Qiang Gao1, Ying-Jun Zhao2, Xiao-Ying Wang1, Wei-Jie Guo3, Song Gao4, Lin Wei3, Jie-Yi Shi1, Guo-Ming Shi1, Zhi-Chao Wang1, Yuan-Nv Zhang3, Ying-Hong Shi1, Jie Ding3, Zhen-Bin Ding1, Ai-Wu Ke1, Zhi Dai1, Fei-Zhen Wu5, Hui Wang3, Zhao-Ping Qiu3, Zhi-Ao Chen3, Zhen-Feng Zhang3, Shuang-Jian Qiu1, Jian Zhou6, Xiang-Huo He7, Jia Fan8. 1. Liver Cancer Institute, Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Fudan University, Shanghai, China. 2. State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Cancer Research Institute, Fudan University Shanghai Cancer Center, Shanghai, China. 3. State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. 4. State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, China. 5. Laboratory of Epigenetics, Institute of Biomedical Sciences, Fudan University, Shanghai, China. 6. Liver Cancer Institute, Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Fudan University, Shanghai, China; Cancer Center, Institute of Biomedical Sciences, Fudan University, Shanghai, China. Electronic address: zhou.jian@zs-hospital.sh.cn. 7. State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Cancer Research Institute, Fudan University Shanghai Cancer Center, Shanghai, China. Electronic address: xhhe@fudan.edu.cn. 8. Liver Cancer Institute, Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Fudan University, Shanghai, China; Cancer Center, Institute of Biomedical Sciences, Fudan University, Shanghai, China. Electronic address: fan.jia@zs-hospital.sh.cn.
Abstract
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. We compared mutations in PTPN3 with tumor recurrence in 124 patients and PTPN3 expression levels with recurrence in 322 patients (the combination of both in 86 patients). The functional effects of PTPN3 variations were determined by RNA interference and transgenic expression in cholangiocarcinoma cell lines (RBE, HCCC-9810, and Huh28). RESULTS: Based on exome sequencing, pathways that regulate protein phosphorylation were among the most frequently altered in ICC samples and genes encoding protein tyrosine phosphatases (PTPs) were among the most frequently mutated. We identified mutations in 9 genes encoding PTPs in 4 of 7 ICC exomes. In the prevalence screen of 124 paired samples, 51.6% of ICCs contained somatic mutations in at least 1 of 9 PTP genes; 41.1% had mutations in PTPN3. Transgenic expression of PTPN3 in cell lines increased cell proliferation, colony formation, and migration. PTPN3(L232R) and PTPN3(L384H), which were frequently detected in ICC samples, were found to be gain-of-function mutations; their expression in cell lines further increased cell proliferation, colony formation, and migration. ICC-associated variants of PTPN3 altered phosphatase activity. Patients whose tumors contained activating mutations or higher levels of PTPN3 protein than nontumor tissues had higher rates of disease recurrence than patients whose tumors did not have these characteristics. CONCLUSIONS: Using whole exome sequencing of ICC samples from patients, we found that more than 40% contain somatic mutations in PTPN3. Activating mutations in and high expression levels of PTPN3 were associated with tumor recurrence.
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 humanICC 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. We compared mutations in PTPN3 with tumor recurrence in 124 patients and PTPN3 expression levels with recurrence in 322 patients (the combination of both in 86 patients). The functional effects of PTPN3 variations were determined by RNA interference and transgenic expression in cholangiocarcinoma cell lines (RBE, HCCC-9810, and Huh28). RESULTS: Based on exome sequencing, pathways that regulate protein phosphorylation were among the most frequently altered in ICC samples and genes encoding protein tyrosine phosphatases (PTPs) were among the most frequently mutated. We identified mutations in 9 genes encoding PTPs in 4 of 7 ICC exomes. In the prevalence screen of 124 paired samples, 51.6% of ICCs contained somatic mutations in at least 1 of 9 PTP genes; 41.1% had mutations in PTPN3. Transgenic expression of PTPN3 in cell lines increased cell proliferation, colony formation, and migration. PTPN3(L232R) and PTPN3(L384H), which were frequently detected in ICC samples, were found to be gain-of-function mutations; their expression in cell lines further increased cell proliferation, colony formation, and migration. ICC-associated variants of PTPN3 altered phosphatase activity. Patients whose tumors contained activating mutations or higher levels of PTPN3 protein than nontumor tissues had higher rates of disease recurrence than patients whose tumors did not have these characteristics. CONCLUSIONS: Using whole exome sequencing of ICC samples from patients, we found that more than 40% contain somatic mutations in PTPN3. Activating mutations in and high expression levels of PTPN3 were associated with tumor recurrence.
Authors: Chirag Nepal; Colm J O'Rourke; Douglas V N P Oliveira; Andrzej Taranta; Steven Shema; Prson Gautam; Julien Calderaro; Andrew Barbour; Chiara Raggi; Krister Wennerberg; Xin W Wang; Anja Lautem; Lewis R Roberts; Jesper B Andersen Journal: Hepatology Date: 2018-06-12 Impact factor: 17.425
Authors: EeeLN H Buckarma; Nathan W Werneburg; Caitlin B Conboy; Ayano Kabashima; Daniel R O'Brien; Chen Wang; Sumera Rizvi; Rory L Smoot Journal: Mol Cancer Res Date: 2020-07-09 Impact factor: 5.852
Authors: Jesus M Banales; Vincenzo Cardinale; Guido Carpino; Marco Marzioni; Jesper B Andersen; Pietro Invernizzi; Guro E Lind; Trine Folseraas; Stuart J Forbes; Laura Fouassier; Andreas Geier; Diego F Calvisi; Joachim C Mertens; Michael Trauner; Antonio Benedetti; Luca Maroni; Javier Vaquero; Rocio I R Macias; Chiara Raggi; Maria J Perugorria; Eugenio Gaudio; Kirsten M Boberg; Jose J G Marin; Domenico Alvaro Journal: Nat Rev Gastroenterol Hepatol Date: 2016-04-20 Impact factor: 46.802