High prevalence of K- ras -2 mutations in hepatocellular carcinomas in workers exposed to vinyl chloride

Weihrauch, Markus; Benicke, Markus; Lehnert, G.; Wittekind, Christian; Bader, Michael; Wrbitzky, Renate; Tannapfel, Andrea

doi:10.1007/s004200100244

Cited by 31 publications

(23 citation statements)

References 24 publications

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“…Mutations in PIK3CA and HRAS were observed but were infrequent (1/88). We did not observe mutations in KRAS, which has been reported in vinyl chloride-associated HCC (Weihrauch et al 2001). Several of the frequently mutated genes identified in this study are not well-established cancer genes, but corroborating evidence from recent studies points to potential roles in cancer.…”

Section: Significantly Mutated Genessupporting

confidence: 89%

Whole-genome sequencing identifies recurrent mutations in hepatocellular carcinoma

et al. 2013

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Hepatocellular carcinoma (HCC) is one of the most deadly cancers worldwide and has no effective treatment, yet the molecular basis of hepatocarcinogenesis remains largely unknown. Here we report findings from a whole-genome sequencing (WGS) study of 88 matched HCC tumor/normal pairs, 81 of which are Hepatitis B virus (HBV) positive, seeking to identify genetically altered genes and pathways implicated in HBV-associated HCC. We find beta-catenin to be the most frequently mutated oncogene (15.9%) and TP53 the most frequently mutated tumor suppressor (35.2%). The Wnt/beta-catenin and JAK/STAT pathways, altered in 62.5% and 45.5% of cases, respectively, are likely to act as two major oncogenic drivers in HCC. This study also identifies several prevalent and potentially actionable mutations, including activating mutations of Janus kinase 1 (JAK1), in 9.1% of patients and provides a path toward therapeutic intervention of the disease.

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Section: Significantly Mutated Genessupporting

confidence: 89%

Whole-genome sequencing identifies recurrent mutations in hepatocellular carcinoma

et al. 2013

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“…However, Raf-1 kinase is overexpressed in a high number of HCC tumors, and the Raf/MEK/ERK pathway can be activated by major etiologic factors such as hepatitis B or C virus infection and mitogenic growth factors. Regarding activating mutations of Ras, the association between exposure to vinyl chloride and K-Ras mutations is well known, with rates of mutation as high as 42% (67). However, K-Ras and H-Ras mutations induced by chronic hepatitis infection or alcohol intake are rare in patients with HCC (68).…”

Section: Hepatocellular Carcinomamentioning

confidence: 99%

Preclinical overview of sorafenib, a multikinase inhibitor that targets both Raf and VEGF and PDGF receptor tyrosine kinase signaling

Wilhelm

Adnane

Newell

et al. 2008

Molecular Cancer Therapeutics

1,261

861

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Although patients with advanced refractory solid tumors have poor prognosis, the clinical development of targeted protein kinase inhibitors offers hope for the future treatment of many cancers. In vivo and in vitro studies have shown that the oral multikinase inhibitor, sorafenib, inhibits tumor growth and disrupts tumor microvasculature through antiproliferative, antiangiogenic, and/or proapoptotic effects. Sorafenib has shown antitumor activity in phase II/III trials involving patients with advanced renal cell carcinoma and hepatocellular carcinoma. The multiple molecular targets of sorafenib (the serine/threonine kinase Raf and receptor tyrosine kinases) may explain its broad preclinical and clinical activity. This review highlights the antitumor activity of sorafenib across a variety of tumor types, including renal cell, hepatocellular, breast, and colorectal carcinomas in the preclinical setting. In particular, preclinical evidence that supports the different mechanisms of action of sorafenib is discussed. [Mol Cancer Ther 2008;7(10):3129 -40]

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“…The overexpression of the p21 ras protein in nearly all HCC examined suggests that the ras-MAPK pathway is hyperactive in these neoplasms (Huynh, 2004). K-ras mutations were found in 5 of 12 (42%) HCC in workers exposed to vinyl chloride (Weihrauch et al, 2001). H-ras mutations, which are often found in spontaneous mouse liver tumors, were not observed in the diethanolamine (DEA)-induced tumors suggesting that these tumors may develop by pathways which are independent of ras signal transduction (Hayashi et al, 2003).…”

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confidence: 99%

Overview of the Molecular Biology of Hepatocellular Neoplasms and Hepatoblastomas of the Mouse Liver

2005

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The molecular pathogenesis of chemically induced hepatocellular neoplasms and hepatoblastomas in the B6C3F1 mouse is unclear but may involve alterations in the β-catenin/Wnt signaling pathway as was recently described for human liver neoplasms. The objectives of this research were to characterize the mutation frequency and spectrum of β-catenin mutations and the intracellular localization of β-catenin protein accumulation in chemically induced hepatoblastomas and hepatocellular neoplasms. In the majority of the hepatoblastomas examined by immunohistochemical methods, both nuclear and cytoplasmic localization of β-catenin protein were detected, whereas in hepatocellular adenomas and carcinomas and normal liver only membrane staining was observed. Genomic DNA was isolated from paraffin sections of each liver tumor. β-catenin exon 2 (corresponds to exon 3 in humans) genetic alterations were identified in the majority of hepatoblastomas from exposed mice. Deletion mutations were identified more frequently than point mutations in hepatoblastomas. Hepatocellular adenomas and carcinomas from treated mice had mutations in exon 2 of the β-catenin gene which ranged from 32-43%, while 10% β-catenin mutations were detected in spontaneous neoplasms. By immunohistochemical methods cyclin D1 was observed in most nuclei of hepatoblastomas and strong expression of cyclin D1 was confirmed by Western analysis regardless of treatment. The cumulative data suggests that β-catenin mutations with upregulation of the β-catenin protein and Wnt signaling most likely increased cyclin D1 expression. Cyclin D1 may provide an advantage during tumor progression of hepatocellular neoplasms and hepatoblastomas. The review will also focus on other genes which are important in mouse and human liver tumors.

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High prevalence of K- ras -2 mutations in hepatocellular carcinomas in workers exposed to vinyl chloride

Cited by 31 publications

References 24 publications

Whole-genome sequencing identifies recurrent mutations in hepatocellular carcinoma

Whole-genome sequencing identifies recurrent mutations in hepatocellular carcinoma

Preclinical overview of sorafenib, a multikinase inhibitor that targets both Raf and VEGF and PDGF receptor tyrosine kinase signaling

Overview of the Molecular Biology of Hepatocellular Neoplasms and Hepatoblastomas of the Mouse Liver

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