Integrated analysis of somatic mutations and focal copy-number changes identifies key genes and pathways in hepatocellular carcinoma

Guichard, Cécile; Amaddeo, Giuliana; Imbeaud, Sandrine; Ladeiro, Yannick; Pelletier, Laura; Maad, Ichrafe Ben; Caldéraro, Julien; Bioulac‐Sage, Paulette; Letexier, Mélanie; Degos, Françoise; Clément, Bruno; Balabaud, Charles; Chevet, Éric; Laurent, Alexis; Couchy, Gabrielle; Letouzé, Éric; Calvo, Fabien; Zucman‐Rossi, Jessica

doi:10.1038/ng.2256

Cited by 1,232 publications

(1,300 citation statements)

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“…21 However, an extremely low frequency of mutation of this gene has been reported in human HCC. 5,6 In agreement with these findings, no mutations of Kras could be observed in 30 preneoplastic nodules. Kras mutations were found only in 1/14 eHCCs and 1/27 aHCCs.…”

Section: Resultssupporting

confidence: 80%

“…Dysregulation of the Wnt/b-catenin pathway and occurrence of activating mutations in CTNNB1 are among the most frequent alterations in human HCC (15%-33%). 5,6,9 However, whether CTNNB1 mutations occur at early stages of the carcinogenic process is unclear. Therefore, we investigated Ctnnb1 mutations in the same samples (38 preneoplastic lesions, 14 eHCCs, and 27 aHCCs) analyzed for Nrf2/ Keap1.…”

Section: Resultsmentioning

confidence: 99%

“…In view of the recent finding of NRF2 mutations in a subset of human HCC, 5 the possibility that Nrf2 might represent a new targetable gene should be actively pursued. This study also provides evidence that Cnntb1 mutations are a very late event as they are absent in preneoplastic hepatocytes and in eHCCs.…”

Section: Discussionmentioning

confidence: 99%

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Nrf2, but not β‐catenin, mutation represents an early event in rat hepatocarcinogenesis

et al. 2015

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Hepatocellular carcinoma (HCC) develops through a multistage process, but the nature of the molecular changes associated with the different steps, the very early ones in particular, is largely unknown. Recently, dysregulation of the NRF2/KEAP1 pathway and mutations of these genes have been observed in experimental and human tumors, suggesting their possible role in cancer development. To assess whether Nrf2/Keap1 mutations are early or late events in HCC development, we investigated their frequency in the rat Resistant Hepatocyte model, consisting of the administration of diethylnitrosamine followed by a brief exposure to 2-acetylaminofluorene. This model enables the dissection of all stages of hepatocarcinogenesis. We found that Nrf2/Keap1 mutations were present in 71% of early preneoplastic lesions and in 78.6% and 59.3% of early and advanced HCCs, respectively. Mutations of Nrf2 were more frequent, missense, and located in the Nrf2-Keap1 binding region. Mutations of Keap1 occurred at a much lower frequency in both preneoplastic lesions and HCCs and were mutually exclusive with those of Nrf2. Functional in vitro and in vivo studies showed that Nrf2 silencing inhibited the ability of tumorigenic rat cells to grow in soft agar and to form tumors. Unlike Nrf2 mutations, those of Ctnnb1, which are frequent in human HCC, were a later event as they appeared only in fully advanced HCCs (18.5%). Conclusion: In the Resistant Hepatocyte model of hepatocarcinogenesis the onset of Nrf2 mutations is a very early event, likely essential for the clonal expansion of preneoplastic hepatocytes to HCC, while Ctnnb1 mutations occur only at very late stages. Moreover, functional experiments demonstrate that Nrf2 is an oncogene critical for HCC progression and development. (HEPATOLOGY 2015;62:851-862) See Editorial on Page 677 H epatocellular carcinoma (HCC) is the third most frequent cause of cancer-related deaths worldwide. 1 Unfortunately, our knowledge of the genomic alterations implicated in HCC initiation and progression is still fragmentary. Moreover, different from other solid tumors, no driving genetic alteration to which tumor cells are addicted and that can be effectively targeted has ever been identified. In this scenario, HCC is probably one of the tumor types where a more complete understanding of the underlying genetic alterations could have a major impact on the development of new treatment strategies. Also known as NFE2L2, NRF2 is of particular interest as conflicting results have been reported concerning the role of the NRF2/KEAP1 pathway in cancer development. 2 It is a master transcriptional activator of genes encoding enzymes that protect cells from oxidative stress and

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Section: Resultssupporting

confidence: 80%

Section: Resultsmentioning

confidence: 99%

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Nrf2, but not β‐catenin, mutation represents an early event in rat hepatocarcinogenesis

et al. 2015

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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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“…2 Interestingly, FGF21 was overexpressed in HCC. 1,3,4 It should be very interesting to assess if, from the data set of genome-wide analysis, HCC samples in which FGF19 high copy amplifications overlap with copy number variations or single mutations localized at 19q13.33 containing the FGF21 gene may emerge. This could be very relevant to understanding if an anti-FGF19 strategy may be potentially sufficient as a therapeutic approach.…”

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confidence: 99%