Focal Gains of <i>VEGFA</i> and Molecular Classification of Hepatocellular Carcinoma

Chiang, Derek Y.; Villanueva, Augusto; Hoshida, Yujin; Peix, Judit; Newell, Philippa; Mínguez, Beatriz; LeBlanc, Amanda C.; Donovan, Diana; Thung, Swan N.; Solé, Manel; Tovar, Victoria; Alsinet, Clara; Ramos, Alex H.; Barretina, Jordi; Roayaie, Sasan; Schwartz, Myron; Waxman, Samuel; Bruix, Jordi; Mazzaferro, Vincenzo; Ligon, Azra H.; Najfeld, Vesna; Friedman, Scott L.; Sellers, William R.; Meyerson, Matthew; Llovet, Josep M.

doi:10.1158/0008-5472.can-08-0742

Cited by 617 publications

(759 citation statements)

References 51 publications

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“…A linear correlation was found between mRNA levels of VEGFA and extent of amplifi cation in human HCC ( 29 ). Amplifi cations in the VEGFA locus and juxtaposed regions were associated with advanced-stage HCC ( 30 ).…”

Section: Discussionmentioning

confidence: 89%

“…Amplifi cation of human Chr6p21 (the region syntenic for murine Chr17qB3) and whole chromosome gains were previously reported in several whole-genome analyses of human HCC with a frequency ranging between 7% and 40% (29)(30)(31)(32)(33). Accordingly, through FISH, we found VEGFA amplifi cations and chromosome 6 polysomies in 11% of human HCCs we tested (21 of 187; Fig.…”

Section: Locus Identifying a Molecularly Distinct Tumor Subpopulationmentioning

confidence: 88%

“…In colorectal carcinoma and breast cancer, this amplifi cation was found in correlation with vascular invasion and shorter survival ( 46 , 51 ). Cumulative analysis of these reported human studies shows that gains and amplifi cations of VEGFA are found in 7% to 30% of human HCCs (29)(30)(31)(32)(33). Our interventional studies in the Mdr2 −/− model indicate that Vegfa is a major driver of this amplicon, which minimally harbors 53 genes in Mdr2 −/− murine tumors and 11 genes in humans ( 32 ).…”

Section: Discussionmentioning

confidence: 99%

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Human and Mouse VEGFA-Amplified Hepatocellular Carcinomas Are Highly Sensitive to Sorafenib Treatment

et al. 2014

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Death rates from hepatocellular carcinoma (HCC) are steadily increasing, yet therapeutic options for advanced HCC are limited. We identify a subset of mouse and human HCCs harboring VEGFA genomic amplifi cation, displaying distinct biologic characteristics. Unlike common tumor amplifi cations, this one seems to work via heterotypic paracrine interactions; stromal VEGF receptors (VEGFR), responding to tumor VEGF-A, produce hepatocyte growth factor (HGF) that reciprocally affects tumor cells. VEGF-A inhibition results in HGF downregulation and reduced proliferation, specifi cally in amplicon-positive mouse HCCs. Sorafenib-the fi rst-line drug in advanced HCC-targets multiple kinases, including VEGFRs, but has only an overall mild benefi cial effect. We found that VEGFA amplifi cation specifi es mouse and human HCCs that are distinctly sensitive to sorafenib. FISH analysis of a retrospective patient cohort showed markedly improved survival of sorafenib-treated patients with VEGFA -amplifi ed HCCs, suggesting that VEGFA amplifi cation is a potential biomarker for HCC response to VEGF-A-blocking drugs. SIGNIFICANCE:Using a mouse model of infl ammation-driven cancer, we identifi ed a subclass of HCC carrying VEGFA amplifi cation, which is particularly sensitive to VEGF-A inhibition. We found that a similar amplifi cation in human HCC identifi es patients who favorably responded to sorafenib-the fi rst-line treatment of advanced HCC-which has an overall moderate therapeutic effi cacy. Cancer Discov; 4(6);

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Section: Discussionmentioning

confidence: 89%

Section: Locus Identifying a Molecularly Distinct Tumor Subpopulationmentioning

confidence: 88%

Section: Discussionmentioning

confidence: 99%

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Human and Mouse VEGFA-Amplified Hepatocellular Carcinomas Are Highly Sensitive to Sorafenib Treatment

et al. 2014

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“…Hitherto, there are three large studies published that classify HCC based on gene expression. Two of them could identify subgroups with common affected pathways such as beta-catenin and proliferation signals [107,108] and one group [70,109] was able to correlate the subgroups with survival. Other studies tried to find common affected genes that are associated with prognostic factors such as vascular invasion and metastasis, but the overlap between these studies is very poor.…”

Section: Molecular Classificationmentioning

confidence: 99%

Tumor initiation and progression in hepatocellular carcinoma: risk factors, classification, and therapeutic targets

Severi¹,

Malenstein²,

Verslype³

et al. 2010

Acta Pharmacol Sin

157

125

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“…Multiple studies have revealed etiological patterns and multiple genes/pathways signifying initiation and progression of HCC. These pathways include CTNNB1/WNT‐β‐catenin, TPp53, ARID1/2s, HGF/c‐Met, and vascular endothelial growth factor/angiogenic signaling 5, 6, 7, 8, 9, 10, 11, 12. However, unlike the transforming growth factor β (TGF‐β) pathway, loss of p53 and/or activation of β‐catenin do not spontaneously drive HCC in animal models 13, 14, 15…”

Section: Introductionmentioning

confidence: 99%

Transforming growth factor‐β in liver cancer stem cells and regeneration

Rao

Zaidi

Banerjee

et al. 2017

Hepatology Communications

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Cancer stem cells have established mechanisms that contribute to tumor heterogeneity as well as resistance to therapy. Over 40% of hepatocellular carcinomas (HCCs) are considered to be clonal and arise from a stem‐like/cancer stem cell. Moreover, HCC is the second leading cause of cancer death worldwide, and an improved understanding of cancer stem cells and targeting these in this cancer are urgently needed. Multiple studies have revealed etiological patterns and multiple genes/pathways signifying initiation and progression of HCC; however, unlike the transforming growth factor β (TGF‐β) pathway, loss of p53 and/or activation of β‐catenin do not spontaneously drive HCC in animal models. Despite many advances in cancer genetics that include identifying the dominant role of TGF‐β signaling in gastrointestinal cancers, we have not reached an integrated view of genetic mutations, copy number changes, driver pathways, and animal models that support effective targeted therapies for these common and lethal cancers. Moreover, pathways involved in stem cell transformation into gastrointestinal cancers remain largely undefined. Identifying the key mechanisms and developing models that reflect the human disease can lead to effective new treatment strategies. In this review, we dissect the evidence obtained from mouse and human liver regeneration, and mouse genetics, to provide insight into the role of TGF‐β in regulating the cancer stem cell niche. (Hepatology Communications 2017;1:477–493)

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Focal Gains of VEGFA and Molecular Classification of Hepatocellular Carcinoma

Abstract: Hepatocellular carcinomas represent the third leading cause of cancer-related deaths worldwide. The vast majority of cases arise in the context of chronic liver injury due to hepatitis B virus or hepatitis C virus infection.

Cited by 617 publications

References 51 publications

Human and Mouse VEGFA-Amplified Hepatocellular Carcinomas Are Highly Sensitive to Sorafenib Treatment

Human and Mouse VEGFA-Amplified Hepatocellular Carcinomas Are Highly Sensitive to Sorafenib Treatment

Tumor initiation and progression in hepatocellular carcinoma: risk factors, classification, and therapeutic targets

Transforming growth factor‐β in liver cancer stem cells and regeneration

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