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Gene mutation of bile duct cancer

Farshad Farshidfar, Siyuan Zheng, Marie-Claude Gingras, Yulia Newton, Juliann Shih, A Gordon Robertson, Toshinori Hinoue, Katherine A Hoadley, Ewan A Gibb, Jason Roszik, Kyle R Covington, Chia-Chin Wu, Eve Shinbrot, Nicolas Stransky, Apurva Hegde, Ju Dong Yang, Ed Reznik, Sara Sadeghi, Chandra Sekhar Pedamallu, Akinyemi I Ojesina, Julian M Hess, J Todd Auman, Suhn K Rhie, Reanne Bowlby, Mitesh J Borad, Andrew X Zhu, Josh M Stuart, Chris Sander, Rehan Akbani, Andrew D Cherniack, Vikram Deshpande, Taofic Mounajjed, Wai Chin Foo, Michael S Torbenson, David E Kleiner, Peter W Laird, David A Wheeler, Autumn J McRee, Oliver F Bathe, Jesper B Andersen, Nabeel Bardeesy, Lewis R Roberts, Lawrence N Kwong
Cholangiocarcinoma (CCA) is an aggressive malignancy of the bile ducts, with poor prognosis and limited treatment options. Here, we describe the integrated analysis of somatic mutations, RNA expression, copy number, and DNA methylation by The Cancer Genome Atlas of a set of predominantly intrahepatic CCA cases and propose a molecular classification scheme. We identified an IDH mutant-enriched subtype with distinct molecular features including low expression of chromatin modifiers, elevated expression of mitochondrial genes, and increased mitochondrial DNA copy number...
March 14, 2017: Cell Reports
Ali Mteyrek, Elisabeth Filipski, Catherine Guettier, Malgorzata Oklejewicz, Gijsbertus T J van der Horst, Alper Okyar, Francis Lévi
A coordinated network of molecular circadian clocks in individual cells generates 24-hr rhythms in liver metabolism and proliferation. Circadian disruption through chronic jet lag or Per2 clock gene mutation was shown to accelerate hepatocarcinoma development in mice. As divergent effects were reported for clock genes Per and Cry regarding xenobiotic toxicity, we questioned the role of Cry1 and Cry2 in liver carcinogenesis. Male WT and Cry1(-/-) Cry2(-/-) mice (C57Bl/6 background) were chronically exposed to diethylnitrosamine (DEN) at ZT11...
February 22, 2017: International Journal of Cancer. Journal International du Cancer
John K L Wong, Desmond Campbell, Ngoc Diem Ngo, Fanny Yeung, Guo Cheng, Clara S M Tang, Patrick H Y Chung, Ngoc Son Tran, Man-Ting So, Stacey S Cherny, Pak C Sham, Paul K Tam, Maria-Mercè Garcia-Barcelo
BACKGROUND: Congenital dilatation of the bile-duct (CDD) is a rare, mostly sporadic, disorder that results in bile retention with severe associated complications. CDD affects mainly Asians. To our knowledge, no genetic study has ever been conducted. METHODS: We aim to identify genetic risk factors by a "trio-based" exome-sequencing approach, whereby 31 CDD probands and their unaffected parents were exome-sequenced. Seven-hundred controls from the local population were used to detect gene-sets significantly enriched with rare variants in CDD patients...
December 12, 2016: BMC Medical Genomics
Jia-Huei Tsai, Jau-Yu Liau, Chang-Tsu Yuan, Mei-Ling Cheng, Ray-Hwang Yuan, Yung-Ming Jeng
AIMS: RNF43 is a tumour suppressor gene that suppresses the Wnt-β-catenin signalling pathway. We investigated the role of RNF43 in intraductal papillary neoplasm of the bile duct (IPNB). METHODS AND RESULTS: We conducted mutation analysis of RNF43 in 50 IPNBs, and identified six (12%) RNF43 mutations. RNF43 mutation was more frequent in the intestinal subtype of IPNB (17%) than in the gastric/pancreatobiliary subtype (5%). There was a strong association of RNF43 mutation with GNAS (P = 0...
April 2017: Histopathology
Wen-Chih Huang, Chien-Chen Tsai, Chih-Chieh Chan
BACKGROUND/PURPOSE: Cholangiocarcinoma (CC) is a fatal malignancy originating from biliary tracts and constitutes approximately 10-20% of hepatobiliary cancers. CC is characterized by a very poor prognosis. The definite molecular mechanisms leading to oncogenesis remain unclear. This study aimed to perform mutation analysis and copy number changes of KRAS and BRAF genes of CC in Taiwan. METHODS: A total of 182 cases of biliary tact CC were studied for point mutation and quantitative real-time polymerase chain reaction analysis of KRAS and BRAF genes...
October 10, 2016: Journal of the Formosan Medical Association, Taiwan Yi Zhi
Michael Devos, Barbara Gilbert, Geertrui Denecker, Kirsten Leurs, Conor Mc Guire, Kelly Lemeire, Tino Hochepied, Marnik Vuylsteke, Jo Lambert, Caroline Van Den Broecke, Louis Libbrecht, Jody Haigh, Geert Berx, Saskia Lippens, Peter Vandenabeele, Wim Declercq
Unlike its family member p53, TP63 is rarely mutated in human cancer. However, ΔNp63α protein levels are often elevated in tumors of epithelial origin, such as squamous cell carcinoma and cholangiocarcinoma. To study the oncogenic properties of ΔNp63α in vivo, we generated transgenic mice overexpressing ΔNp63α from the Rosa26 locus promoter controlled by keratin 5-Cre. We found that these mice spontaneously develop epidermal cysts and ectopic ΔNp63α expression in the bile duct epithelium that leads to dilatation of the intrahepatic biliary ducts, to hepatic cyst formation and bile duct adenoma...
October 7, 2016: Journal of Investigative Dermatology
Terumi Kamisawa, Sawako Kuruma, Kazuro Chiba, Taku Tabata, Satomi Koizumi, Masataka Kikuyama
Pancreaticobiliary maljunction (PBM) is a congenital malformation in which the pancreatic and bile ducts join anatomically outside the duodenal wall. Because of the excessive length of the common channel in PBM, sphincter action does not directly affect the pancreaticobiliary junction, which allows pancreatic juice to reflux into the biliary tract. According to the results of a nationwide survey, bile duct and gallbladder cancers were found in 6.9 and 13.4 % of adult patients with congenital biliary dilatation, respectively, and in 3...
February 2017: Journal of Gastroenterology
Anne Tr Noll, Thorsten Cramer, Steven Wm Olde Damink, Frank G Schaap
Cholangiocarcinoma (CCA) is a relatively rare malignancy of the intra- or extra-hepatic bile ducts that is classified according to its anatomical localization as intrahepatic, perihilar or distal. Overall, CCA has a dismal prognosis due to typical presentation at an advanced irresectable stage, lack of effective non-surgical treatments, and a high rate of disease recurrence. CCA frequently arises on a background of chronic liver inflammation and cholestasis. Chronic inflammation is accompanied by enhanced cell turnover with generation of additional inflammatory stimuli, and a microenvironment rich in pro-inflammatory mediators and proliferative factors that enable accumulation of mutations, transformation and expansion of mutated cells...
September 18, 2016: World Journal of Hepatology
Motoko Sasaki, Takeo Nitta, Yasunori Sato, Yasuni Nakanuma
OBJECTIVES: Given frequent inactivating mutations in a chromatin-remodeling gene (ARID1A) in intrahepatic cholangiocarcinoma in recent exome sequencing analysis, this study investigates the clinicopathologic significance of the loss of ARID1A expression in biliary carcinomas. METHODS: We examined the inactivating mutations in ARID1A by immunohistochemistry and the relationship with clinicopathologic features in 13 patients with combined hepatocellular-cholangiocarcinoma (cHC-CC), 49 with intrahepatic cholangiocarcinoma (ICC), 17 with intraductal papillary neoplasm of the bile duct (IPNB), 72 with extrahepatic cholangiocarcinoma (EHCC), and 43 with gallbladder carcinoma (GBC)...
June 2016: American Journal of Clinical Pathology
Kwai Han Yoo, Nayoung K D Kim, Woo Il Kwon, Chung Lee, Sun Young Kim, Jiryeon Jang, Jungmi Ahn, Mihyun Kang, Hyojin Jang, Seung Tae Kim, Soomin Ahn, Kee-Taek Jang, Young Suk Park, Woong-Yang Park, Jeeyun Lee, Jin Seok Heo, Joon Oh Park
BACKGROUND: Biliary tract cancers (BTCs) are rare and heterogeneous group of tumors classified anatomically into intrahepatic and extrahepatic bile ducts and gallbladder adenocarcinomas. Patient-derived tumor cell (PDC) models with genome analysis can be a valuable platform to develop a method to overcome the clinical barrier on BTCs. MATERIAL AND METHODS: Between January 2012 and June 2015, 40 BTC patients' samples were collected. PDCs were isolated and cultured from surgical specimens, biopsy tissues, or malignant effusions including ascites and pleural fluid...
June 2016: Translational Oncology
John A Bridgewater, Karyn A Goodman, Aparna Kalyan, Mary F Mulcahy
Biliary tract cancer, or cholangiocarcinoma, arises from the biliary epithelium of the small ducts in the periphery of the liver (intrahepatic) and the main ducts of the hilum (extrahepatic), extending into the gallbladder. The incidence and epidemiology of biliary tract cancer are fluid and complex. It is shown that intrahepatic cholangiocarcinoma is on the rise in the Western world, and gallbladder cancer is on the decline. Radiation therapy has emerged as an important component of adjuvant therapy for resected disease and definitive therapy for locally advanced disease...
2016: American Society of Clinical Oncology Educational Book
Ahrim Moon, Susie Chin, Hee Kyung Kim, Jeong Ja Kwak, Eun Suk Koh, Youn Wha Kim, Kee-Taek Jang
Distal extrahepatic bile duct (EBD) carcinoma is a rare but highly aggressive malignant neoplasm. Some in vitro studies have shown that EGFR and PI3K-Akt pathway play an important role in the carcinogenesis of bile duct carcinoma. The aim of the present study is to investigate the expression of EGFR, p-AKT, and COX-2 and the mutation of PIK3CA in distal EBD carcinoma and evaluate the association with clinicopathological factors. Ninety cases of distal extrahepatic bile duct (EBD) carcinoma specimens were studied...
January 2016: Pathology
Toni Seppälä, Kirsi Pylvänäinen, Laura Renkonen-Sinisalo, Jan Böhm, Teijo Kuopio, Heikki J Järvinen, Jukka-Pekka Mecklin
Lynch syndrome (LS) refers to an autosomal dominant genetic predisposition to develop colon cancer or cancers or the uterine corpus, stomach, urinary tract, ovaries, small intestine, mammary gland or bile ducts at a young age. The predisposition to cancer is caused by a germline mutation in one of the genes of the mismatch repair (MMR) system. International recommendations suggest immunohistochemical analysis of tumor tissue from at least those having developed colorectal cancer or endometrial cancer at an age of less than 70 years...
2016: Duodecim; Lääketieteellinen Aikakauskirja
Marie-Claude Gingras, Kyle R Covington, David K Chang, Lawrence A Donehower, Anthony J Gill, Michael M Ittmann, Chad J Creighton, Amber L Johns, Eve Shinbrot, Ninad Dewal, William E Fisher, Christian Pilarsky, Robert Grützmann, Michael J Overman, Nigel B Jamieson, George Van Buren, Jennifer Drummond, Kimberly Walker, Oliver A Hampton, Liu Xi, Donna M Muzny, Harsha Doddapaneni, Sandra L Lee, Michelle Bellair, Jianhong Hu, Yi Han, Huyen H Dinh, Mike Dahdouli, Jaswinder S Samra, Peter Bailey, Nicola Waddell, John V Pearson, Ivon Harliwong, Huamin Wang, Daniela Aust, Karin A Oien, Ralph H Hruban, Sally E Hodges, Amy McElhany, Charupong Saengboonmee, Fraser R Duthie, Sean M Grimmond, Andrew V Biankin, David A Wheeler, Richard A Gibbs
The ampulla of Vater is a complex cellular environment from which adenocarcinomas arise to form a group of histopathologically heterogenous tumors. To evaluate the molecular features of these tumors, 98 ampullary adenocarcinomas were evaluated and compared to 44 distal bile duct and 18 duodenal adenocarcinomas. Genomic analyses revealed mutations in the WNT signaling pathway among half of the patients and in all three adenocarcinomas irrespective of their origin and histological morphology. These tumors were characterized by a high frequency of inactivating mutations of ELF3, a high rate of microsatellite instability, and common focal deletions and amplifications, suggesting common attributes in the molecular pathogenesis are at play in these tumors...
February 2, 2016: Cell Reports
Kerstin Abshagen, Moritz Senne, Berit Genz, Maria Thomas, Brigitte Vollmar
BACKGROUND: Wnt signaling is involved in the pathogenesis of liver fibrosis. Axin2 is a negative regulator of the canonical Wnt pathway by promoting β-catenin degradation. β-Catenin-activating and loss-of-function mutations of Axin2 are thought to be functionally relevant for liver diseases and cancer. Thus, we hypothesized that Axin2 deficiency promotes fibrogenesis. METHODS: As the functions and mechanisms of how Axin2/β-catenin signaling participates in the progression of liver fibrosis are unclear, we investigated the progression of liver fibrosis in Axin2-deficient mice using Axin2-LacZ reporter mice (Axin2+/-, Axin2-/-, and Axin2+/+) which underwent bile duct ligation (BDL)...
October 28, 2015: European Surgical Research. Europäische Chirurgische Forschung. Recherches Chirurgicales Européennes
Goro Ueno, Satoshi Ishikawa, Yoshitoshi Ichikawa, Takaomi Hagi, Nobuatsu Taniura, Hyonsu Chong, Akifumi Kanazawa, Shouichi Takayama, Masayoshi Nishihara, Kentaro Maruyama, Mamoru Shimada, Kyowon Lee, Hiroshi Oka, Tamaki Maeda
A 58-year-old man was diagnosed with liver dysfunction during a health exam and subsequently visited a doctor. Abdominal ultrasonography revealed space-occupying lesions in the gall bladder and bile duct, and he was hospitalized for further examination and treatment. Computed tomography (CT), endoscopic retrograde cholangiopancreatography (ERCP), and magnetic resonance cholangiopancreatography (MRCP) revealed double cancer of the gall bladder and bile duct with pancreaticobiliary maljunction (PBM), and we performed a pancreatoduodenectomy...
November 2014: Gan to Kagaku Ryoho. Cancer & Chemotherapy
Supriya K Saha, Christine A Parachoniak, Nabeel Bardeesy
Intrahepatic cholangiocarcinoma (ICC) is an aggressive cancer associated with the bile ducts within the liver. These tumors are characterized by frequent gain-of-function mutations in the isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) genes-that are also common in subsets of neural, haematopoietic and bone tumors, but rare or absent in the other types of gastrointestinal malignancy. Mutant IDH acts through a novel mechanism of oncogenesis, producing high levels of the metabolite 2-hydroxyglutarate, which interferes with the function of α-ketoglutarate-dependent enzymes that regulate diverse cellular processes including histone demethylation and DNA modification...
2014: Cell Cycle
Paxton V Dickson, Stephen W Behrman
Cholangiocarcinoma involving the distal common bile duct (distal cholangiocarcinoma [DCC]) is a periampullary neoplasm that is less common than, but often difficult to distinguish from, pancreatic adenocarcinoma (PDA). The prognosis and cure rate of DCC is improved over that of PDA, but it remains a highly lethal disease. Although the diagnostic and therapeutic management of DCC is not dissimilar from PDA, the pathophysiology is, in many instances, distinctly different. A multi-disciplinary approach toward DCC is important...
April 2014: Surgical Clinics of North America
Qiang Gao, Ying-Jun Zhao, Xiao-Ying Wang, Wei-Jie Guo, Song Gao, Lin Wei, Jie-Yi Shi, Guo-Ming Shi, Zhi-Chao Wang, Yuan-Nv Zhang, Ying-Hong Shi, Jie Ding, Zhen-Bin Ding, Ai-Wu Ke, Zhi Dai, Fei-Zhen Wu, Hui Wang, Zhao-Ping Qiu, Zhi-Ao Chen, Zhen-Feng Zhang, Shuang-Jian Qiu, Jian Zhou, Xiang-Huo He, Jia Fan
BACKGROUND & AIMS: The pathogenesis of intrahepatic cholangiocarcinoma (ICC), the second most common hepatic cancer, is poorly understood, and the incidence of ICC is increasing worldwide. We searched for mutations in human ICC tumor samples and investigated how they affect ICC cell function. METHODS: We performed whole exome sequencing of 7 pairs of ICC tumors and their surrounding nontumor tissues to detect somatic alterations. We then screened 124 pairs of ICC and nontumor samples for these mutations, including 7 exomes...
May 2014: Gastroenterology
Akiko Matsubara, Satoshi Nara, Shigeki Sekine, Hidenori Ojima, Tomoo Kosuge, Kazuaki Shimada, Ryoji Kushima, Yae Kanai, Nobuyoshi Hiraoka
It has been speculated that intraductal dissemination, via the pancreatic duct, bile duct, or mammary duct, is a unique form of cancer cell spread. However, clinical evidence to confirm this form of dissemination has been lacking. Here we report a case of papillary adenocarcinoma of the ampulla of Vater in which retrograde dissemination to the pancreatic duct was strongly suggested. A 79-year-old woman underwent pancreatoduodenectomy for a 22 mm microinvasive papillary adenocarcinoma of the ampulla. Multiple carcinomas in situ were found in the pancreatic duct distant from the ampulla...
January 2014: Pathology International
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