF43 to p53 and E-cadherin breakdown. Our data also suggest that only colorectal cancer cells harboring N-terminal mutations of RNF43 convey Wnt-dependency onto the tumor cells. Results of this study have potentially important clinical implications indicating that Wnt-based therapeutics should be applied cautiously in cancer patients harboring RNF43 mutations.
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Affiliation(s)
- Shan Li
- Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, The Netherlands.,Department of Hepatobiliary Surgery, Daping Hospital, Army Medical University, Chongqing, China
| | - Marla Lavrijsen
- Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, The Netherlands
| | - Aron Bakker
- Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, The Netherlands
| | - Marcin Magierowski
- Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, The Netherlands.,Department of Physiology, Jagiellonian University Medical College, Cracow, Poland
| | - Katarzyna Magierowska
- Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, The Netherlands.,Department of Physiology, Jagiellonian University Medical College, Cracow, Poland
| | - Pengyu Liu
- Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, The Netherlands
| | - Wenhui Wang
- Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, The Netherlands.,State Key Laboratory of Natural Medicines, Department of Pharmacology, China Pharmaceutical University, Nanjing, China
| | - Maikel P Peppelenbosch
- Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, The Netherlands
| | - Ron Smits
- Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, The Netherlands.
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Taggart MW, Foo WC, Lee SM. Tumors of the Gastrointestinal System Including the Pancreas. ONCOLOGICAL SURGICAL PATHOLOGY 2020:691-870. [DOI: 10.1007/978-3-319-96681-6_12] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2025]
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18
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Targeted next-generation sequencing identifies distinct clinicopathologic and molecular entities of intraductal papillary neoplasms of the bile duct. Mod Pathol 2019; 32:1637-1645. [PMID: 31231124 DOI: 10.1038/s41379-019-0306-9] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2019] [Revised: 04/13/2019] [Accepted: 05/22/2019] [Indexed: 12/14/2022]
Abstract
Intraductal papillary neoplasm of the bile duct (IPNB) is a mass-forming neoplasm in the bile duct considered to be the biliary counterpart of pancreatic intraductal papillary mucinous neoplasm (IPMN). By its cell lineage, IPNB can be classified into gastric, intestinal, pancreatobiliary, and oncocytic types. Recently, a group of Japanese and Korean pathologists proposed that IPNB be classified into two types, with type 1, being the histological counterpart of IPMN and type 2, having a more complex histological architecture. We used targeted next-generation sequencing to study the molecular change of 37 IPNBs and identified frequent mutations of KRAS (49%), GNAS (32%), RNF43 (24%), APC (24%), TP53 (24%), and CTNNB1 (11%) in IPNBs. Intestinal-type IPNB was associated with KRAS, GNAS, and RNF43 mutations. Japan-Korea consensus type 1 was associated with KRAS and GNAS mutations. All four IPNBs with CTNNB1 mutations were of pancreatobiliary type and located in the extrahepatic bile duct. A hierarchical analysis identified three distinct groups within IPNB: group 1 was Japan-Korea consensus type 1 tumors with macroscopic mucin, old age, and frequent KRAS, GNAS, and RNF43 mutations. Group 2 was Japan-Korea consensus type 2 with intestinal differentiation and frequent KRAS mutation but rare GNAS mutation, MUC2 expression, and macroscopic mucin. Group 3 was characterized by CTNNB1 mutation, extrahepatic location, lack of expression of intestinal markers, Japan-Korea consensus type 2, and lack of mutations in KRAS, APC, RNF43, and GNAS. Our results indicated that IPNB is a heterogeneous disease and that the activation of Ras-mitogen-activated protein kinase (MAPK), Wnt/β-catenin, and G-protein-coupled receptor (GPCR)-cAMP signaling is the main oncogenic mechanism of IPNB.
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Recurrent Mutations in APC and CTNNB1 and Activated Wnt/β-catenin Signaling in Intraductal Papillary Neoplasms of the Bile Duct: A Whole Exome Sequencing Study. Am J Surg Pathol 2019; 42:1674-1685. [PMID: 30212390 DOI: 10.1097/pas.0000000000001155] [Citation(s) in RCA: 42] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
This study aimed to elucidate the genetic landscape of biliary papillary neoplasms. Of 28 cases examined, 7 underwent whole exome sequencing, while the remaining 21 were used for validation studies with targeted sequencing. In the whole exome sequencing study, 4/7 cases had mutations in either APC or CTNNB1, both of which belong to the Wnt/β-catenin pathway. Somatic mutations were also identified in genes involved in RAS signaling (KRAS, BRAF), a cell cycle regulator (CDC27), histone methyltransferase (KMT2C, KMT2D), and DNA mismatch repair (MSH3, MSH6, PMS1). Combined with discovery and validation cohorts, mutations in APC or CTNNB1 were observed in 6/28 subjects (21%) and were mutually exclusive. When the cases were classified into intraductal papillary neoplasms of the bile duct (IPNBs, n=14) and papillary cholangiocarcinomas (n=14) based on the recently proposed classification criteria, mutations in APC and CTNNB1 appeared to be entirely restricted to IPNBs with 6/14 cases (43%) harboring mutations in either gene. These genetic alterations were detected across the 3 nonintestinal histologic types. In immunohistochemistry, the aberrant cytoplasmic and/or nuclear expression of β-catenin was found in not only 5/6 IPNBs with APC or CTNNB1 mutations, but also 6/8 cases with wild-type APC and CTNNB1 (total 79%). In addition, APC and CTNNB1 alterations were exceptional in nonpapillary cholangiocarcinomas (n=29) with a single case harboring CTNNB1 mutation (3%). This study demonstrated recurrent mutations in APC and CTNNB1 in nonintestinal-type IPNBs, suggesting that activation of the Wnt/β-catenin signaling pathway is relevant to the development and progression of IPNBs.
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20
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The Pathologic and Genetic Characteristics of the Intestinal Subtype of Intraductal Papillary Neoplasms of the Bile Duct. Am J Surg Pathol 2019; 43:1212-1220. [DOI: 10.1097/pas.0000000000001295] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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21
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Ueno M, Takabatake H, Kayahara T, Morimoto Y, Yamamoto H, Mizuno M. Mucin-producing hepatocellular carcinoma without morphological features of biliary differentiation: A case report. Medicine (Baltimore) 2018; 97:e12159. [PMID: 30200114 PMCID: PMC6133640 DOI: 10.1097/md.0000000000012159] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
RATIONALE Hepatocellular carcinoma has been believed not to produce mucin unless it has biliary differentiation. However, some cases of hepatocellular carcinoma with extracellular myxoid change have been reported recently, raising the possibility that, in rare cases, hepatocellular carcinoma cells produce mucin. PATIENT CONCERNS Here we report a case of hepatocellular carcinoma that contained intracellular and extracellular myxoid matrix without morphological evidence of biliary differentiation, although cells in a portion of the tumor were positive for the epithelial markers cytokeratin 7 and 19. She was brought to our hospital due to abnormal liver tests and a large liver tumor found by ultrasound examination. DIAGNOSES The liver tumor showed typical imaging findings of hepatocellular carcinoma. INTERVENTIONS The tumor was resected with negative margins, and pathologically diagnosed as hepatocellular carcinoma with mucin production. OUTCOMES The patient has been free from recurrence of cancer during two-years' follow-up. LESSONS Our case suggests that hepatocellular carcinoma cells can produce mucin without or before morphological differentiation to biliary phenotypes, an observation that may help elucidate the mechanism for the development of combined hepatocellular and cholangiocarcinoma.
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22
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Ghurburrun E, Borbath I, Lemaigre FP, Jacquemin P. Liver and Pancreas: Do Similar Embryonic Development and Tissue Organization Lead to Similar Mechanisms of Tumorigenesis? Gene Expr 2018; 18:149-155. [PMID: 29580319 PMCID: PMC6190115 DOI: 10.3727/105221618x15216414278706] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
The liver and pancreas are closely associated organs that share a common embryological origin. They display amphicrine properties and have similar exocrine organization with parenchymal cells, namely, hepatocytes and acinar cells, secreting bile and pancreatic juice into the duodenum via a converging network of bile ducts and pancreatic ducts. Here we compare and highlight the similarities of molecular mechanisms leading to liver and pancreatic cancer development. We suggest that unraveling tumor development in an organ may provide insight into our understanding of carcinogenesis in the other organ.
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Affiliation(s)
- Elsa Ghurburrun
- *Université catholique de Louvain, de Duve Institute, Brussels, Belgium
| | - Ivan Borbath
- †Université catholique de Louvain, Department of Hepato-Gastro-Enterology, Cliniques Universitaires Saint-Luc, Brussels, Belgium
| | | | - Patrick Jacquemin
- *Université catholique de Louvain, de Duve Institute, Brussels, Belgium
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23
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Xian ZH, Qin C, Cong WM. KRAS mutation and immunohistochemical profile in intraductal papillary neoplasm of the intrahepatic bile ducts. Pathol Res Pract 2017; 214:105-111. [PMID: 29103773 DOI: 10.1016/j.prp.2017.10.017] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/20/2017] [Revised: 10/16/2017] [Accepted: 10/16/2017] [Indexed: 12/16/2022]
Abstract
Intraductal papillary neoplasm of bile duct (IPNB) is characterized by a spectrum of diseases ranging from low-grade intraepithelial neoplasia to invasive carcinoma. In the present study, we aimed to investigate immunophenotypic features and KRAS mutations in relation to pathological subtypes and grades in Chinese patients with IPNBs. A total of 46 patients with IPNBs and 11 invasive adenocarcinomas arising in IPNBs (invasive IPNBs) were enrolled and clinicopathological data were analyzed. It was found that CK7 was expressed in 42 of the 46 neoplastic lesions. HepPar1 was expressed in 11 of the 46 noninvasive IPNBs, but not in invasive IPNBs. Additionally, CK19 was frequently expressed in both noninvasive IPNBs and invasive IPNBs. The intestinal-type IPNBs had a significantly higher percentage of MUC2 expression relative to the pancreaticobiliary (P=0.015) and gastric-type IPNBs (P<0.001). High-grade IPNBs and invasive IPNBs showed increased expression of cyclin D1, Ki-67, p53, mCEA, and CA19-9. The rate of KRAS mutation was significantly higher in high-grade IPNBs (P=0.001) and invasive IPNBs (P=0.006) than that in low- to intermediate-grade IPNBs. Additionally, KRAS mutation was significantly associated with tumor size, and Ki-67 expression. In conclusion, the expression of cyclin D, Ki-67, p53, mCEA and CA19-9 and KRAS mutation status are significantly correlated with histological grades of IPNBs.
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Affiliation(s)
- Zhi-Hong Xian
- Department of Pathology, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China.
| | - Chun Qin
- Department of Pathology, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China
| | - Wen-Ming Cong
- Department of Pathology, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China
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24
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Fujikura K, Akita M, Abe-Suzuki S, Itoh T, Zen Y. Mucinous cystic neoplasms of the liver and pancreas: relationship between KRAS
driver mutations and disease progression. Histopathology 2017; 71:591-600. [DOI: 10.1111/his.13271] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2016] [Accepted: 05/29/2017] [Indexed: 12/14/2022]
Affiliation(s)
- Kohei Fujikura
- Department of Diagnostic Pathology; Kobe University Graduate School of Medicine; Kobe Japan
| | - Masayuki Akita
- Department of Diagnostic Pathology; Kobe University Graduate School of Medicine; Kobe Japan
| | - Shiho Abe-Suzuki
- Department of Diagnostic Pathology; Kobe University Graduate School of Medicine; Kobe Japan
| | - Tomoo Itoh
- Department of Diagnostic Pathology; Kobe University Graduate School of Medicine; Kobe Japan
| | - Yoh Zen
- Department of Diagnostic Pathology; Kobe University Graduate School of Medicine; Kobe Japan
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