Diversité et plasticité des tumeurs de l’enfant

Publications de l’équipe

Année de publication : 2015

Angela Bellini, Virginie Bernard, Quentin Leroy, Thomas Rio Frio, Gaelle Pierron, Valérie Combaret, Eve Lapouble, Nathalie Clement, Herve Rubie, Estelle Thebaud, Pascal Chastagner, Anne Sophie Defachelles, Christophe Bergeron, Nimrod Buchbinder, Sophie Taque, Anne Auvrignon, Dominique Valteau-Couanet, Jean Michon, Isabelle Janoueix-Lerosey, Olivier Delattre, Gudrun Schleiermacher (2015 Feb 20)

Deep Sequencing Reveals Occurrence of Subclonal ALK Mutations in Neuroblastoma at Diagnosis.

Clinical cancer research : an official journal of the American Association for Cancer Research : 4913-21 : DOI : 10.1158/1078-0432.CCR-15-0423 En savoir plus
Résumé

In neuroblastoma, activating ALK receptor tyrosine kinase point mutations play a major role in oncogenesis. We explored the potential occurrence of ALK mutations at a subclonal level using targeted deep sequencing.

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Thomas F Eleveld, Derek A Oldridge, Virginie Bernard, Jan Koster, Leo Colmet Daage, Sharon J Diskin, Linda Schild, Nadia Bessoltane Bentahar, Angela Bellini, Mathieu Chicard, Eve Lapouble, Valérie Combaret, Patricia Legoix-Né, Jean Michon, Trevor J Pugh, Lori S Hart, JulieAnn Rader, Edward F Attiyeh, Jun S Wei, Shile Zhang, Arlene Naranjo, Julie M Gastier-Foster, Michael D Hogarty, Shahab Asgharzadeh, Malcolm A Smith, Jaime M Guidry Auvil, Thomas B K Watkins, Danny A Zwijnenburg, Marli E Ebus, Peter van Sluis, Anne Hakkert, Esther van Wezel, C Ellen van der Schoot, Ellen M Westerhout, Johannes H Schulte, Godelieve A Tytgat, M Emmy M Dolman, Isabelle Janoueix-Lerosey, Daniela S Gerhard, Huib N Caron, Olivier Delattre, Javed Khan, Rogier Versteeg, Gudrun Schleiermacher, Jan J Molenaar, John M Maris (2015 Jan 15)

Relapsed neuroblastomas show frequent RAS-MAPK pathway mutations.

Nature genetics : 864-71 : DOI : 10.1038/ng.3333 En savoir plus
Résumé

The majority of patients with neuroblastoma have tumors that initially respond to chemotherapy, but a large proportion will experience therapy-resistant relapses. The molecular basis of this aggressive phenotype is unknown. Whole-genome sequencing of 23 paired diagnostic and relapse neuroblastomas showed clonal evolution from the diagnostic tumor, with a median of 29 somatic mutations unique to the relapse sample. Eighteen of the 23 relapse tumors (78%) showed mutations predicted to activate the RAS-MAPK pathway. Seven of these events were detected only in the relapse tumor, whereas the others showed clonal enrichment. In neuroblastoma cell lines, we also detected a high frequency of activating mutations in the RAS-MAPK pathway (11/18; 61%), and these lesions predicted sensitivity to MEK inhibition in vitro and in vivo. Our findings provide a rationale for genetic characterization of relapse neuroblastomas and show that RAS-MAPK pathway mutations may function as a biomarker for new therapeutic approaches to refractory disease.

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Année de publication : 2014

Benjamin Gibert, Céline Delloye-Bourgeois, Charles-Henry Gattolliat, Olivier Meurette, Solen Le Guernevel, Joanna Fombonne, Benjamin Ducarouge, Fabrice Lavial, Frantz Bouhallier, Marion Creveaux, Ana Maria Negulescu, Jean Bénard, Isabelle Janoueix-Lerosey, Annick Harel-Bellan, Olivier Delattre, Patrick Mehlen (2014 Oct 15)

Regulation by miR181 family of the dependence receptor CDON tumor suppressive activity in neuroblastoma.

Journal of the National Cancer Institute : DOI : 10.1093/jnci/dju318 En savoir plus
Résumé

The Sonic Hedgehog (SHH) signaling pathway plays an important role in neural crest cell fate during embryonic development and has been implicated in the progression of multiple cancers that include neuroblastoma, a neural crest cell-derived disease. While most of the SHH signaling is mediated by the well-described canonical pathway leading to the activation of Smoothened and Gli, it has recently been shown that cell-adhesion molecule-related/downregulated by oncogenes (CDON) serves as a receptor for SHH and contributes to SHH-induced signaling. CDON has also been recently described as a dependence receptor, triggering apoptosis in the absence of SHH. This CDON proapoptotic activity has been suggested to constrain tumor progression.

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André Oberthuer, Dilafruz Juraeva, Barbara Hero, Ruth Volland, Carolina Sterz, Rene Schmidt, Andreas Faldum, Yvonne Kahlert, Anne Engesser, Shahab Asgharzadeh, Robert Seeger, Miki Ohira, Akira Nakagawara, Paola Scaruffi, Gian Paolo Tonini, Isabelle Janoueix-Lerosey, Olivier Delattre, Gudrun Schleiermacher, Jo Vandesompele, Frank Speleman, Rosa Noguera, Marta Piqueras, Jean Bénard, Alexander Valent, Smadar Avigad, Isaac Yaniv, Richard G Grundy, Monika Ortmann, Chunxuan Shao, Manfred Schwab, Roland Eils, Thorsten Simon, Jessica Theissen, Frank Berthold, Frank Westermann, Benedikt Brors, Matthias Fischer (2014 Sep 19)

Revised risk estimation and treatment stratification of low- and intermediate-risk neuroblastoma patients by integrating clinical and molecular prognostic markers.

Clinical cancer research : an official journal of the American Association for Cancer Research : 1904-15 : DOI : 10.1158/1078-0432.CCR-14-0817 En savoir plus
Résumé

To optimize neuroblastoma treatment stratification, we aimed at developing a novel risk estimation system by integrating gene expression-based classification and established prognostic markers.

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Franck Tirode, Didier Surdez, Xiaotu Ma, Matthew Parker, Marie Cécile Le Deley, Armita Bahrami, Zhaojie Zhang, Eve Lapouble, Sandrine Grossetête-Lalami, Michael Rusch, Stéphanie Reynaud, Thomas Rio-Frio, Erin Hedlund, Gang Wu, Xiang Chen, Gaelle Pierron, Odile Oberlin, Sakina Zaidi, Gordon Lemmon, Pankaj Gupta, Bhavin Vadodaria, John Easton, Marta Gut, Li Ding, Elaine R Mardis, Richard K Wilson, Sheila Shurtleff, Valérie Laurence, Jean Michon, Perrine Marec-Bérard, Ivo Gut, James Downing, Michael Dyer, Jinghui Zhang, Olivier Delattre, (2014 Sep 15)

Genomic landscape of Ewing sarcoma defines an aggressive subtype with co-association of STAG2 and TP53 mutations.

Cancer discovery : 1342-53 : DOI : 10.1158/2159-8290.CD-14-0622 En savoir plus
Résumé

Ewing sarcoma is a primary bone tumor initiated by EWSR1-ETS gene fusions. To identify secondary genetic lesions that contribute to tumor progression, we performed whole-genome sequencing of 112 Ewing sarcoma samples and matched germline DNA. Overall, Ewing sarcoma tumors had relatively few single-nucleotide variants, indels, structural variants, and copy-number alterations. Apart from whole chromosome arm copy-number changes, the most common somatic mutations were detected in STAG2 (17%), CDKN2A (12%), TP53 (7%), EZH2, BCOR, and ZMYM3 (2.7% each). Strikingly, STAG2 mutations and CDKN2A deletions were mutually exclusive, as confirmed in Ewing sarcoma cell lines. In an expanded cohort of 299 patients with clinical data, we discovered that STAG2 and TP53 mutations are often concurrent and are associated with poor outcome. Finally, we detected subclonal STAG2 mutations in diagnostic tumors and expansion of STAG2-immunonegative cells in relapsed tumors as compared with matched diagnostic samples.

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Sarah Cohen-Gogo, Cécile Cellier, Jean-Michel Coindre, Véronique Mosseri, Gaëlle Pierron, Cécile Guillemet, Antoine Italiano, Laurence Brugières, Daniel Orbach, Valérie Laurence, Olivier Delattre, Jean Michon (2014 Sep 2)

Ewing-like sarcomas with BCOR-CCNB3 fusion transcript: a clinical, radiological and pathological retrospective study from the Société Française des Cancers de L’Enfant.

Pediatric blood & cancer : 2191-8 : DOI : 10.1002/pbc.25210 En savoir plus
Résumé

This retrospective multicenter study assessed the clinical, radiological and pathological presentation, treatment and outcome of 26 patients with Ewing-like sarcoma harboring BCOR-CCNB3 gene fusion transcript. Tumor samples had been collected between 1994 and April 2012.

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Gudrun Schleiermacher, Isabelle Janoueix-Lerosey, Olivier Delattre (2014 Aug 16)

Recent insights into the biology of neuroblastoma.

International journal of cancer : 2249-61 : DOI : 10.1002/ijc.29077 En savoir plus
Résumé

Neuroblastoma (NB) is an embryonal tumor of the sympathetic nervous system which accounts for 8-10% of pediatric cancers. It is characterized by a broad spectrum of clinical behaviors from spontaneous regression to fatal outcome despite aggressive therapies. Considerable progress has been made recently in the germline and somatic genetic characterization of patients and tumors. Indeed, predisposition genes that account for a significant proportion of familial and syndromic cases have been identified and genome-wide association studies have retrieved a number of susceptibility loci. In addition, genome-wide sequencing, copy-number and expression studies have been conducted on tumors and have detected important gene modifications, profiles and signatures that have strong implications for the therapeutic stratification of patients. The identification of major players in NB oncogenesis, including MYCN, ALK, PHOX2B and LIN28B, has enabled the development of new animal models. Our review focuses on these recent advances, on the insights they provide on the mechanisms involved in NB development and their applications for the clinical management of patients.

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Gudrun Schleiermacher, Niloufar Javanmardi, Virginie Bernard, Quentin Leroy, Julie Cappo, Thomas Rio Frio, Gaelle Pierron, Eve Lapouble, Valérie Combaret, Frank Speleman, Bram de Wilde, Anna Djos, Ingrid Ora, Fredrik Hedborg, Catarina Träger, Britt-Marie Holmqvist, Jonas Abrahamsson, Michel Peuchmaur, Jean Michon, Isabelle Janoueix-Lerosey, Per Kogner, Olivier Delattre, Tommy Martinsson (2014 Jul 30)

Emergence of new ALK mutations at relapse of neuroblastoma.

Journal of clinical oncology : official journal of the American Society of Clinical Oncology : 2727-34 : DOI : 10.1200/JCO.2013.54.0674 En savoir plus
Résumé

In neuroblastoma, the ALK receptor tyrosine kinase is activated by point mutations. We investigated the potential role of ALK mutations in neuroblastoma clonal evolution.

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Anne Guimier, Sandrine Ferrand, Gaëlle Pierron, Jérôme Couturier, Isabelle Janoueix-Lerosey, Valérie Combaret, Véronique Mosseri, Estelle Thebaud, Marion Gambart, Dominique Plantaz, Aurélien Marabelle, Carole Coze, Xavier Rialland, Sylvie Fasola, Eve Lapouble, Paul Fréneaux, Michel Peuchmaur, Jean Michon, Olivier Delattre, Gudrun Schleiermacher (2014 Jul 12)

Clinical characteristics and outcome of patients with neuroblastoma presenting genomic amplification of loci other than MYCN.

PloS one : e101990 : DOI : 10.1371/journal.pone.0101990 En savoir plus
Résumé

Somatically acquired genomic alterations with MYCN amplification (MNA) are key features of neuroblastoma (NB), the most common extra-cranial malignant tumour of childhood. Little is known about the frequency, clinical characteristics and outcome of NBs harbouring genomic amplification(s) distinct from MYCN.

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Alex Cazes, Lucille Lopez-Delisle, Konstantina Tsarovina, Cécile Pierre-Eugène, Katleen De Preter, Michel Peuchmaur, André Nicolas, Claire Provost, Caroline Louis-Brennetot, Romain Daveau, Candy Kumps, Ilaria Cascone, Gudrun Schleiermacher, Aurélie Prignon, Frank Speleman, Hermann Rohrer, Olivier Delattre, Isabelle Janoueix-Lerosey (2014 May 10)

Activated Alk triggers prolonged neurogenesis and Ret upregulation providing a therapeutic target in ALK-mutated neuroblastoma.

Oncotarget : 2688-702 En savoir plus
Résumé

Activating mutations of the ALK (Anaplastic lymphoma Kinase) gene have been identified in sporadic and familial cases of neuroblastoma, a cancer of early childhood arising from the sympathetic nervous system (SNS). To decipher ALK function in neuroblastoma predisposition and oncogenesis, we have characterized knock-in (KI) mice bearing the two most frequent mutations observed in neuroblastoma patients. A dramatic enlargement of sympathetic ganglia is observed in AlkF1178L mice from embryonic to adult stages associated with an increased proliferation of sympathetic neuroblasts from E14.5 to birth. In a MYCN transgenic context, the F1178L mutation displays a higher oncogenic potential than the R1279Q mutation as evident from a shorter latency of tumor onset. We show that tumors expressing the R1279Q mutation are sensitive to ALK inhibition upon crizotinib treatment. Furthermore, our data provide evidence that activated ALK triggers RET upregulation in mouse sympathetic ganglia at birth as well as in murine and human neuroblastoma. Using vandetanib, we show that RET inhibition strongly impairs tumor growth in vivo in both MYCN/KI AlkR1279Q and MYCN/KI AlkF1178L mice. Altogether, our findings demonstrate the critical role of activated ALK in SNS development and pathogenesis and identify RET as a therapeutic target in ALK mutated neuroblastoma.

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Marcel Kool, David T W Jones, Natalie Jäger, Paul A Northcott, Trevor J Pugh, Volker Hovestadt, Rosario M Piro, L Adriana Esparza, Shirley L Markant, Marc Remke, Till Milde, Franck Bourdeaut, Marina Ryzhova, Dominik Sturm, Elke Pfaff, Sebastian Stark, Sonja Hutter, Huriye Seker-Cin, Pascal Johann, Sebastian Bender, Christin Schmidt, Tobias Rausch, David Shih, Jüri Reimand, Laura Sieber, Andrea Wittmann, Linda Linke, Hendrik Witt, Ursula D Weber, Marc Zapatka, Rainer König, Rameen Beroukhim, Guillaume Bergthold, Peter van Sluis, Richard Volckmann, Jan Koster, Rogier Versteeg, Sabine Schmidt, Stephan Wolf, Chris Lawerenz, Cynthia C Bartholomae, Christof von Kalle, Andreas Unterberg, Christel Herold-Mende, Silvia Hofer, Andreas E Kulozik, Andreas von Deimling, Wolfram Scheurlen, Jörg Felsberg, Guido Reifenberger, Martin Hasselblatt, John R Crawford, Gerald A Grant, Nada Jabado, Arie Perry, Cynthia Cowdrey, Sydney Croul, Gelareh Zadeh, Jan O Korbel, Francois Doz, Olivier Delattre, Gary D Bader, Martin G McCabe, V Peter Collins, Mark W Kieran, Yoon-Jae Cho, Scott L Pomeroy, Olaf Witt, Benedikt Brors, Michael D Taylor, Ulrich Schüller, Andrey Korshunov, Roland Eils, Robert J Wechsler-Reya, Peter Lichter, Stefan M Pfister, (2014 Mar 22)

Genome sequencing of SHH medulloblastoma predicts genotype-related response to smoothened inhibition.

Cancer cell : 393-405 : DOI : 10.1016/j.ccr.2014.02.004 En savoir plus
Résumé

Smoothened (SMO) inhibitors recently entered clinical trials for sonic-hedgehog-driven medulloblastoma (SHH-MB). Clinical response is highly variable. To understand the mechanism(s) of primary resistance and identify pathways cooperating with aberrant SHH signaling, we sequenced and profiled a large cohort of SHH-MBs (n = 133). SHH pathway mutations involved PTCH1 (across all age groups), SUFU (infants, including germline), and SMO (adults). Children >3 years old harbored an excess of downstream MYCN and GLI2 amplifications and frequent TP53 mutations, often in the germline, all of which were rare in infants and adults. Functional assays in different SHH-MB xenograft models demonstrated that SHH-MBs harboring a PTCH1 mutation were responsive to SMO inhibition, whereas tumors harboring an SUFU mutation or MYCN amplification were primarily resistant.

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Toby D Hocking, Valentina Boeva, Guillem Rigaill, Gudrun Schleiermacher, Isabelle Janoueix-Lerosey, Olivier Delattre, Wilfrid Richer, Franck Bourdeaut, Miyuki Suguro, Masao Seto, Francis Bach, Jean-Philippe Vert (2014 Feb 5)

SegAnnDB: interactive Web-based genomic segmentation.

Bioinformatics (Oxford, England) : 1539-46 : DOI : 10.1093/bioinformatics/btu072 En savoir plus
Résumé

DNA copy number profiles characterize regions of chromosome gains, losses and breakpoints in tumor genomes. Although many models have been proposed to detect these alterations, it is not clear which model is appropriate before visual inspection the signal, noise and models for a particular profile.

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Année de publication : 2013

Anne Vincent-Salomon, Vanessa Benhamo, Eléonore Gravier, Guillem Rigaill, Nadège Gruel, Stéphane Robin, Yann de Rycke, Odette Mariani, Gaëlle Pierron, David Gentien, Fabien Reyal, Paul Cottu, Alain Fourquet, Roman Rouzier, Xavier Sastre-Garau, Olivier Delattre (2013 Oct 22)

Genomic instability: a stronger prognostic marker than proliferation for early stage luminal breast carcinomas.

PloS one : e76496 : DOI : 10.1371/journal.pone.0076496 En savoir plus
Résumé

The accurate prognosis definition to tailor treatment for early luminal invasive breast carcinoma patients remains challenging.

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Franck Bourdeaut, Catherine Miquel, Wilfrid Richer, Jacques Grill, Michel Zerah, Camille Grison, Gaelle Pierron, Jeanne Amiel, Clementine Krucker, Francois Radvanyi, Laurence Brugieres, Olivier Delattre (2013 Oct 12)

Rubinstein-Taybi syndrome predisposing to non-WNT, non-SHH, group 3 medulloblastoma.

Pediatric blood & cancer : 383-6 : DOI : 10.1002/pbc.24765 En savoir plus
Résumé

Medulloblastomas (MB) are classified in four subgroups: the well defined WNT and Sonic Hedgehog (SHH) subgroups, and the less defined groups 3 and 4. They occasionally occur in the context of a cancer predisposition syndrome. While germline APC mutations predispose to WNT MB, germline mutations in SUFU, PTCH1, and TP53 predispose to SHH tumors. We report on a child with a Rubinstein-Taybi syndrome (RTS) due to a germline deletion in CREBBP, who developed a MB. Biological profilings demonstrate that this tumor belongs to the group 3. RTS may therefore be the first predisposition syndrome identified for non-WNT/non-SHH MB.

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Popova T., Hebert L., Jacquemin V., Gad S., Caux-Moncoutier V., Dubois-d&aquote;Enghien C., Richaudeau B., Renaudin X., Sellers J., Nicolas A., Sastre-Garau X., Desjardins L., Gyapay G., Raynal V., Sinilnikova O.M., Andrieu N., Manié E., de Pauw A., Gesta P., Bonadona V., Maugard C.M., Penet C., Avril M.F.c., Barillot E., Cabaret O., Delattre O., Richard S., Caron O., Benfodda M., Hu H.H., Soufir N., Bressac-de Paillerets B., Stoppa-Lyonnet D., Stern M.H. (2013 Jun 6)

Germline BAP1 mutations predispose to renal cell carcinomas.

American journal of human genetics : 92 : 974-80 : DOI : 10.1158/0008-5472.CAN-08-1560 En savoir plus
Résumé

The genetic cause of some familial nonsyndromic renal cell carcinomas (RCC) defined by at least two affected first-degree relatives is unknown. By combining whole-exome sequencing and tumor profiling in a family prone to cases of RCC, we identified a germline BAP1 mutation c.277A>G (p.Thr93Ala) as the probable genetic basis of RCC predisposition. This mutation segregated with all four RCC-affected relatives. Furthermore, BAP1 was found to be inactivated in RCC-affected individuals from this family. No BAP1 mutations were identified in 32 familial cases presenting with only RCC. We then screened for germline BAP1 deleterious mutations in familial aggregations of cancers within the spectrum of the recently described BAP1-associated tumor predisposition syndrome, including uveal melanoma, malignant pleural mesothelioma, and cutaneous melanoma. Among the 11 families that included individuals identified as carrying germline deleterious BAP1 mutations, 6 families presented with 9 RCC-affected individuals, demonstrating a significantly increased risk for RCC. This strongly argues that RCC belongs to the BAP1 syndrome and that BAP1 is a RCC-predisposition gene.

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