Gene Deletions and Amplifications in Human Hepatocellular Carcinomas

Nalesnik, Michael A.; Tseng, George C.; Ding, Ying; Xiang, Guosheng; Zheng, Zhaohui; Yu, Yanping; Marsh, J. Wallis; Michalopoulos, George K.; Luo, Jianhua

doi:10.1016/j.ajpath.2011.12.021

Cited by 69 publications

(75 citation statements)

References 67 publications

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“…On the one hand, hepatic aneuploidy could have pathological consequences. Aneuploidy has been extensively described in hepatocellular carcinoma (28)(29)(30), but it is unknown whether tumors arose from preexisting aneuploid hepatocytes or simply became aneuploid during tumorigenesis. It is intriguing that whole chromosome gains/losses were reported in dozens of lesions (28).…”

Section: Discussionmentioning

confidence: 99%

Aneuploidy as a mechanism for stress-induced liver adaptation

Duncan¹,

et al. 2012

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Over half of the mature hepatocytes in mice and humans are aneuploid and yet retain full ability to undergo mitosis. This observation has raised the question of whether this unusual somatic genetic variation evolved as an adaptive mechanism in response to hepatic injury. According to this model, hepatotoxic insults select for hepatocytes with specific numerical chromosome abnormalities, rendering them differentially resistant to injury. To test this hypothesis, we utilized a strain of mice heterozygous for a mutation in the homogentisic acid dioxygenase (Hgd) gene located on chromosome 16. Loss of the remaining Hgd allele protects from fumarylacetoacetate hydrolase (Fah) deficiency, a genetic liver disease model. When adult mice heterozygous for Hgd and lacking Fah were exposed to chronic liver damage, injury-resistant nodules consisting of Hgdnull hepatocytes rapidly emerged. To determine whether aneuploidy played a role in this phenomenon, array comparative genomic hybridization (aCGH) and metaphase karyotyping were performed. Strikingly, loss of chromosome 16 was dramatically enriched in all mice that became completely resistant to tyrosinemiainduced hepatic injury. The frequency of chromosome 16-specific aneuploidy was approximately 50%. This result indicates that selection of a specific aneuploid karyotype can result in the adaptation of hepatocytes to chronic liver injury. The extent to which aneuploidy promotes hepatic adaptation in humans remains under investigation.

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Section: Discussionmentioning

confidence: 99%

Aneuploidy as a mechanism for stress-induced liver adaptation

Duncan¹,

et al. 2012

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“…Accordingly, in CCA development, N1ICD association with protein kinase B signaling in hepatocytes stimulated their malignant dedifferentiation (82). The stimulation of N1ICD expression by inflammatory mediators has also been reported in human CCA, which additionally supports the role of Notch in liver cancer (83) (Table II) (9,12,24,31,(84)(85)(86)(87).…”

Section: Role Of Notch In Hcc and Icc Developmentmentioning

confidence: 54%

Oncogenic role of the Notch pathway in primary liver cancer

et al. 2016

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Abstract. Primary liver cancer, which includes hepatocellular carcinoma (HCC), intrahepatic cholangiocarcinoma (ICC) and fibrolamellar HCC, is one of the most common malignancies and the third leading cause of cancer-associated mortality, worldwide. Despite the development of novel therapies, the prognosis of liver cancer patients remains extremely poor. Thus, investigation of the genetic background and molecular mechanisms underlying the development and progression of this disease has gained significant attention. The Notch signaling pathway is a crucial determinant of cell fate during development and disease in several organs. In the liver, Notch signaling is involved in biliary tree development and tubulogenesis, and is also significant in the development of HCC and ICC. These findings suggest that the modulation of Notch pathway activity may have therapeutic relevance. The present review summarizes Notch signaling during HCC and ICC development and discusses the findings of recent studies regarding Notch expression, which reveal novel insights into its function in liver cancer progression.

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“…Comparison of proteomics analysis from primary fibroblast cultures derived from morphologically normal colonic mucosa of familial adenomatous polyposis patients with those obtained from unaffected controls RSU-1 down-regulated in six human polyposis samples compared to six samples from morphologically normal colonic mucosa [12] Hepatocellular carcinoma Somatic copy number variation (CNV) analysis in 98 hepatocellular carcinoma samples RSU-1 gene exhibited a high frequency of CNVs (9 out of 98 samples) with 7 deletions and 3 amplifications present in the RSU-1 gene [14] High-grade gliomas Southern blotting…”

Section: Type Of Lesion Methodsology Observation Related To Rsu-1 Refementioning

confidence: 99%

“…Furthermore, a somatic copy number variation (CNV) analysis of 98 hepatocellular carcinoma samples showed that the RSU-1 gene exhibited a high frequency of CNVs (9 out of 98 samples) with 7 deletions and 3 amplifications present in the RSU-1 gene, indicating that RSU-1 gene is frequently deleted in human liver cancer [14] .…”

mentioning

confidence: 99%