B Terris

Université René Descartes - Paris 5, Lutetia Parisorum, Île-de-France, France

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Publications (224)1016.53 Total impact

  • The American journal of surgical pathology 08/2015; 39(8):1156-7. DOI:10.1097/PAS.0000000000000483 · 4.59 Impact Factor
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    ABSTRACT: Here, we show that autophagy is activated in the intestinal epithelium in murine and human colorectal cancer and that the conditional inactivation of Atg7 in intestinal epithelial cells inhibits the formation of pre-cancerous lesions in Apc(+/-) mice by enhancing anti-tumour responses. The antibody-mediated depletion of CD8(+) T cells showed that these cells are essential for the anti-tumoral responses mediated by the inhibition of autophagy. We show that Atg7 deficiency leads to intestinal dysbiosis and that the microbiota is required for anticancer responses. In addition, Atg7 deficiency resulted in a stress response accompanied by metabolic defects, AMPK activation and p53-mediated cell-cycle arrest in tumour cells but not in normal tissue. This study reveals that the inhibition of autophagy within the epithelium may prevent the development and progression of colorectal cancer in genetically predisposed patients.
    Nature Cell Biology 07/2015; DOI:10.1038/ncb3206 · 20.06 Impact Factor
  • Journal of Hepatology 04/2015; 62:S783. DOI:10.1016/S0168-8278(15)31345-3 · 10.40 Impact Factor
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    ABSTRACT: Endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) using standard needles has a high diagnostic value in the evaluation of solid pancreatic masses. Fenestrated needles have been developed to improve the quality of EUS-guided tissue sampling by providing core biopsies (FNB). Patients with solid pancreatic masses of >2 cm were prospectively included in our study and randomized to receive EUS sampling, using either a standard 22G FNA or a 22G Procore® FNB needle. The main study endpoint was the number of needle passes required to obtain a diagnosis in more than 90% of cases. We included 100 patients (male = 63, female = 37; mean age = 68.4 years) in our study. We found that 88% of the lesions were malignant, with a mean size of 32 mm. A sample adequate for diagnosis was obtained in more than 90% of cases after the second needle pass in the FNB group, versus the third needle pass in the FNA group. Slide cellularity and presence of tissue microfragments were significantly higher in the FNB group. Sensitivity for the diagnosis of malignancy was 88.4% versus 97.8% for the EUS-FNA and EUS-FNB group, respectively, while specificity for both techniques was 100%. No complications were recorded. Although the accuracy of both needle types for proving malignancy was similar, a lower number of passes was required with the FNB needles to achieve the same contributive sample rate as with the FNA needles. FNB also improved the histopathological quality of specimens, suggesting an overall superiority of FNB sampling.
    03/2015; 3(4). DOI:10.1177/2050640615577533
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    ABSTRACT: Hepatocellular carcinoma (HCC) is the most prevalent primary tumour of the liver. About a third of these tumours presents activating mutations of the β-catenin gene. The molecular pathogenesis of HCC has been elucidated, but mortality remains high, and new therapeutic approaches, including treatments based on microRNAs, are required. We aimed to identify candidate microRNAs, regulated by β-catenin, potentially involved in liver tumorigenesis. We used a mouse model, in which β-catenin signalling was overactivated exclusively in the liver by the tamoxifen-inducible and Cre-Lox-mediated inactivation of the Apc gene. This model develops tumours with properties similar to human HCC. We found that miR-34a was regulated by β-catenin, and significantly induced by the overactivation of β-catenin signalling in mouse tumours and in patients with HCC. An inhibitor of miR-34a (locked nucleic acid, LNA-34a) exerted antiproliferative activity in primary cultures of hepatocyte. This inhibition of proliferation was associated with a decrease in cyclin D1 levels, orchestrated principally by HNF-4α, a target of miR-34a considered to act as a tumour suppressor in the liver. In vivo, LNA-34a approximately halved progression rates for tumours displaying β-catenin activation together with an activation of caspases 2 and 3. This work demonstrates the key oncogenic role of miR-34a in liver tumours with β-catenin gene mutations. We suggest that patients diagnosed with HCC with β-catenin mutations could be treated with an inhibitor of miR-34a. The potential value of this strategy lies in the modulation of the tumour suppressor HNF-4α, which targets cyclin D1, and the induction of a proapoptotic programme. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
    Gut 03/2015; DOI:10.1136/gutjnl-2014-308969 · 13.32 Impact Factor
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    ABSTRACT: Hepatocellular carcinoma usually afflicts individuals in their later years following longstanding liver disease. In Peru, hepatocellular carcinoma exists in a unique clinical presentation, which affects patients around age 25 with a normal, healthy liver. In order to deepen our understanding of the molecular processes ongoing in Peruvian liver tumors, mutation spectrum analysis was carried out on hepatocellular carcinomas from 80 Peruvian patients. Sequencing analysis focused on nine genes typically altered during liver carcinogenesis, i.e. ARID2, AXIN1, BRAF, CTNNB1, NFE2L2, H/K/N-RAS, and TP53. We also assessed the transcription level of factors involved in the control of the alpha-fetoprotein expression and the Hippo signaling pathway that controls contact inhibition in metazoans. The mutation spectrum of Peruvian patients was unique with a major class of alterations represented by Insertions/Deletions. There were no changes at hepatocellular carcinoma-associated mutation hotspots in more than half of the specimens analyzed. Furthermore, our findings support the theory of a consistent collapse in the Hippo axis, as well as an expression of the stemness factor NANOG in high alpha-fetoprotein-expressing hepatocellular carcinomas. These results confirm the specificity of Peruvian hepatocellular carcinoma at the molecular genetic level. The present study emphasizes the necessity to widen cancer research to include historically neglected patients from South America, and more broadly the Global South, where cancer genetics and tumor presentation are divergent from canonical neoplasms.
    PLoS ONE 12/2014; 9(12):e114912. DOI:10.1371/journal.pone.0114912 · 3.23 Impact Factor
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    ABSTRACT: Aims Uveal melanoma (UM) is the most common malignant tumour of the eye. Diagnosis often occurs late in the course of disease, and prognosis is generally poor. Recently, recurrent somatic mutations were described, unravelling additional specific altered pathways in UM. Targeted next-generation sequencing (NGS) can now be applied to an accurate and fast identification of somatic mutations in cancer. The aim of the present study was to characterise the mutation pattern of five UM hepatic metastases with well-defined clinical and pathological features. Methods We analysed the UM mutation spectrum using targeted NGS on 409 cancer genes. Results Four previous reported genes were found to be recurrently mutated. All tumours presented mutually exclusive GNA11 or GNAQ missense mutations. BAP1 loss-of-function mutations were found in three UMs. SF3B1 missense mutations were found in the two UMs with no BAP1 mutations. We then searched for additional mutation targets. We identified the Arg505Cys mutation in the tumour suppressor FBXW7. The same mutation was previously described in different cancer types, and FBXW7 was recently reported to be mutated in UM exomes. Conclusions Further studies are required to confirm FBXW7 implication in UM tumorigenesis. Elucidating the molecular mechanisms underlying UM tumorigenesis holds the promise for novel and effective targeted UM therapies.
    British Journal of Ophthalmology 10/2014; 99(4). DOI:10.1136/bjophthalmol-2014-305371 · 2.81 Impact Factor
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    ABSTRACT: Until the past two decades, almost all colorectal polyps were divided into two main groups: hyperplastic polyps and adenomas. Sessile serrated adenomas presented endoscopic, pathological and molecular profiles distinct from others polyps. Previously under-diagnosed, physicians now identified sessile serrated adenomas. The serrated neoplastic pathway is accounting for up to one-third of all sporadic colorectal cancers and sessile serrated adenomas have been identified as the main precursor lesions in serrated carcinogenesis. By analogy with the adenoma–adenocarcinoma sequence, the sessile serrated adenomas–adenocarcinoma sequence, has been identified. The development of endoscopic resection techniques permits the consideration of a non-surgical approach as the first option regardless of the size of the lesion. Sessile serrated adenoma warrants the watchfulness of physicians and requires an optimal quality of the colonoscopy procedure, a thorough evaluation of the lesion, an adequate endoscopic resection and follow-up colonoscopies in accordance with sessile serrated adenomas guidelines. We herein present a review on sessile serrated adenomas focusing on their pathological specificities, epidemiology, treatment modalities and follow-up.
    Digestive and Liver Disease 10/2014; 47(2). DOI:10.1016/j.dld.2014.09.006 · 2.89 Impact Factor
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    ABSTRACT: Depuis l’avènement du traitement par Vemurafénib des mélanomes non résécables ou métastatiques porteurs d’une mutation BRAF sur le codon V600, les plateformes de pathologie et d’oncogénétique somatique sont de plus en plus sollicitées pour la recherche de mutation BRAF dans le mélanome. BRAF est muté dans 40 à 50 % des mélanomes, la mutation V600E représentant 80–90 % des mutations. Actuellement, les méthodes de biologie moléculaires sont le standard pour ce diagnostic. Une approche par immuno-histochimie (IHC) première utilisant un anticorps reconnaissant spécifiquement la protéine BRAF mutée V600E a été récemment proposée.
    Annales de Pathologie 10/2014; 34(5). DOI:10.1016/j.annpat.2014.08.008 · 0.29 Impact Factor
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    ABSTRACT: Background & Aims: Quantitative shear wave elastography was shown to be an effective tool for the non-invasive diagnosis and staging of chronic liver diseases. The liver shear modulus, estimated from the propagation velocity of shear waves, is correlated to the degree of fibrosis and can therefore be used for the non-invasive staging of fibrosis. Methods:We performed a clinical prospective study in a total of 120 patients with various chronic liver diseases to compare the accuracy of supersonic shear imaging (SSI), a technique based on acoustic radiation and ultrafast ultrasound imaging, to 1D transient elastography (FibroScan) for the staging and grading of fibrosis as assessed by liver biopsy. Since shear wave propagation spectroscopy can also provide additional mechanical information on soft tissues, such as viscosity, we also investigated those new mechanical parameters as possible predictors of fibrosis, steatosis, and disease activity. Results: SSI was successfully performed in 98.3% of patients and it was shown to be as accurate as FibroScan for the staging of fibrosis both for the whole population (N = 120) and for the subgroup with viral hepatitis (n = 70) (AUC = 0.85 [0.77-0.96] and 0.89 [0.81-0.97] for significant fibrosis, AUC = 0.90 [0.83-0.97] and 0.87 [0.75-0.98] for cirrhosis, with respect to SSI [n = 68/70] and FibroScan [n = 66/68]). Viscosity could also be used to stage the degree of fibrosis (AUC = 0.76 [0.64-0.87] for significant fibrosis and AUC = 0.87 [0.74-0.99] for cirrhosis), for the subgroup of patients with viral hepatitis (n = 67/70) but was a poor predictor of disease activity and steatosis levels. Conclusions: Supersonic shear imaging is a robust technique for the staging of liver fibrosis. Liver viscosity was found to be correlated with fibrosis but not to steatosis or disease activity.
    Journal of Hepatology 09/2014; 62(2). DOI:10.1016/j.jhep.2014.09.020 · 10.40 Impact Factor
  • Benoît Terris · Catherine Cavard
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    ABSTRACT: Solid-pseudopapillary neoplasm of the pancreas (SPN) is an uncommon low-grade malignant neoplasm occurring mostly in young women. In addition to its distinctive pathological appearance of pseudopapillae with poorly cohesive neoplastic cells, rare variants exist raising the differential diagnosis especially with neuroendocrine neoplasms. The overall prognosis for patients with SPNs is excellent after surgical resection. Nevertheless, 10% of cases may have malignant behavior characterized by tumor recurrence and/or metastasis. Despite numerous studies, the histogenesis of this neoplasm remains unclear. Distinctive molecular alterations such as the presence of CTNNB1 mutations are observed in nearly all cases, while mutations classically observed in ductal adenocarcinoma, such as KRAS, TP53 and SMAD4, are not observed in SPNs, reinforcing its distinct nature compared to all other pancreatic neoplasms. Recent transcriptional studies have shown that activation of the Wnt/beta-catenin pathway in these tumors is associated with the upregulation of genes belonging to Notch, Hedgehog and androgen receptor signaling pathways.
    Seminars in Diagnostic Pathology 09/2014; 31(6). DOI:10.1053/j.semdp.2014.08.010 · 1.80 Impact Factor
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    Human pathology 09/2014; 45(9). DOI:10.1016/j.humpath.2014.05.017 · 2.81 Impact Factor
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    ABSTRACT: The LKB1 tumor suppressor gene encodes a master kinase that coordinates the regulation of energetic metabolism and cell polarity. We now report the identification of a novel isoform of LKB1 (named ΔN-LKB1) that is generated through alternative transcription and internal initiation of translation of the LKB1 mRNA. The ΔN-LKB1 protein lacks the N-terminal region and a portion of the kinase domain. Although ΔN-LKB1 is catalytically inactive, it potentiates the stimulating effect of LKB1 on the AMP-activated protein kinase (AMPK) metabolic sensor through a direct interaction with the regulatory autoinhibitory domain of AMPK. In contrast, ΔN-LKB1 negatively interferes with the LKB1 polarizing activity. Finally, combining in vitro and in vivo approaches, we showed that ΔN-LKB1 has an intrinsic oncogenic property. ΔN-LKB1 is expressed solely in the lung cancer cell line, NCI-H460. Silencing of ΔN-LKB1 decreased the survival of NCI-H460 cells and inhibited their tumorigenicity when engrafted in nude mice. In conclusion, we have identified a novel LKB1 isoform that enhances the LKB1-controlled AMPK metabolic activity but inhibits LKB1-induced polarizing activity. Both the LKB1 tumor suppressor gene and the oncogene ΔN-LKB1 are expressed from the same locus and this may account for some of the paradoxical effects of LKB1 during tumorigenesis.Oncogene advance online publication, 7 July 2014; doi:10.1038/onc.2014.182.
    Oncogene 07/2014; 34(18). DOI:10.1038/onc.2014.182 · 8.56 Impact Factor
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    ABSTRACT: β-catenin signaling can be both a physiological and an oncogenic pathway in the liver. It controls compartmentalized gene expression, allowing the liver to ensure its essential metabolic function. It is activated by mutations in 20 to 40% of hepatocellular carcinomas with specific metabolic features. We decipher the molecular determinants of β-catenin-dependent zonal transcription using mice with β-catenin-activated or -inactivated hepatocytes, characterizing in vivo their chromatin occupancy by Tcf4 and β-catenin, their transcriptome and their metabolome. We find that Tcf4 DNA-bindings depend on β-catenin. Tcf4/β-catenin binds Wnt-responsive elements preferentially around β-catenin-induced genes. In contrast, genes repressed by β-catenin bind Tcf4 on Hnf4-responsive elements. β-catenin, Tcf4 and Hnf4α interact, dictating β-catenin transcription which is antagonistic to that elicited by Hnf4α. Finally, we find the drug/bile metabolism pathway to be the one most heavily targeted by β-catenin, partly through xenobiotic nuclear receptors. We conclude that β-catenin patterns the zonal liver together with Tcf4, Hnf4α and xenobiotic nuclear receptors. This network represses lipid metabolism, and exacerbates glutamine, drug and bile metabolism, mirroring hepatocellular carcinomas with β-catenin mutational activation. (Hepatology 2013;).
    Hepatology 06/2014; 59(6). DOI:10.1002/hep.26924 · 11.19 Impact Factor
  • Gastrointestinal Endoscopy 05/2014; 79(5):AB428-AB429. DOI:10.1016/j.gie.2014.02.593 · 4.90 Impact Factor
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    ABSTRACT: Hepatocellular adenomas (HCA) are benign liver tumors predominantly developed in women using oral contraceptives. Here, exome sequencing identified recurrent somatic FRK mutations that induce constitutive kinase activity, STAT3 activation, and cell proliferation sensitive to Src inhibitors. We also found uncommon recurrent mutations activating JAK1, gp130, or β-catenin. Chromosome copy number and methylation profiling revealed patterns that correlated with specific gene mutations and tumor phenotypes. Finally, integrative analysis of HCAs transformed to hepatocellular carcinoma revealed β-catenin mutation as an early alteration and TERT promoter mutations as associated with the last step of the adenoma-carcinoma transition. In conclusion, we identified the genomic diversity in benign hepatocyte proliferation, several therapeutic targets, and the key genomic determinants of the adenoma-carcinoma transformation sequence.
    Cancer cell 04/2014; 25(4):428-41. DOI:10.1016/j.ccr.2014.03.005 · 23.89 Impact Factor
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    ABSTRACT: The data describing the urologic extracolonic cancers associated with Lynch syndrome (hereditary non-polyposis colorectal cancer [HNPCC]) are variable. The aim of our study was to establish the frequency of mutations in mismatch repair (MMR) genes in patients with upper urinary tract transitional cell carcinoma (UUT-TCC) and to evaluate the clinical benefits of a systematic screening. Specimen blocks were obtained from 146 patients treated for UUT-TCC in our center. Clinicopathological characteristics and survival data of patients were collected (median follow-up = 42.5 months). Immunohistochemistry was performed by tissue microarray (TMA), in order to detect mutations in mismatch repair genes. Results obtained after TMA analysis were confirmed at a molecular level by microsatellite instability (MSI) analysis. Mutations in mismatch repair genes were detected in seven patients (4.8%) at immunohistochemistry screening, and confirmed by MSI analysis for five of them (3.4%). Clinicopathological characteristics and survival data did not differ significantly in patients with instability compared with patients without. After a median follow-up of 42.5 months, none of them experienced a new HNPCC manifestation. The frequency of mutations in mismatch repair genes in UUT-TCC was very low, with a good accuracy of immunohistochemistry. Systematic screening should not be proposed in daily practice.
    Bulletin du cancer 02/2014; 101(2). DOI:10.1684/bdc.2014.1896 · 0.64 Impact Factor
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    ABSTRACT: The hallmark of neurofibromatosis type 1 (NF1) is the onset of dermal or plexiform neurofibromas, mainly composed of Schwann cells. Plexiform neurofibromas can transform into malignant peripheral nerve sheath tumors (MPNSTs) that are resistant to therapies. Experimental design: The aim of this study was to identify an additional pathway in the NF1-tumorigenesis. We focused our work on Wnt signalling that is highly implicated in cancer, mainly in regulating the proliferation of cancer stem cells. We quantified mRNAs of 89 Wnt pathway genes in 57 NF1-associated tumors including dermal and plexiform neurofibromas and MPNSTs. Expression of two major stem cell marker genes and five major epithelial-mesenchymal transition marker genes was also assessed. The expression of significantly deregulated Wnt genes was then studied in normal human Schwann cells, fibroblasts, endothelial cells, and mast cells and in seven MPNST cell lines. The expression of nine Wnt genes was significantly deregulated in plexiform neurofibromas in comparison with dermal neurofibromas. Twenty Wnt genes showed altered expression in MPNST biopsies and cell lines. Immunohistochemical studies confirmed the Wnt pathway activation in NF1-associated MPNSTs. We then confirmed that the knock-down of NF1 in Schwann cells but not in epithelial cells provoked the activation of Wnt pathway by functional transfection assays. Furthermore, we showed that the protein expression of active beta-catenin was increased in NF1-silenced cell lines. Wnt pathway activation was strongly associated to both cancer stem cell reservoir and Schwann-mesenchymal transition. We highlighted the implication of Wnt pathway in NF1-associated tumorigenesis.
    Clinical Cancer Research 11/2013; 20(2). DOI:10.1158/1078-0432.CCR-13-0780 · 8.19 Impact Factor
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    ABSTRACT: A number of methods allowing the detection of low levels of KRAS mutations have been developed in the last years. However, although these methods have become increasingly sensitive, they can rarely identify the mutated base directly without prior knowledge on the mutated base and are often incompatible with a sequencing based read-out desirable in clinical practice. Here we present a modified version of the ice-COLD-PCR assay called Enhanced-ice-COLD-PCR for KRAS mutation detection and identification, which allows the enrichment of the six most frequent KRAS mutations. The method is based on a non-extendable chemically modified blocker sequence, complementary to the wild type sequence leading to the enrichment of mutated sequences. This assay permits the reliable detection of down to 0.1% mutated sequences in a wild-type background. A single genotyping assay of the amplification product by pyrosequencing directly following the Enhanced-ice-COLD-PCR is performed to identify the mutated base. This developed two-step method is rapid, cost-effective and requires only a small amount of starting material permitting the sensitive detection and sequence identification of KRAS mutations within three hours. This method is applied in the current study to clinical colorectal cancer samples and enables detection of mutations in samples, which appear as wild-type using standard detection technologies. This article is protected by copyright. All rights reserved.
    Human Mutation 11/2013; 34(11). DOI:10.1002/humu.22427 · 5.05 Impact Factor

Publication Stats

7k Citations
1,016.53 Total Impact Points


  • 2006–2015
    • Université René Descartes - Paris 5
      • • Faculté de Médecine
      • • Thérapeutiques Innovantes des Maladies du Foie (EA 1833)
      Lutetia Parisorum, Île-de-France, France
  • 2008–2014
    • Assistance Publique – Hôpitaux de Paris
      • Department of Radiology
      Lutetia Parisorum, Île-de-France, France
  • 2007–2014
    • French National Centre for Scientific Research
      Lutetia Parisorum, Île-de-France, France
    • Institut Cochin
      Lutetia Parisorum, Île-de-France, France
  • 1996–2013
    • French Institute of Health and Medical Research
      • • Institut Cochin U1016
      • • Unit of Nuclear Organization and Oncogenesis
      Lutetia Parisorum, Île-de-France, France
  • 2012
    • Vesalius Research Center
      Louvain, Flemish, Belgium
  • 2006–2012
    • Hôpital Cochin (Hôpitaux Universitaires Paris Centre)
      Lutetia Parisorum, Île-de-France, France
  • 1996–2009
    • Unité Inserm U1077
      Caen, Lower Normandy, France
  • 2005
    • University of Geneva
      Genève, Geneva, Switzerland
    • Hôpitaux Universitaires La Pitié salpêtrière - Charles Foix
      Lutetia Parisorum, Île-de-France, France
  • 2003
    • Università degli Studi di Palermo
      Palermo, Sicily, Italy
    • Imperial College London
      Londinium, England, United Kingdom
  • 1993–2001
    • Institut Pasteur
      • Department of Virology
      Lutetia Parisorum, Île-de-France, France
  • 1996–1999
    • Hôpital Bichat - Claude-Bernard (Hôpitaux Universitaires Paris Nord Val de Seine)
      Lutetia Parisorum, Île-de-France, France