Genomic Profiling of Hepatocellular Adenomas Reveals Recurrent FRK-Activating Mutations and the Mechanisms of Malignant Transformation

Pilati, Camilla; Letouzé, Éric; Nault, Jean–Charles; Imbeaud, Sandrine; Boulai, Anaïs; Caldéraro, Julien; Poussin, Karine; Franconi, Andrea; Couchy, Gabrielle; Morcrette, Guillaume; Mallet, Maxime; Taouji, Saı̈d; Balabaud, Charles; Terris, Benoı̂t; Canal, Frédéric; Paradis, Valérie; Scoazec, Jean‐Yves; Muret, A. De; Guettier, Catherine; Bioulac‐Sage, Paulette; Chevet, Éric; Calvo, Fabien; Zucman‐Rossi, Jessica

doi:10.1016/j.ccr.2014.03.005

Cited by 246 publications

(294 citation statements)

References 44 publications

(53 reference statements)

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“…Evidence that Cnntb1 mutations are late events in the tumorigenic process, and thus b-catenin is unlikely a driving force in early HCC development, also came from a mouse model of hepatocarcinogenesis 11 ; moreover, our data showing that Ctnnb1 mutations are a late event are in agreement with other works that identified b-catenin mutation only in tumors (adenomas and HCCs) and not in cirrhotic nodules. 23,33,36 Taken together, all these findings indicate that b-catenin activating mutations are not involved in the onset of HCC but that they occur in already transformed cells and are probably implicated in the final steps of cancer progression. Because the R-H model reflects a histological and molecular signature similar to that of KRT-19-positive human HCCs characterized by poor prognosis, 13 results stemming from this model are potentially relevant for human hepatic tumorigenesis.…”

Section: Discussionmentioning

confidence: 86%

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: Discussionmentioning

confidence: 86%

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

et al. 2015

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“…Similar to the previously reported coexistence with BRAF-activating mutations or with concomitant BRAF and CDKN2A alterations in melanomas (Horn et al 2013, Heidenreich et al 2014, Pó pulo et al 2014, two independent groups displayed a preferential occurrence of TERT promoter mutations in BRAF V600E mutationpositive papillary thyroid carcinomas (Liu et al 2013a, Vinagre et al 2013, while Landa et al (2013) observed a significant co-occurrence of TERT mutations with BRAF and RAS mutations in poorly differentiated thyroid carcinomas and anaplastic thyroid carcinomas. In bladder cancer and mesotheliomas, TERT promoter mutations were frequently associated with inactivating mutations in the TP53/RB1 signaling pathway (Wu et al 2014b) and tumor suppressor CDKN2A gene inactivation respectively (Tallet et al 2013), while a significant co-occurrence with CTNNB1-activating mutations has been reported in hepatocellular carcinomas and adenomas with malignant transformation , Pilati et al 2014.…”

Section: Discussionmentioning

confidence: 99%

Telomerase reverse transcriptase promoter mutations in tumors originating from the adrenal gland and extra-adrenal paraganglia

Papathomas¹,

Oudijk²,

Zwarthoff³

et al. 2014

Endocrine-Related Cancer

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Hotspot mutations in the promoter of the telomerase reverse transcriptase (TERT) gene have been recently reported in human cancers and proposed as a novel mechanism of telomerase activation. To explore TERT promoter mutations in tumors originating from the adrenal gland and extra-adrenal paraganglia, a set of 253 tumors (38 adrenocortical carcinomas (ACCs), 127 pheochromocytomas (PCCs), 18 extra-adrenal paragangliomas (ea PGLs), 37 head and neck PGLs (HN PGLs), and 33 peripheral neuroblastic tumors) was selected along with 16 human neuroblastoma (NBL) and two ACC cell lines to assess TERT promoter mutations by the Sanger sequencing method. All mutations detected were confirmed by a SNaPshot assay. Additionally, 36 gastrointestinal stromal tumors (GISTs) were added to explore an association between TERT promoter mutations and SDH deficiency. TERT promoter mutations were found in seven out of 289 tumors and in three out of 18 human cell lines; four C228T mutations in 38 ACCs (10.5%), two C228T mutations in 18 ea PGLs (11.1%), one C250T mutation in 36 GISTs (2.8%), and three C228T mutations in 16 human NBL cell lines (18.75%). No mutation was detected in PCCs, HN PGLs, neuroblastic tumors as well as ACC cell lines. TERT promoter mutations preferentially occurred in a SDH-deficient setting (PZ0.01) being present in three out of 47 (6.4%) SDH-deficient tumors vs zero out of 171 (0%) SDH-intact

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“…DNA sequencing was performed as previously described, 6 and all samples were systematically sequenced for CTNNB1 (exons 2, 3, 4, 6, 7, and 8), HNF1A…”

Section: Dna Extraction and Sequencingmentioning

confidence: 99%

“…3,5 Beta-catenin-mutated hepatocellular adenomas (15-20%) are characterized by CTNNB1-activating mutations responsible for constitutive Wnt/Beta-catenin pathway activation. 2,6 This subgroup has the higher risk of malignant transformation, 3,6,7 and microscopic examination may demonstrate moderate atypia. 2,5 The third group of hepatocellular adenoma, namely inflammatory adenoma (about 50% of all hepatocellular adenomas), harbor somatic gain-offunction mutations in either IL6ST, FRK, JAK1, STAT3, or GNAS genes activating the interleukin-6/ JAK/STAT pathway.…”

mentioning

confidence: 99%

“…2,5 The third group of hepatocellular adenoma, namely inflammatory adenoma (about 50% of all hepatocellular adenomas), harbor somatic gain-offunction mutations in either IL6ST, FRK, JAK1, STAT3, or GNAS genes activating the interleukin-6/ JAK/STAT pathway. 3,6,8,9 They are histologically characterized by sinusoidal dilation, inflammatory infiltrates, and dystrophic vessels often surrounded by fibrotic tissue. An immunohistochemical panel has been developed to allow pathological identification of all three hepatocellular adenoma subgroups and inflammatory adenomas are characterized by an overexpression of the C-reactive and serum amyloid A proteins in tumor hepatocytes.…”

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confidence: 99%

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Inflammatory hepatocellular adenomas developed in the setting of chronic liver disease and cirrhosis

et al. 2016

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Hepatocellular adenoma is considered to occur exclusively in non-fibrotic livers. It is a heterogeneous entity and a molecular classification is now widely accepted. The most frequent hepatocellular adenoma subtype, namely inflammatory adenoma, harbor somatic activating mutations of genes involved in the interleukin-6 pathway that lead to high C-reactive protein and serum amyloid A expression. The aim of our study was to investigate a series of benign hepatocellular neoplasms developed on cirrhotic livers and characterized by an unequivocal histological diagnosis. We performed a clinical, pathological, and molecular study of 10 benign hepatocellular neoplasms developed in three patients with cirrhosis. Markers allowing hepatocellular adenoma classification were assessed by quantitative real-time PCR and immunohistochemistry. Samples were sequenced for CTNNB1, HNF1A, IL6ST, GNAS, STAT3, and TERT (promoter) mutations. A control series of 32 classical macronodules developed in cirrhosis related to various etiologies was screened by immunohistochemistry and gene sequencing. The three patients had cirrhosis related to metabolic syndrome and/or alcohol intake; two had a single tumor, while the third developed more than 30 lesions. Microscopic examination showed welldifferentiated neoplasms sharing features with inflammatory adenoma including inflammatory infiltrates, sinusoidal dilatation, and dystrophic vessels. Sequencing revealed classical hotspot somatic mutations (IL6ST, n = 8; STAT3, n = 1; and GNAS, n = 1) known to be responsible for IL-6/JAK/STAT pathway activation. Two classical high-grade macronodules demonstrated high serum amyloid A and/or C-reactive protein expression, without gene mutations. Altogether, our findings support the existence of rare inflammatory adenoma developed in cirrhosis.

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Genomic Profiling of Hepatocellular Adenomas Reveals Recurrent FRK-Activating Mutations and the Mechanisms of Malignant Transformation

Cited by 246 publications

References 44 publications

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

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

Telomerase reverse transcriptase promoter mutations in tumors originating from the adrenal gland and extra-adrenal paraganglia

Inflammatory hepatocellular adenomas developed in the setting of chronic liver disease and cirrhosis

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