OBJECTIVES: Vinyl chloride (VC) and its metabolites are human carcinogens associated with liver angiosarcomas (LAS) and also with hepatocellular carcinomas (HCCs). In VC associated LAS mutations of the K-ras-2 gene have been reported, however, no data about the prevalence of such mutations in VC-associated HCCs are available. The aim of the study was to evaluate possible specific K-ras-2 oncogene mutations in the case of HCCs due to VC. METHODS: The presence of K-ras-2 mutations was analysed in tissue from 12 patients with VC-associated HCCs. All patients had known long-term exposure to VC (average exposure amount: 9,942 ppm-years). Twenty patients with hepatocellular carcinoma due to hepatitis B (n = 7), hepatitis C (n = 5) and alcoholic liver cirrhosis (n= 8) served as a control group. The specific mutations were determined by direct sequencing of codons 12 and 13 of the K-ras-2 gene in carcinomatous and adjacent non-neoplastic liver tissue after microdissection. Immunohistochemical analysis was performed to detect p21ras protein. RESULTS: K-ras-2 mutations were found in five of 12 (42%) examined HCCs and in three cases of adjacent non-neoplastic liver tissue (25%). There were three guanine to adenine (G --> A) point mutations in the tumour tissue. All three mutations found in non-neoplastic liver from VC-exposed patients were also G --> A point mutations (codon 12- and codon 13-aspartate mutations). Within the control group, K-ras-2 mutations were found in three of 20 (15%) examined HCCs. CONCLUSIONS: Mutations of the K-ras-2 gene in hepatocellular carcinomas associated with VC exposure are frequent events. We observed a K-ras-2 mutation pattern characteristic of chloroethylene oxide, one of the carcinogenic metabolites of VC analysed in animal models. Our results suggest that VC had direct toxic effects not only on endothelial cells but also on hepatocytes, as it was previously only described in animal models.
OBJECTIVES:Vinyl chloride (VC) and its metabolites are human carcinogens associated with liver angiosarcomas (LAS) and also with hepatocellular carcinomas (HCCs). In VC associated LAS mutations of the K-ras-2 gene have been reported, however, no data about the prevalence of such mutations in VC-associated HCCs are available. The aim of the study was to evaluate possible specific K-ras-2 oncogene mutations in the case of HCCs due to VC. METHODS: The presence of K-ras-2 mutations was analysed in tissue from 12 patients with VC-associated HCCs. All patients had known long-term exposure to VC (average exposure amount: 9,942 ppm-years). Twenty patients with hepatocellular carcinoma due to hepatitis B (n = 7), hepatitis C (n = 5) and alcoholic liver cirrhosis (n= 8) served as a control group. The specific mutations were determined by direct sequencing of codons 12 and 13 of the K-ras-2 gene in carcinomatous and adjacent non-neoplastic liver tissue after microdissection. Immunohistochemical analysis was performed to detect p21ras protein. RESULTS:K-ras-2 mutations were found in five of 12 (42%) examined HCCs and in three cases of adjacent non-neoplastic liver tissue (25%). There were three guanine to adenine (G --> A) point mutations in the tumour tissue. All three mutations found in non-neoplastic liver from VC-exposed patients were also G --> A point mutations (codon 12- and codon 13-aspartate mutations). Within the control group, K-ras-2 mutations were found in three of 20 (15%) examined HCCs. CONCLUSIONS: Mutations of the K-ras-2 gene in hepatocellular carcinomas associated with VC exposure are frequent events. We observed a K-ras-2 mutation pattern characteristic of chloroethylene oxide, one of the carcinogenic metabolites of VC analysed in animal models. Our results suggest that VC had direct toxic effects not only on endothelial cells but also on hepatocytes, as it was previously only described in animal models.
Authors: Vladimir V Kalinichenko; Michael L Major; Xinhe Wang; Vladimir Petrovic; Joseph Kuechle; Helena M Yoder; Margaret B Dennewitz; Brian Shin; Abhishek Datta; Pradip Raychaudhuri; Robert H Costa Journal: Genes Dev Date: 2004-04-01 Impact factor: 11.361
Authors: Chan Kwon Jung; Mark P Little; Jay H Lubin; Alina V Brenner; Samuel A Wells; Alice J Sigurdson; Yuri E Nikiforov Journal: J Clin Endocrinol Metab Date: 2013-11-18 Impact factor: 5.958
Authors: Zhengyan Kan; Hancheng Zheng; Xiao Liu; Shuyu Li; Thomas D Barber; Zhuolin Gong; Huan Gao; Ke Hao; Melinda D Willard; Jiangchun Xu; Robert Hauptschein; Paul A Rejto; Julio Fernandez; Guan Wang; Qinghui Zhang; Bo Wang; Ronghua Chen; Jian Wang; Nikki P Lee; Wei Zhou; Zhao Lin; Zhiyu Peng; Kang Yi; Shengpei Chen; Lin Li; Xiaomei Fan; Jie Yang; Rui Ye; Jia Ju; Kai Wang; Heather Estrella; Shibing Deng; Ping Wei; Ming Qiu; Isabella H Wulur; Jiangang Liu; Mariam E Ehsani; Chunsheng Zhang; Andrey Loboda; Wing Kin Sung; Amit Aggarwal; Ronnie T Poon; Sheung Tat Fan; Jun Wang; James Hardwick; Christoph Reinhard; Hongyue Dai; Yingrui Li; John M Luk; Mao Mao Journal: Genome Res Date: 2013-06-20 Impact factor: 9.043