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1. Cellular origin and clonal evolution of human dedifferentiated liposarcoma

Author

Nadège Gruel, Chloé Quignot, Laëtitia Lesage, Sophie El Zein, Sylvie Bonvalot, Dimitri Tzanis, Khadija Ait Rais, Fabien Quinquis, Bastien Manciot, Julien Vibert, Nadine El Tannir, Ahmed Dahmani, Héloïse Derrien, Didier Decaudin, Ivan Bièche, Laura Courtois, Odette Mariani, Laëtitia K. Linares, Laurie Gayte, Sylvain Baulande, Joshua J. Waterfall, Olivier Delattre, Gaëlle Pierron, and Sarah Watson

Subjects
Science
Abstract

Abstract Dedifferentiated liposarcoma (DDLPS) is the most frequent high-grade soft tissue sarcoma subtype. It is characterized by a component of undifferentiated tumor cells coexisting with a component of well-differentiated adipocytic tumor cells. Both dedifferentiated (DD) and well-differentiated (WD) components exhibit MDM2 amplification, however their cellular origin remains elusive. Using single-cell RNA sequencing, DNA sequencing, in situ multiplex immunofluorescence and functional assays in paired WD and DD components from primary DDLPS tumors, we characterize the cellular heterogeneity of DDLPS tumor and micro-environment. We identify a population of tumor adipocyte stem cells (ASC) showing striking similarities with adipocyte stromal progenitors found in white adipose tissue. We show that tumor ASC harbor the ancestral genomic alterations of WD and DD components, suggesting that both derive from these progenitors following clonal evolution. Last, we show that DD tumor cells keep important biological properties of ASC including pluripotency and that their adipogenic properties are inhibited by a TGF-β-high immunosuppressive tumor micro-environment.

Published
2024
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2. Diffuse glioneuronal tumor with oligodendroglioma-like features and nuclear clusters (DGONC), new name and new problems: an illustration of one case with atypical morphology and biology

Author

Arnault Tauziède-Espariat, Lelio Guida, Volodia Dangouloff-Ros, Nathalie Boddaert, Gaëlle Pierron, Delphine Guillemot, Julien Masliah-Planchon, Lauren Hasty, Alice Métais, Fabrice Chrétien, and Pascale Varlet

Subjects
DGONC, Chromosome 14, PIK3R1, Embryonal, Neurology. Diseases of the nervous system, RC346-429
Abstract

Abstract A novel histomolecular tumor of the central nervous system (CNS), the “diffuse glioneuronal tumor with oligodendroglioma-like features and nuclear clusters (DGONC),” has recently been identified, based on a distinct DNA methylation profile and has been added to the 2021 World Health Organization Classification of CNS Tumors. This glioneuronal tumor mainly affects the supratentorial area in children and recurrently presents with a monosomy of chromosome 14. Herein, we report the case of a DNA-methylation based diagnosis of DGONC having atypical features, such as pseudo-rosettes and the absence of a chromosome 14 monosomy, thus rendering its diagnosis very challenging. Because of the wide variety of morphologies harbored by DGONC, a large range of differential diagnoses may be hypothesized from benign to malignant. Interestingly, the current case, like one previously reported, exhibited a co-expression of OLIG2, synaptophysin and SOX10, without GFAP immunopositivity. This particular immunophenotype seems to be a good indicator for a DGONC diagnosis. The classification of DGONC amongst glioneuronal or embryonal tumors is still debated. The clinical (a pediatric supratentorial tumor), morphological (from a benign oligodendroglioma-like tumor with microcalcifications and possible neuropil-like islands to a malignant embryonal tumor with a possible spongioblastic pattern), and immunohistochemical (co-expression of OLIG2 and synaptophsyin) profiles resemble CNS, neuroblastoma, FOXR2-activated and may potentially bring them together in a future classification. Further comprehensive studies are needed to conclude the cellular origin of DGONC and its prognosis.

Published
2024
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3. CNS tumors with PLAGL1-fusion: beyond ZFTA and YAP1 in the genetic spectrum of supratentorial ependymomas

Author

Arnault Tauziède-Espariat, Yvan Nicaise, Philipp Sievers, Felix Sahm, Andreas von Deimling, Delphine Guillemot, Gaëlle Pierron, Mathilde Duchesne, Myriam Edjlali, Volodia Dangouloff-Ros, Nathalie Boddaert, Alexandre Roux, Edouard Dezamis, Lauren Hasty, Benoît Lhermitte, Edouard Hirsch, Maria Paola Valenti Hirsch, François-Daniel Ardellier, Mélodie-Anne Karnoub, Marie Csanyi, Claude-Alain Maurage, Karima Mokhtari, Franck Bielle, Valérie Rigau, Thomas Roujeau, Marine Abad, Sébastien Klein, Michèle Bernier, Catherine Horodyckid, Clovis Adam, Petter Brandal, Pitt Niehusmann, Quentin Vannod-Michel, Corentin Provost, Nicolas Menjot de Champfleur, Lucia Nichelli, Alice Métais, Cassandra Mariet, Fabrice Chrétien, Thomas Blauwblomme, Kévin Beccaria, Johan Pallud, Stéphanie Puget, Emmanuelle Uro-Coste, Pascale Varlet, and RENOCLIP-LOC

Subjects
Ependymoma, PLAGL1, Subependymoma, DNA-methylation, Neurology. Diseases of the nervous system, RC346-429
Abstract

Abstract A novel methylation class, “neuroepithelial tumor, with PLAGL1 fusion” (NET-PLAGL1), has recently been described, based on epigenetic features, as a supratentorial pediatric brain tumor with recurrent histopathological features suggesting an ependymal differentiation. Because of the recent identification of this neoplastic entity, few histopathological, radiological and clinical data are available. Herein, we present a detailed series of nine cases of PLAGL1-fused supratentorial tumors, reclassified from a series of supratentorial ependymomas, non-ZFTA/non-YAP1 fusion-positive and subependymomas of the young. This study included extensive clinical, radiological, histopathological, ultrastructural, immunohistochemical, genetic and epigenetic (DNA methylation profiling) data for characterization. An important aim of this work was to evaluate the sensitivity and specificity of a novel fluorescent in situ hybridization (FISH) targeting the PLAGL1 gene. Using histopathology, immunohistochemistry and electron microscopy, we confirmed the ependymal differentiation of this new neoplastic entity. Indeed, the cases histopathologically presented as “mixed subependymomas-ependymomas” with well-circumscribed tumors exhibiting a diffuse immunoreactivity for GFAP, without expression of Olig2 or SOX10. Ultrastructurally, they also harbored features reminiscent of ependymal differentiation, such as cilia. Different gene partners were fused with PLAGL1: FOXO1, EWSR1 and for the first time MAML2. The PLAGL1 FISH presented a 100% sensitivity and specificity according to RNA sequencing and DNA methylation profiling results. This cohort of supratentorial PLAGL1-fused tumors highlights: 1/ the ependymal cell origin of this new neoplastic entity; 2/ benefit of looking for a PLAGL1 fusion in supratentorial cases of non-ZFTA/non-YAP1 ependymomas; and 3/ the usefulness of PLAGL1 FISH.

Published
2024
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4. CNS erythroblastic sarcoma: a potential emerging pediatric tumor type characterized by NFIA::RUNX1T1/3 fusions

Author

Arnault Tauziède-Espariat, Lucille Lew-Derivry, Samuel Abbou, Alice Métais, Gaëlle Pierron, Stéphanie Reynaud, Julien Masliah-Planchon, Cassandra Mariet, Lauren Hasty, Volodia Dangouloff-Ros, Nathalie Boddaert, Marie Csanyi, Aude Aline-Fardin, Claire Lamaison, Fabrice Chrétien, Kévin Beccaria, Stéphanie Puget, and Pascale Varlet

Subjects
Myeloid sarcoma, NFIA::RUNX1T1, Central nervous system, CNS leukemia, Neurology. Diseases of the nervous system, RC346-429
Abstract

Abstract Erythroblastic sarcoma (ES) (previously called chloroma or granulocytic sarcoma) are rare hematological neoplams characterized by the proliferation of myeloid blasts at extramedullary sites, and primarily involve the skin and soft tissue of middle-aged adults. ES may be concomitant with or secondary to myeloid neoplasms (mostly acute myeloid leukemia (AML)) or in isolated cases (de novo) without infiltration of the bone marrow by blasts. ES share cytogenetic and molecular abnormalities with AML, including RUNX1T1 fusions. Some of these alterations seem to be correlated with particular sites of involvement. Herein, we report an isolated erythroblastic sarcoma with NFIA::RUNX1T1 located in the central nervous system (CNS) of a 3-year-old boy. Recently, two pediatric cases of CNS MS with complete molecular characterization have been documented. Like the current case, they concerned infants (2 and 3 years-old) presenting a brain tumor (pineal involvement) with leptomeningeal dissemination. Both cases also harbored a NFIA::RUNX1T3 fusion. ES constitutes a diagnostic challenge for neuropathologists because it does not express differentiation markers such as CD45, and may express CD99 which could be confused with CNS Ewing sarcoma. CD43 is the earliest pan-hematopoietic marker and CD45 is not expressed by erythroid lineage cells. E-cadherin (also a marker of erythroid precursors) and CD117 (expressed on the surface of erythroid lineage cells) constitute other immunhistochemical hallmarks of ES. The prognosis of patients with ES is similar to that of other patients with AML but de novo forms seem to have a poorer prognosis, like the current case. To conclude, pediatric ES with NFIA::RUNX1T1/3 fusions seem to have a tropism for the CNS and thus constitute a potential pitfall for neuropathologists. Due to the absence of circulating blasts and a DNA-methylation signature, the diagnosis must currently be made by highlighting the translocation and expression of erythroid markers.

Published
2024
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5. Leiomyosarcoma and liposarcoma in young patients: The national netsarc+ network experience

Author

Anne-Laure Genevois, Matthieu Carton, Myriam Jean-Denis, Joanna Cyrta, Nadège Corradini, Pablo Berlanga, Claire Chemin-Airiau, Charles Honore, Sophie El Zein, Anne-Sophie Defachelles, Emmanuelle Bompas, Philippe Anract, Justine Gantzer, Marie Karanian, Angélique Rome, Florence Duffaud, Christine Chevreau, Sarah Watson, Axel Le Cesne, Carmen Llacer, François Le Loarer, Gaëlle Pierron, François Gouin, Anne Gomez-Mascard, Sylvain Causeret, Françoise Ducimetière, Elsa Kalbacher, Maud Toulmonde, Jean-Yves Blay, and Daniel Orbach

Subjects
Liposarcoma, Leiomyosarcoma, Ultra-rare sarcoma, Children, Adolescent-young adults, NETSARC+, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Background: Leiomyosarcoma (LMS) and liposarcoma (LPS) are ultra-rare sarcomas in pediatric (0–18 years) and young adult (19−30) populations. We aimed to analyze their clinical characteristics at these young ages and to determine whether they should be considered with the same therapeutic strategy in both populations. Methods: National retrospective multicenter study of all young patients (0–30 years) included in the sarcoma database “ConticaBase”, treated for LMS or LPS between 2010 and 2019 via the national NETSARC+ network, with available pathology/biology review. Findings: A total of 218 patients were identified, 34 children (nine LMS, 25 LPS) and 184 young adults (58 LMS, 126 LPS). Myxoid/Round Cell LPS (M/RC-LPS) was the most frequent LPS subtype (72 %). All children had localized LMS and LPS, versus 52/58 and 116/126 respectively in adults. Clinical presentation of LMS and all LPS subtypes was comparable in both populations, except for a preferential limb location of LMS in children. The therapeutic strategy was mainly based on primary surgery in LMS (9/9 children, 52/58 adults) and for LPS (respectively 25/25 and 122/126), exclusively or with adjuvant radiotherapy and systemic treatment. With a median follow-up of 62.4 months (range, 2.5–146), 5-year overall survival was respectively 83 % [95 % CI, 58–100] in children and 73 % [61–88] in young adults for LMS, 100 % [100] vs 92 % [87–99] for M/RC-LPS and 25 % [5–100] vs 60 % [29–100] for pleomorphic LPS. Interpretation: LMS and all LPS subtypes appear to display comparable behavior in children and young adults. The authors propose that the same therapeutic strategy should be considered for both groups.

Published
2023
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6. Reversible transitions between noradrenergic and mesenchymal tumor identities define cell plasticity in neuroblastoma

Author

Cécile Thirant, Agathe Peltier, Simon Durand, Amira Kramdi, Caroline Louis-Brennetot, Cécile Pierre-Eugène, Margot Gautier, Ana Costa, Amandine Grelier, Sakina Zaïdi, Nadège Gruel, Irène Jimenez, Eve Lapouble, Gaëlle Pierron, Déborah Sitbon, Hervé J. Brisse, Arnaud Gauthier, Paul Fréneaux, Sandrine Grossetête, Laura G. Baudrin, Virginie Raynal, Sylvain Baulande, Angela Bellini, Jaydutt Bhalshankar, Angel M. Carcaboso, Birgit Geoerger, Hermann Rohrer, Didier Surdez, Valentina Boeva, Gudrun Schleiermacher, Olivier Delattre, and Isabelle Janoueix-Lerosey

Subjects
Science
Abstract

Abstract Noradrenergic and mesenchymal identities have been characterized in neuroblastoma cell lines according to their epigenetic landscapes and core regulatory circuitries. However, their relationship and relative contribution in patient tumors remain poorly defined. We now document spontaneous and reversible plasticity between the two identities, associated with epigenetic reprogramming, in several neuroblastoma models. Interestingly, xenografts with cells from each identity eventually harbor a noradrenergic phenotype suggesting that the microenvironment provides a powerful pressure towards this phenotype. Accordingly, such a noradrenergic cell identity is systematically observed in single-cell RNA-seq of 18 tumor biopsies and 15 PDX models. Yet, a subpopulation of these noradrenergic tumor cells presents with mesenchymal features that are shared with plasticity models, indicating that the plasticity described in these models has relevance in neuroblastoma patients. This work therefore emphasizes that intrinsic plasticity properties of neuroblastoma cells are dependent upon external cues of the environment to drive cell identity.

Published
2023
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7. CNS neuroblastoma, FOXR2-activated and its mimics: a relevant panel approach for work-up and accurate diagnosis of this rare neoplasm

Author

Arnault Tauziède-Espariat, Dominique Figarella-Branger, Alice Métais, Emmanuelle Uro-Coste, Claude-Alain Maurage, Benoît Lhermitte, Aude Aline-Fardin, Lauren Hasty, Alexandre Vasiljevic, Dan Chiforeanu, Guillaume Chotard, Homa Adle-Biassette, Alexandra Meurgey, Raphaël Saffroy, Delphine Guillemot, Gaëlle Pierron, Philipp Sievers, Pascale Varlet, and the RENOCLIP-LOC

Subjects
Neurology. Diseases of the nervous system, RC346-429
Published
2023
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8. CNS tumor with EP300::BCOR fusion: discussing its prevalence in adult population

Author

Arnault Tauziède-Espariat, Emmanuelle Uro-Coste, Philipp Sievers, Yvan Nicaise, Cassandra Mariet, Aurore Siegfried, Gaëlle Pierron, Delphine Guillemot, Joseph Benzakoun, Johan Pallud, Margaux Roques, Fabrice Bonneville, Delphine Larrieu-Ciron, Patrick Chaynes, Raphaël Saffroy, Jocelyne Hamelin, Lauren Hasty, Alice Métais, Fabrice Chrétien, Marcel Kool, Johannes Gojo, Pascale Varlet, and RENOCLIP-LOC

Subjects
EP300, BCOR, Adult, Neurology. Diseases of the nervous system, RC346-429
Abstract

Abstract The Central Nervous System (CNS) tumor with BCOR internal tandem duplication (ITD) has recently been added as a novel embryonal histomolecular tumor type to the 2021 World Health Organization (WHO) Classification of CNS Tumors. In addition, other CNS tumors harboring a BCOR/BCORL1 fusion, which are defined by a distinct DNA-methylation profile, have been recently identified in the literature but clinical, radiological and histopathological data remain scarce. Herein, we present two adult cases of CNS tumors with EP300::BCOR fusion. These two cases presented radiological, histopathological, and immunohistochemical homologies with CNS tumors having BCOR ITD in children. To compare these tumors with different BCOR alterations, we performed a literature review with a meta-analysis. CNS tumors with EP300::BCOR fusion seem to be distinct from their BCOR ITD counterparts in terms of age, location, progression-free survival, tumor growth pattern, and immunopositivity for the BCOR protein. CNS tumors from the EP300::BCOR fusion methylation class in adults may be added to the future WHO classification.

Published
2023
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9. Intra‐ and extra‐cranial BCOR‐ITD tumours are separate entities within the BCOR‐rearranged family

Author

Yassine Bouchoucha, Arnault Tauziède‐Espariat, Arnaud Gauthier, Delphine Guillemot, Dorian Bochaton, Julien Vibert, Matthieu Carton, Sarah Watson, Sandrine Grossetête, Chloé Quignot, Daniel Orbach, Nadège Corradini, Gudrun Schleiermacher, Franck Bourdeaut, Marie Simbozel, Christelle Dufour, Véronique Minard‐Colin, Mehdi Brahmi, Franck Tirode, Daniel Pissaloux, Marie Karanian, Marie‐Christine Machet, Julien Masliah‐Planchon, Olivier Delattre, Liesbeth Cardoen, Gaëlle Pierron, and François Doz

Subjects
CNS BCOR‐ITD, BCOR‐ITD sarcomas, CCSK, ESS, clustering, transcriptome, Pathology, RB1-214
Abstract

Abstract BCOR‐ITD tumours form an emerging family of aggressive entities with an internal tandem duplication (ITD) in the last exon of the BCOR gene. The family includes cerebral tumours, termed central nervous system BCOR‐ITD (CNS BCOR‐ITD), and sarcomatous types described in the kidney as clear cell sarcoma of the kidney (CCSK), in the endometrium as high‐grade endometrial stromal sarcoma, and in the bone and soft tissue as undifferentiated round cell sarcoma or primitive myxoid mesenchymal tumour of infancy. Based on a series of 33 retrospective cases, including 10 CNS BCOR‐ITD and 23 BCOR‐ITD sarcomas, we interrogated the homogeneity of the entity regarding clinical, radiological, and histopathological findings, and molecular signatures. Whole‐transcriptomic sequencing and DNA methylation profiling were used for unsupervised clustering. BCOR‐ITD tumours mostly affected young children with a median age at diagnosis of 2.1 years (range 0–62.4). Median overall survival was 3.9 years and progression‐free survival was 1.4 years. This dismal prognosis is shared among tumours in all locations except CCSK. Histopathological review revealed marked differences between CNS BCOR‐ITD and BCOR‐ITD sarcomas. These two groups were consistently segregated by unsupervised clustering of expression (n = 22) and DNA methylation (n = 21) data. Proximity between the two groups may result from common somatic changes within key pathways directly related to the novel activity of the ITD itself. Conversely, comparison of gene signatures with single‐cell RNA‐Seq atlases suggests that the distinction between BCOR‐ITD sarcomas and CNS BCOR‐ITD may result from differences in cells of origin.

Published
2022
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10. A novel SMARCA2-CREM fusion: expanding the molecular spectrum of intracranial mesenchymal tumors beyond the FET genes

Author

Arnault Tauziède-Espariat, Gaëlle Pierron, Delphine Guillemot, Philipp Sievers, Dominique Cazals-Hatem, Thierry Faillot, Alexandre Roux, Joseph Benzakoun, Sophie Bockel, Nicolas Weinbreck, Lauren Hasty, Emmanuèle Lechapt, Fabrice Chrétien, and Pascale Varlet

Subjects
SMARCA2, CREM, Intracranial mesenchymal tumor, Neurology. Diseases of the nervous system, RC346-429
Abstract

Abstract A novel histomolecular tumor of the central nervous system, the “intracranial mesenchymal tumor (IMT), FET-CREB fusion-positive” has recently been identified in the literature and will be added to the 2021 World Health Organization Classification of Tumors of the Central Nervous System. However, our latest study using DNA-methylation analyses has revealed that intracranial FET-CREB fused tumors do not represent a single molecular tumor entity. Among them, the main subgroup presented classical features of angiomatoid fibrous histiocytoma, having ultrastructural features of arachnoidal cells, for. Another tumor type with clear cell component and histopathological signs of aggressivity clustered in close vicinity with clear cell sarcoma of soft tissue. Herein, we report one case of IMT with a novel SMARCA2-CREM fusion which has until now never been described in soft tissue or the central nervous system. We compare its clinical, histopathological, immunophenotypic, genetic and epigenetic features with those previously described in IMT, FET-CREB fusion-positive. Interestingly, the current case did not cluster with IMT, FET-CREB fusion-positive but rather presented histopathological (clear cell morphology with signs of malignancy), clinical (with a dismal course with several recurrences, metastases and finally the patient’s death), genetic (fusion implicating the CREM gene), and epigenetic (DNA-methylation profiling) similarities with our previously reported clear cell sarcoma-like tumor of the central nervous system. Our results added data suggesting that different clinical and histomolecular tumor subtypes or grades seem to be included within the terminology “IMT, FET-CREB fusion-positive”, and that further series of cases are needed to better characterize them.

Published
2021
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11. CNS tumors with YWHAE:NUTM2 and KDM2B-fusions present molecular similarities to extra-CNS tumors having BCOR internal tandem duplication or alternative fusions

Author

Arnault Tauziède-Espariat, Gaëlle Pierron, Delphine Guillemot, Dorian Bochaton, Sarah Watson, Julien Masliah-Planchon, Alexandre Vasiljevic, Alexandra Meurgey, Guillaume Chotard, Lauren Hasty, Ellen Wahler, Emmanuèle Lechapt, Fabrice Chrétien, Jacques Grill, Franck Bourdeaut, Yassine Bouchoucha, Stéphanie Puget, Céline Icher-de-Bouyn, Vincent Jecko, Liesbeth Cardoen, Volodia Dangouloff-Ros, Nathalie Boddaert, Pascale Varlet, and on behalf of the RENOCLIP-LOC

Subjects
Neurology. Diseases of the nervous system, RC346-429
Published
2021
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12. The EP300:BCOR fusion extends the genetic alteration spectrum defining the new tumoral entity of 'CNS tumors with BCOR internal tandem duplication'

Author

Arnault Tauziède-Espariat, Gaëlle Pierron, Aurore Siegfried, Delphine Guillemot, Emmanuelle Uro-Coste, Yvan Nicaise, David Castel, Isabelle Catalaa, Delphine Larrieu-Ciron, Patrick Chaynes, Amaury de Barros, Julien Nicolau, Albane Gareton, Emmanuèle Lechapt, Fabrice Chrétien, Franck Bourdeaut, François Doz, Yassine Bouchoucha, Jacques Grill, Kévin Beccaria, Nathalie Boddaert, Raphaël Saffroy, Mélanie Pagès, and Pascale Varlet

Subjects
Neurology. Diseases of the nervous system, RC346-429
Published
2020
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13. Iris melanoma relapsing sixteen years after proton-beam therapy: The importance of lifelong follow-up

Author

Laetitia-Claire Msika, Laurence Desjardins, Vincent Cockenpot, Rémi Dendale, Olivier Berges, Khadija Aït Raïs, Gaëlle Pierron, Raymond L. Barnhill, Nathalie Cassoux, and Alexandre Matet

Subjects
Ophthalmology, RE1-994
Abstract

Purpose: To report a case of locally recurrent spindle-cell iris amelanotic melanoma 16 years after proton-beam therapy. Observations: In 2001, a 45-year-old man presented with an amelanotic iris melanoma, extending from the 5 to 10 o'clock positions on his left eye. High-frequency ultrasonography showed extension of melanoma into the ciliary body. He was initially managed with proton-beam therapy (60 Gy delivered in four fractions over four consecutive days) and underwent ocular and systemic examination at regular intervals over the following years. Local tumor control was achieved, and the patient did not develop metastasis during sixteen consecutive years. In 2017, 16 years after he received proton-beam therapy, the patient developed a focal amelanotic lesion strongly suggestive of a local recurrence of iris melanoma, although it extended from the 1 to 6 o'clock positions. He also presented with treatment-resistant glaucoma with an intraocular pressure (IOP) of 37 mmHg, despite maximal topical IOP-lowering therapy. Since a second irradiation of the anterior segment was contraindicated, the eye was enucleated. Pathological analysis confirmed the diagnosis of iris melanoma and demonstrated iridocorneal angle invasion extending from the initial site to the recurrent tumor location. Conclusions and importance: Regular ophthalmological surveillance for life with gonioscopy and high-frequency ultrasonography is recommended in patients with iris melanoma, due to the possibility of delayed local recurrence more than a decade after the initial treatment. Keywords: Ciliary body, Iris, Melanoma, Radiotherapy, Irido-corneal angle, Proton-beam therapy

Published
2019
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14. Clinical characteristics and outcome of patients with neuroblastoma presenting genomic amplification of loci other than MYCN.

Author

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, and Gudrun Schleiermacher

Subjects
Medicine, Science
Abstract

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.Genomic profiles of 1100 NBs from French centres studied by array-CGH were re-examined specifically to identify regional amplifications. Patients were included if amplifications distinct from the MYCN locus were seen. A subset of NBs treated at Institut Curie and harbouring MNA as determined by array-CGH without other amplification was also studied. Clinical and histology data were retrospectively collected.In total, 56 patients were included and categorised into 3 groups. Group 1 (n = 8) presented regional amplification(s) without MNA. Locus 12q13-14 was a recurrent amplified region (4/8 cases). This group was heterogeneous in terms of INSS stages, primary localisations and histology, with atypical clinical features. Group 2 (n = 26) had MNA as well as other regional amplifications. These patients shared clinical features of those of a group of NBs MYCN amplified (Group 3, n = 22). Overall survival for group 1 was better than that of groups 2 and 3 (5 year OS: 87.5%±11% vs 34.9%±7%, log-rank p

Published
2014
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15. Genomic instability: a stronger prognostic marker than proliferation for early stage luminal breast carcinomas.

Author

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, and Olivier Delattre

Subjects
Medicine, Science
Abstract

BACKGROUND:The accurate prognosis definition to tailor treatment for early luminal invasive breast carcinoma patients remains challenging. MATERIALS AND METHODS:Two hundred fourteen early luminal breast carcinomas were genotyped with single nucleotide polymorphisms (SNPs) array to determine the number of chromosomal breakpoints as a marker of genomic instability. Proliferation was assessed by KI67 (immunohistochemistry) and genomic grade index (transcriptomic analysis). IHC3 (IHC4 score for HER2 negative tumors) was also determined. RESULTS:In the training set (109 cases), the optimal cut-off was 34 breakpoints with a specificity of 0.94 and a sensitivity of 0.57 (Area under the curve (AUC): 0.81[0.71; 0.91]). In the validation set (105 cases), the outcome of patients with > 34 breakpoints (11 events / 22 patients) was poorer (logrank test p < 0.001; Relative Risk (RR): 3.7 [1.73; 7.92]), than that of patients with < 34 breakpoints (19 events / 83 patients).Whereas genomic grade and KI67 had a significant prognostic value in univariate analysis in contrast to IHC3 that failed to have a statistical significant prognostic value in this series, the number of breakpoints remained the only significant parameter predictive of outcome (RR: 3.47, Confidence Interval (CI [1.29; 9.31], p = 0.014)) in multivariate analysis . CONCLUSION:Genomic instability, defined herein as a high number of chromosomal breakpoints, in early stage luminal breast carcinoma is a stronger prognostic marker than proliferation.

Published
2013
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16. Breakpoint features of genomic rearrangements in neuroblastoma with unbalanced translocations and chromothripsis.

Author

Valentina Boeva, Stéphanie Jouannet, Romain Daveau, Valérie Combaret, Cécile Pierre-Eugène, Alex Cazes, Caroline Louis-Brennetot, Gudrun Schleiermacher, Sandrine Ferrand, Gaëlle Pierron, Alban Lermine, Thomas Rio Frio, Virginie Raynal, Gilles Vassal, Emmanuel Barillot, Olivier Delattre, and Isabelle Janoueix-Lerosey

Subjects
Medicine, Science
Abstract

Neuroblastoma is a pediatric cancer of the peripheral nervous system in which structural chromosome aberrations are emblematic of aggressive tumors. In this study, we performed an in-depth analysis of somatic rearrangements in two neuroblastoma cell lines and two primary tumors using paired-end sequencing of mate-pair libraries and RNA-seq. The cell lines presented with typical genetic alterations of neuroblastoma and the two tumors belong to the group of neuroblastoma exhibiting a profile of chromothripsis. Inter and intra-chromosomal rearrangements were identified in the four samples, allowing in particular characterization of unbalanced translocations at high resolution. Using complementary experiments, we further characterized 51 rearrangements at the base pair resolution that revealed 59 DNA junctions. In a subset of cases, complex rearrangements were observed with templated insertion of fragments of nearby sequences. Although we did not identify known particular motifs in the local environment of the breakpoints, we documented frequent microhomologies at the junctions in both chromothripsis and non-chromothripsis associated breakpoints. RNA-seq experiments confirmed expression of several predicted chimeric genes and genes with disrupted exon structure including ALK, NBAS, FHIT, PTPRD and ODZ4. Our study therefore indicates that both non-homologous end joining-mediated repair and replicative processes may account for genomic rearrangements in neuroblastoma. RNA-seq analysis allows the identification of the subset of abnormal transcripts expressed from genomic rearrangements that may be involved in neuroblastoma oncogenesis.

Published
2013
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17. Base-excision repair pathway shapes 5-methylcytosine deamination signatures in pan-cancer genomes

Author

André Bortolini Silveira, Alexandre Houy, Olivier Ganier, Begüm Özemek, Sandra Vanhuele, Anne Vincent-Salomon, Nathalie Cassoux, Pascale Mariani, Gaelle Pierron, Serge Leyvraz, Damian Rieke, Alberto Picca, Franck Bielle, Marie-Laure Yaspo, Manuel Rodrigues, and Marc-Henri Stern

Subjects
Science
Abstract

Abstract Transition of cytosine to thymine in CpG dinucleotides is the most frequent type of mutation in cancer. This increased mutability is commonly attributed to the spontaneous deamination of 5-methylcytosine (5mC), which is normally repaired by the base-excision repair (BER) pathway. However, the contribution of 5mC deamination in the increasing diversity of cancer mutational signatures remains poorly explored. We integrate mutational signatures analysis in a large series of tumor whole genomes with lineage-specific epigenomic data to draw a detailed view of 5mC deamination in cancer. We uncover tumor type-specific patterns of 5mC deamination signatures in CpG and non-CpG contexts. We demonstrate that the BER glycosylase MBD4 preferentially binds to active chromatin and early replicating DNA, which correlates with lower mutational burden in these domains. We validate our findings by modeling BER deficiencies in isogenic cell models. Here, we establish MBD4 as the main actor responsible for 5mC deamination repair in humans.

Published
2024
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18. Prospective assessment of circulating tumor DNA in patients with metastatic uveal melanoma treated with tebentafusp

Author

Manuel Rodrigues, Toulsie Ramtohul, Aurore Rampanou, José Luis Sandoval, Alexandre Houy, Vincent Servois, Léah Mailly-Giacchetti, Gaelle Pierron, Anne Vincent-Salomon, Nathalie Cassoux, Pascale Mariani, Caroline Dutriaux, Marc Pracht, Thomas Ryckewaert, Jean-Emmanuel Kurtz, Sergio Roman-Roman, Sophie Piperno-Neumann, François-Clément Bidard, Marc-Henri Stern, and Shufang Renault

Subjects
Science
Abstract

Abstract Tebentafusp, a bispecific immune therapy, is the only drug that demonstrated an overall survival benefit in patients with metastatic uveal melanoma (MUM). Circulating tumor DNA (ctDNA) has emerged as a potential prognostic and predictive marker in the phase 3 IMCgp100-202 trial using multiplex PCR-based next-generation sequencing (NGS). In this study (NCT02866149), ctDNA dynamics were assessed using droplet digital PCR (ddPCR) in 69 MUM patients undergoing tebentafusp treatment. Notably, 61% of patients exhibited detectable ctDNA before treatment initiation, which was associated with shorter overall survival (median 12.9 months versus 40.5 months for patients with undetectable ctDNA; p

Published
2024
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19. A novel SMARCA2-CREM fusion: expanding the molecular spectrum of intracranial mesenchymal tumors beyond the FET genes

Author

Lauren Hasty, Dominique Cazals-Hatem, Gaëlle Pierron, Sophie Bockel, Emmanuèle Lechapt, Arnault Tauziède-Espariat, Nicolas Weinbreck, Delphine Guillemot, Fabrice Chrétien, Pascale Varlet, Alexandre Roux, Thierry Faillot, Joseph Benzakoun, and Philipp Sievers

Subjects
Adult, Male, Pathology, medicine.medical_specialty, Neurology, Oncogene Proteins, Fusion, Central nervous system, Case Report, Malignancy, Pathology and Forensic Medicine, Cyclic AMP Response Element Modulator, Cellular and Molecular Neuroscience, CREM, Fatal Outcome, SMARCA2, Meningeal Neoplasms, medicine, Humans, Epigenetics, RC346-429, Intracranial mesenchymal tumor, Brain Neoplasms, Angiomatoid fibrous histiocytoma, business.industry, Mesenchymal stem cell, Neoplasms, Second Primary, medicine.disease, medicine.anatomical_structure, Neurology (clinical), Clear-cell sarcoma, Neurology. Diseases of the nervous system, Meningioma, business, Clear cell, Transcription Factors
Abstract

A novel histomolecular tumor of the central nervous system, the “intracranial mesenchymal tumor (IMT), FET-CREB fusion-positive” has recently been identified in the literature and will be added to the 2021 World Health Organization Classification of Tumors of the Central Nervous System. However, our latest study using DNA-methylation analyses has revealed that intracranial FET-CREB fused tumors do not represent a single molecular tumor entity. Among them, the main subgroup presented classical features of angiomatoid fibrous histiocytoma, having ultrastructural features of arachnoidal cells, for. Another tumor type with clear cell component and histopathological signs of aggressivity clustered in close vicinity with clear cell sarcoma of soft tissue. Herein, we report one case of IMT with a novel SMARCA2-CREM fusion which has until now never been described in soft tissue or the central nervous system. We compare its clinical, histopathological, immunophenotypic, genetic and epigenetic features with those previously described in IMT, FET-CREB fusion-positive. Interestingly, the current case did not cluster with IMT, FET-CREB fusion-positive but rather presented histopathological (clear cell morphology with signs of malignancy), clinical (with a dismal course with several recurrences, metastases and finally the patient’s death), genetic (fusion implicating the CREM gene), and epigenetic (DNA-methylation profiling) similarities with our previously reported clear cell sarcoma-like tumor of the central nervous system. Our results added data suggesting that different clinical and histomolecular tumor subtypes or grades seem to be included within the terminology “IMT, FET-CREB fusion-positive”, and that further series of cases are needed to better characterize them.

Published
2021

20. CNS tumors with YWHAE:NUTM2 and KDM2B-fusions present molecular similarities to extra-CNS tumors having BCOR internal tandem duplication or alternative fusions

Author

Alexandre Vasiljevic, Stéphanie Puget, Alexandra Meurgey, Nathalie Boddaert, Lauren Hasty, Pascale Varlet, Julien Masliah-Planchon, Delphine Guillemot, Dorian Bochaton, Emmanuèle Lechapt, Jacques Grill, Liesbeth Cardoen, Franck Bourdeaut, Ellen Wahler, Céline Icher-de-Bouyn, Vincent Jecko, Gaëlle Pierron, Yassine Bouchoucha, Fabrice Chrétien, Volodia Dangouloff-Ros, Arnault Tauziède-Espariat, Guillaume Chotard, and Sarah Watson

Subjects
Cellular and Molecular Neuroscience, KDM2B, Internal tandem duplication, Neurology. Diseases of the nervous system, Neurology (clinical), Computational biology, CNS TUMORS, Biology, RC346-429, YWHAE, Letter to the Editor, Pathology and Forensic Medicine
Published
2021

21. Study of chromatin remodeling genes implicates SMARCA4 as a putative player in oncogenesis in neuroblastoma

Author

Gaëlle Pierron, Nadège Corradini, Marion Gambart, Eve Lapouble, Valérie Combaret, Dominique Valteau-Couanet, Léo Colmet-Daage, Isabelle Janoueix-Lerosey, Mathieu Chicard, Jean Michon, Virginie Bernard, Adrien Danzon, Virginie Raynal, Gudrun Schleiermacher, Angela Bellini, Laura Le Roux, Olivier Delattre, Sylvain Baulande, Estelle Thebaud, Franck Bourdeaut, Jaydutt Bhalshankar, Caroline Louis-Brennetot, Julien Maslian Planchon, Anne-Sophie Defachelles, Nathalie Clément, and Nadia Bessoltane‐Bentahar

Subjects
Male, Cancer Research, X-linked Nuclear Protein, Adolescent, DNA Copy Number Variations, Carcinogenesis, Kaplan-Meier Estimate, Biology, Genome, Polymorphism, Single Nucleotide, Chromatin remodeling, Germline, 03 medical and health sciences, Molecular Cancer Biology, Neuroblastoma, 0302 clinical medicine, INDEL Mutation, epigenetic modifier, SMARCA4, Exome Sequencing, Humans, Child, Gene, Exome, ATRX, Germ-Line Mutation, Genetics, Whole genome sequencing, DNA Helicases, Infant, Newborn, Infant, Nuclear Proteins, Exons, Chromatin Assembly and Disassembly, Progression-Free Survival, SWI/SNF, Oncology, 030220 oncology & carcinogenesis, Case-Control Studies, Child, Preschool, Female, chromatin remodeling complex, Transcription Factors
Abstract

In neuroblastoma (NB), genetic alterations in chromatin remodeling (CRGs) and epigenetic modifier genes (EMGs) have been described. We sought to determine their frequency and clinical impact. Whole exome (WES)/whole genome sequencing (WGS) data and targeted sequencing (TSCA®) of exonic regions of 33 CRGs/EMGs were analyzed in tumor samples from 283 NB patients, with constitutional material available for 55 patients. The frequency of CRG/EMG variations in NB cases was then compared to the Genome Aggregation Database (gnomAD). The sequencing revealed SNVs/small InDels or focal CNAs of CRGs/EMGs in 20% (56/283) of all cases, occurring at a somatic level in 4 (7.2%), at a germline level in 12 (22%) cases, whereas for the remaining cases, only tumor material could be analyzed. The most frequently altered genes were ATRX (5%), SMARCA4 (2.5%), MLL3 (2.5%) and ARID1B (2.5%). Double events (SNVs/small InDels/CNAs associated with LOH) were observed in SMARCA4 (n = 3), ATRX (n = 1) and PBRM1 (n = 1). Among the 60 variations, 24 (8.4%) targeted domains of functional importance for chromatin remodeling or highly conserved domains but of unknown function. Variations in SMARCA4 and ATRX occurred more frequently in the NB as compared to the gnomAD control cohort (OR = 4.49, 95%CI: 1.63–9.97, p = 0.038; OR 3.44, 95%CI: 1.46–6.91, p = 0.043, respectively). Cases with CRG/EMG variations showed a poorer overall survival compared to cases without variations. Genetic variations of CRGs/EMGs with likely functional impact were observed in 8.4% (24/283) of NB. Our case–control approach suggests a role of SMARCA4 as a player of NB oncogenesis., What's new? Mutations that affect chromatin remodeling can lead to cancer. In this paper, the authors investigated the impact of variations in chromatin remodeling genes and epigenetic modifier genes on neuroblastoma patients. They compared the frequency of these variations in NB cases with data from the Genome Aggregation Database (gnomAD). Neuroblastoma cases had a higher frequency of SMARCA4 and ATRX gene variations than the general population. Furthermore, NB patients with CRG/EMG mutations had poorer overall survival than NB cases without such mutations. These findings highlight the importance of chromatin remodeling in neuroblastoma as an avenue for new therapeutics.

Published
2019

22. Iris melanoma relapsing sixteen years after proton-beam therapy: The importance of lifelong follow-up

Author

Gaëlle Pierron, Rémi Dendale, Khadija Aït Raïs, O Berges, Laurence Desjardins, Alexandre Matet, Raymond L. Barnhill, Nathalie Cassoux, Vincent Cockenpot, and Laetitia-Claire Msika

Subjects
medicine.medical_specialty, Intraocular pressure, medicine.medical_treatment, Glaucoma, Iris, Ciliary body, 03 medical and health sciences, 0302 clinical medicine, lcsh:Ophthalmology, Irido-corneal angle, Case report, medicine, Gonioscopy, Amelanotic melanoma, Melanoma, Proton-beam therapy, medicine.diagnostic_test, Radiotherapy, business.industry, Iris melanoma, medicine.disease, Radiation therapy, Ophthalmology, medicine.anatomical_structure, lcsh:RE1-994, 030221 ophthalmology & optometry, Radiology, business, 030217 neurology & neurosurgery
Abstract

Purpose: To report a case of locally recurrent spindle-cell iris amelanotic melanoma 16 years after proton-beam therapy. Observations: In 2001, a 45-year-old man presented with an amelanotic iris melanoma, extending from the 5 to 10 o'clock positions on his left eye. High-frequency ultrasonography showed extension of melanoma into the ciliary body. He was initially managed with proton-beam therapy (60 Gy delivered in four fractions over four consecutive days) and underwent ocular and systemic examination at regular intervals over the following years. Local tumor control was achieved, and the patient did not develop metastasis during sixteen consecutive years. In 2017, 16 years after he received proton-beam therapy, the patient developed a focal amelanotic lesion strongly suggestive of a local recurrence of iris melanoma, although it extended from the 1 to 6 o'clock positions. He also presented with treatment-resistant glaucoma with an intraocular pressure (IOP) of 37 mmHg, despite maximal topical IOP-lowering therapy. Since a second irradiation of the anterior segment was contraindicated, the eye was enucleated. Pathological analysis confirmed the diagnosis of iris melanoma and demonstrated iridocorneal angle invasion extending from the initial site to the recurrent tumor location. Conclusions and importance: Regular ophthalmological surveillance for life with gonioscopy and high-frequency ultrasonography is recommended in patients with iris melanoma, due to the possibility of delayed local recurrence more than a decade after the initial treatment. Keywords: Ciliary body, Iris, Melanoma, Radiotherapy, Irido-corneal angle, Proton-beam therapy

Published
2018

23. Prognostic Implications of MRI Melanin Quantification and Cytogenetic Abnormalities in Liver Metastases of Uveal Melanoma

Author

Gaëlle Pierron, Khadija Ait Rais, Pascale Mariani, Sergio Roman-Roman, Toulsie Ramtohul, Manuel Rodrigues, Raymond L. Barnhill, Vincent Servois, Leanne De Koning, Sophie Gardrat, and Nathalie Cassoux

Subjects
Cancer Research, Monosomy, Pathology, medicine.medical_specialty, Article, Melanin, 03 medical and health sciences, 0302 clinical medicine, metastatic uveal melanoma, medicine, Pathological, RC254-282, medicine.diagnostic_test, Proportional hazards model, business.industry, Melanoma, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Magnetic resonance imaging, Retrospective cohort study, medicine.disease, genetic classification, Oncology, 030220 oncology & carcinogenesis, 030221 ophthalmology & optometry, prognosis, business, melanin quantification, Comparative genomic hybridization
Abstract

To evaluate the prognostic implications of melanin quantification assessed by magnetic resonance imaging (MRI) with respect to the clinical, pathological, and genetic features of liver metastases of uveal melanoma (LMUM). This single-center retrospective cohort study included 63 patients eligible for margin-free resection of LMUM between 2007 and 2018. Comparative genomic hybridization of resected liver metastases on microarrays was performed for genetic risk classification. Metastases exhibiting monosomy 3 with any type of gain of chromosome 8 (M3/8g) were considered high-genetic-risk. MRI melanin quantification using the mean T1 signal (mT1s) in liver metastases was assessed quantitatively on preoperative imaging examination and compared to that of gross pathological evaluation. The association between MRI melanin quantification and overall survival (OS) was assessed by multivariate analysis using the Cox proportional hazards model. Gross pathological assessment of melanin content and MRI melanin quantification were strongly correlated (r = 0.8, p &lt, 0.001). Independent prognostic factors associated with OS were disease-free interval ≤ 24 months (HR = 3.1, 95% CI, 1.6–6.0, p &lt, 0.001), high-genetic-risk (HR = 2.2, 95% CI, 1.1–4.8, p = 0.04), mT1s &gt, 1.1 (HR = 2.3, 95% CI, 1.2–4.7, p = 0.019), and complete hepatic resection (HR = 0.3, 95% CI, 0.2–0.7, p = 0.004). In patients with high-genetic-risk, mT1s showed a significant association with OS (HR = 3.7, 95% CI, 1.5–9.3, p = 0.006). The median OS was 17.5 months vs. 27 months for &gt, 1.1 and ≤1.1 mT1s tumors, respectively (p = 0.003). We showed that the level of pigmentation in M3/8g LMUM identified two subsets that were correlated with distinct clinical outcomes.

Published
2021
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24. Infantile Rhabdomyosarcomas With VGLL2 Rearrangement Are Not Always an Indolent Disease: A Study of 4 Aggressive Cases With Clinical, Pathologic, Molecular, and Radiologic Findings

Author

Corinne Bouvier, Paul Fréneaux, Bénédicte Brichard, Angélique Rome, Megane Bouvet, Stéphanie Pannier, Nina Jehanno, Gaëlle Pierron, Philippe Petit, Hervé Brisse, André Filipe Vieira, Joanna Cyrta, G Schleiermacher, Camille Benoist, François Le Loarer, Arnaud Gauthier, Mina Komuta, Veronique Minard-Colin, Estelle Thebaud, Marleen Renard, Birgit Geoerger, Liesbeth Cardoen, Anne Vincent-Salomon, Marie Karanian, Claire Pluchart, Daniel Orbach, UCL - SSS/IREC/PEDI - Pôle de Pédiatrie, and UCL - (SLuc) Service d'hématologie et d'oncologie pédiatrique

Subjects
0301 basic medicine, Male, Pathology, medicine.medical_specialty, medicine.medical_treatment, Muscle Proteins, Disease, Pathology and Forensic Medicine, 03 medical and health sciences, 0302 clinical medicine, Fatal Outcome, Belgium, CDKN2A, Rhabdomyosarcoma, Exome Sequencing, Biomarkers, Tumor, Medicine, Humans, Medical history, Genetic Predisposition to Disease, RNA-Seq, Gene Rearrangement, Chemotherapy, business.industry, Fibromatosis, Infant, Newborn, Infant, medicine.disease, Immunohistochemistry, 030104 developmental biology, Phenotype, Treatment Outcome, 030220 oncology & carcinogenesis, Disease Progression, Surgery, Desmin, Female, Sarcoma, France, Anatomy, Neoplasm Grading, business, Infantile Fibrosarcoma, Transcription Factors
Abstract

VGLL2-rearranged rhabdomyosarcomas (RMS) are rare low-grade tumors with only favorable outcomes reported to date. We describe 4 patients with VGLL2-rearranged RMS confirmed by molecular studies, who experienced local progression and distant metastases, including 2 with fatal outcomes. Tumors were diagnosed at birth (n=3) or at 12 months of age (n=1), and were all localized at initial diagnosis, but unresectable and therefore managed with chemotherapy and surveillance. Metastatic progression occurred from 1 to 8 years from diagnosis (median, 3.5 y). Three patients experienced multimetastatic spread and one showed an isolated adrenal metastasis. At initial diagnosis, 3 tumors displaying bland morphology were misdiagnosed as fibromatosis or infantile fibrosarcoma and initially managed as such, while 1 was a high-grade sarcoma. At relapse, 3 tumors showed high-grade morphology, while 1 retained a low-grade phenotype. Low-grade primary tumors showed only very focal positivity for desmin, myogenin, and/or MyoD1, while high-grade tumors were heterogenously or diffusely positive. Whole-exome sequencing, performed on primary and relapse samples for 3 patients, showed increased genomic instability and additional genomic alterations (eg, TP53, CDKN2A/B, FGFR4) at relapse, but no recurrent events. RNA sequencing confirmed that high-grade tumors retained VGLL2 fusion transcripts and transcriptomic profiles consistent with VGLL2-rearranged RMS. High-grade samples showed a high expression of genes encoding cell cycle proteins, desmin, and some developmental factors. These 4 cases with distinct medical history imply the importance of complete surgical resection, and suggest that RMS-type chemotherapy should be considered in unresectable cases, given the risk of high-grade transformation. They also emphasize the importance of correct initial diagnosis.

Published
2021

25. Frequency and prognostic impact of ALK amplifications and mutations in the European Neuroblastoma Study Group (SIOPEN) high-risk neuroblastoma trial (HR-NBL1)

Author

Ulrike Pötschger, Gudrun Schleiermacher, Sally L George, Nick Bown, Jaydutt Bhalshankar, Sylvain Baulande, Peter F. Ambros, Josef Malis, Gaëlle Pierron, Eve Lapouble, Katia Mazzocco, Virginie Bernard, Jaime Font de Mora, Katleen De Preter, Annick Mühlethaler-Mottet, Nadine Van Roy, Martina Morini, Genevieve Laureys, Bárbara Marques, Dominique Valteau-Couanet, Olivier Delattre, Marta Jeison, Victoria Castel, Shifra Ash, Valérie Combaret, Nathalie Auger, Ruth Ladenstein, Sabine Taschner-Mandl, Louis Chesler, Maria Rossing, David R. Betts, Ales Vicha, Rosa Noguera, Klaus Beiske, Angela Bellini, Walentyna Balwierz, Deborah A. Tweddle, Maja Popovic-Beck, Marie Bernkopf, Nathalie Clément, Per Kogner, Tommy Martinsson, Roberto Luksch, Martin Elliott, and Irene Jiménez

Subjects
0301 basic medicine, Cancer Research, Prognostic Impact, Anaplastic Lymphoma Kinase/genetics, Child, Preschool, Clinical Trials, Phase III as Topic, Europe, Female, Follow-Up Studies, Gene Amplification, Humans, Infant, Male, Mutation Rate, N-Myc Proto-Oncogene Protein/genetics, Neuroblastoma/genetics, Prognosis, Randomized Controlled Trials as Topic, Risk Factors, Survival Rate, European Neuroblastoma Study Group, SIOPEN, RELAPSE, 03 medical and health sciences, Neuroblastoma, 0302 clinical medicine, Text mining, hemic and lymphatic diseases, REVEALS, Medicine and Health Sciences, KINASE, Medicine, High risk neuroblastoma, HETEROGENEITY, CRIZOTINIB, SEGMENTAL CHROMOSOMAL ALTERATIONS, ACTIVATING MUTATIONS, PEDIATRIC-PATIENTS, business.industry, ALK receptor tyrosine kinase, Point mutation, REARRANGEMENTS, CHEMOTHERAPY, medicine.disease, Doenças Genéticas, 030104 developmental biology, ALK, Oncology, 030220 oncology & carcinogenesis, Cancer research, business
Abstract

Purpose: In neuroblastoma (NB), the ALK receptor tyrosine kinase can be constitutively activated through activating point mutations or genomic amplification. We studied ALK genetic alterations in high-risk (HR) patients on the HR-NBL1/SIOPEN trial to determine their frequency, correlation with clinical parameters, and prognostic impact. Materials and methods: Diagnostic tumor samples were available from 1,092 HR-NBL1/SIOPEN patients to determine ALK amplification status (n = 330), ALK mutational profile (n = 191), or both (n = 571). Results: Genomic ALK amplification (ALKa) was detected in 4.5% of cases (41 out of 901), all except one with MYCN amplification (MNA). ALKa was associated with a significantly poorer overall survival (OS) (5-year OS: ALKa [n = 41] 28% [95% CI, 15 to 42]; no-ALKa [n = 860] 51% [95% CI, 47 to 54], [P < .001]), particularly in cases with metastatic disease. ALK mutations (ALKm) were detected at a clonal level (> 20% mutated allele fraction) in 10% of cases (76 out of 762) and at a subclonal level (mutated allele fraction 0.1%-20%) in 3.9% of patients (30 out of 762), with a strong correlation between the presence of ALKm and MNA (P < .001). Among 571 cases with known ALKa and ALKm status, a statistically significant difference in OS was observed between cases with ALKa or clonal ALKm versus subclonal ALKm or no ALK alterations (5-year OS: ALKa [n = 19], 26% [95% CI, 10 to 47], clonal ALKm [n = 65] 33% [95% CI, 21 to 44], subclonal ALKm (n = 22) 48% [95% CI, 26 to 67], and no alteration [n = 465], 51% [95% CI, 46 to 55], respectively; P = .001). Importantly, in a multivariate model, involvement of more than one metastatic compartment (hazard ratio [HR], 2.87; P < .001), ALKa (HR, 2.38; P = .004), and clonal ALKm (HR, 1.77; P = .001) were independent predictors of poor outcome. Conclusion: Genetic alterations of ALK (clonal mutations and amplifications) in HR-NB are independent predictors of poorer survival. These data provide a rationale for integration of ALK inhibitors in upfront treatment of HR-NB with ALK alterations. Key Objective: High risk neuroblastoma (HR-NB) is one of the most difficult childhood cancers to cure. This study examined whether the presence of an ALK alteration (amplification or mutation) was associated with a poor prognosis in a large patient series treated on the prospective European high-risk neuroblastoma trial (HR-NBL1). Knowledge Generated: We found that ALK amplification or clonal mutation was associated with inferior prognosis in patients with HR-NB and both are independent prognostic variables on multivariate analysis. To our knowledge, this is the first study to report the highly prognostic significance of ALK amplification in HR-NB. Relevance: As ALK can be targeted therapeutically, this study convincingly argues for the introduction of ALK inhibitors for upfront management of patients with HR-NB with ALK aberrations. Importantly, the prognostic significance of ALK alterations included a subgroup of trial patients treated with the current standard of care for HR-NB including anti-GD2 immunotherapy. info:eu-repo/semantics/publishedVersion

Published
2021
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26. Different Pigmentation Risk Loci for High-Risk Monosomy 3 and Low-Risk Disomy 3 Uveal Melanomas

Author

Josselin Noirel, Anne Boland, Olivier Cussenot, Anne-Céline Derrien, Nathalie Cassoux, Alexandre Houy, Ghislaine Scelo, Lenha Mobuchon, Gaëlle Pierron, Manuel Rodrigues, Thibault Verrier, Marc-Henri Stern, Geraldine Cancel-Tassin, Maud Milder, Jean-François Deleuze, Mitchell J. Machiela, Unité de génétique et biologie des cancers (U830), Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Systématique, Evolution, Biodiversité (ISYEB ), Muséum national d'Histoire naturelle (MNHN)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Université des Antilles (UA), Institut Curie [Paris], Département de Biologie des Tumeurs, Centre National de Recherche en Génomique Humaine (CNRGH), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Université Paris-Saclay, Laboratoire Génomique, bioinformatique et chimie moléculaire (GBCM), Conservatoire National des Arts et Métiers [CNAM] (CNAM), Centre International de Recherche contre le Cancer - International Agency for Research on Cancer (CIRC - IARC), Organisation Mondiale de la Santé / World Health Organization Office (OMS / WHO), Centre de Recherche pour les Pathologies Prostatiques [Paris] (CeRePP), Sorbonne Université (SU), National Cancer Institute [Bethesda] (NCI-NIH), National Institutes of Health [Bethesda] (NIH), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM), and Noirel, Josselin

Subjects
Uveal Neoplasms, Oncology, Cancer Research, medicine.medical_specialty, Monosomy, Locus (genetics), Genome-wide association study, [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, 03 medical and health sciences, Chromosome 15, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, Internal medicine, Genetic predisposition, medicine, Humans, GWAS, pigmentation, [SDV.MHEP.OS]Life Sciences [q-bio]/Human health and pathology/Sensory Organs, Melanoma, 030304 developmental biology, 0303 health sciences, business.industry, Odds ratio, medicine.disease, Eye pigmentation, Chromosome 3, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, [SDV.MHEP.OS] Life Sciences [q-bio]/Human health and pathology/Sensory Organs, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, 030220 oncology & carcinogenesis, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, uveal melanoma, business, Genome-Wide Association Study
Abstract

Background Uveal melanoma (UM), a rare malignant tumor of the eye, is predominantly observed in populations of European ancestry. UMs carrying a monosomy 3 (M3) frequently relapse mainly in the liver, whereas UMs with disomy 3 (D3) are associated with more favorable outcome. Here, we explored the UM genetic predisposition factors in a large genome-wide association study (GWAS) of 1142 European UM patients and 882 healthy controls . Methods We combined 2 independent datasets (Global Screening Array) with the dataset described in a previously published GWAS in UM (Omni5 array), which were imputed separately and subsequently merged. Patients were stratified according to their chromosome 3 status, and identified UM risk loci were tested for differential association with M3 or D3 subgroups. All statistical tests were 2-sided. Results We recapitulated the previously identified risk locus on chromosome 5 on CLPTM1L (rs421284: odds ratio [OR] =1.58, 95% confidence interval [CI] = 1.35 to 1.86; P = 1.98 × 10-8) and identified 2 additional risk loci involved in eye pigmentation: IRF4 locus on chromosome 6 (rs12203592: OR = 1.76, 95% CI = 1.44 to 2.16; P = 3.55 × 10-8) and HERC2 locus on chromosome 15 (rs12913832: OR= 0.57, 95% CI = 0.48 to 0.67; P = 1.88 × 10-11). The IRF4 rs12203592 single-nucleotide polymorphism was found to be exclusively associated with risk for the D3 UM subtype (ORD3 = 2.73, 95% CI = 1.87 to 3.97; P = 1.78 × 10-7), and the HERC2 rs12913832 single-nucleotide polymorphism was exclusively associated with risk for the M3 UM subtype (ORM3 = 2.43, 95% CI = 1.79 to 3.29; P = 1.13 × 10-8). However, the CLPTM1L risk locus was equally statistically significant in both subgroups. Conclusions This work identified 2 additional UM risk loci known for their role in pigmentation. Importantly, we demonstrate that UM tumor biology and metastatic potential are influenced by patients’ genetic backgrounds.

Published
2021
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27. Multimodal analysis of cell-free DNA whole-genome sequencing for pediatric cancers with low mutational burden

Author

Manuela Krumbholz, Caroline Hutter, Susan A. Burchill, Mathieu Chicard, Eleni M. Tomazou, Nathan C. Sheffield, André F. Rendeiro, Adrian M. Stütz, Heidrun Boztug, Ola Myklebost, Bekir Ergüner, Marcus Tötzl, Gaëlle Pierron, Sabine Taschner-Mandl, Perrine Marec-Berard, Didier Surdez, Markus Metzler, Marie Bernkopf, G Schleiermacher, Sandra J. Strauss, Gernot Engstler, Uta Dirksen, Peter F. Ambros, Inge M. Ambros, Eve Lapouble, Jeremy Whelan, Michael Dworzak, Christiane Schaefer, Kjetil Boye, Christoph Bock, Bernadette Brennan, Olivier Delattre, Sabine Semper, Abbas Agaimy, Daniele Barreca, and Peter Peneder

Subjects
Epigenomics, Male, 0301 basic medicine, DNA Mutational Analysis, Medizin, General Physics and Astronomy, Circulating Tumor DNA, 0302 clinical medicine, Cancer genomics, Medicine, Child, Multidisciplinary, Middle Aged, 3. Good health, Cell-free fetal DNA, Child, Preschool, 030220 oncology & carcinogenesis, DNA fragmentation, Female, Adult, Adolescent, Science, Bone Neoplasms, Sarcoma, Ewing, Computational biology, Article, General Biochemistry, Genetics and Molecular Biology, Paediatric cancer, Young Adult, 03 medical and health sciences, Biomarkers, Tumor, Humans, Epigenetics, Liquid biopsy, Whole genome sequencing, Whole Genome Sequencing, business.industry, Liquid Biopsy, Infant, Cancer, General Chemistry, medicine.disease, 030104 developmental biology, Case-Control Studies, Mutation, business, Software, Biomarkers
Abstract

Sequencing of cell-free DNA in the blood of cancer patients (liquid biopsy) provides attractive opportunities for early diagnosis, assessment of treatment response, and minimally invasive disease monitoring. To unlock liquid biopsy analysis for pediatric tumors with few genetic aberrations, we introduce an integrated genetic/epigenetic analysis method and demonstrate its utility on 241 deep whole-genome sequencing profiles of 95 patients with Ewing sarcoma and 31 patients with other pediatric sarcomas. Our method achieves sensitive detection and classification of circulating tumor DNA in peripheral blood independent of any genetic alterations. Moreover, we benchmark different metrics for cell-free DNA fragmentation analysis, and we introduce the LIQUORICE algorithm for detecting circulating tumor DNA based on cancer-specific chromatin signatures. Finally, we combine several fragmentation-based metrics into an integrated machine learning classifier for liquid biopsy analysis that exploits widespread epigenetic deregulation and is tailored to cancers with low mutation rates. Clinical associations highlight the potential value of cfDNA fragmentation patterns as prognostic biomarkers in Ewing sarcoma. In summary, our study provides a comprehensive analysis of circulating tumor DNA beyond recurrent genetic aberrations, and it renders the benefits of liquid biopsy more readily accessible for childhood cancers., Liquid biopsies enable minimally invasive applications for diagnosis and treatment monitoring. Here the authors analyse fragmentation patterns of circulating tumour DNA on multiple levels and develop a bioinformatic tool, LIQUORICE, to accurately detect and classify paediatric cancers with low mutational burden.

Published
2021

28. Identification of Tissue of Origin and Guided Therapeutic Applications in Cancers of Unknown Primary Using Deep Learning and RNA Sequencing (TransCUPtomics)

Author

Joshua J. Waterfall, Anne Vincent-Salomon, François-Clément Bidard, Alain Livartowski, Delphine Guillemot, Odette Mariani, Camille Benoist, Sylvain Baulande, Gaëlle Pierron, Christophe Le Tourneau, Sarah Watson, Julien Vibert, Olivier Delattre, Nadège Gruel, Unité de génétique et biologie des cancers (U830), Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Curie [Paris], Cancer et génome: Bioinformatique, biostatistiques et épidémiologie d'un système complexe, MINES ParisTech - École nationale supérieure des mines de Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre d'Investigation Clinique en Biotherapie des cancers (CIC 1428 , CBT 507 ), Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Versailles Saint-Quentin-en-Yvelines - UFR Sciences de la santé Simone Veil (UVSQ Santé), and Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)

Subjects
Adult, Male, Oncology, medicine.medical_specialty, [SDV]Life Sciences [q-bio], Pathology and Forensic Medicine, 03 medical and health sciences, Deep Learning, 0302 clinical medicine, Internal medicine, Biomarkers, Tumor, medicine, Humans, Prospective Studies, RNA-Seq, Aged, Retrospective Studies, 030304 developmental biology, Interpretability, Aged, 80 and over, 0303 health sciences, business.industry, Deep learning, Cancer, Retrospective cohort study, Middle Aged, medicine.disease, Primary tumor, Autoencoder, Data Accuracy, 3. Good health, Identification (information), 030220 oncology & carcinogenesis, Unknown primary, Neoplasms, Unknown Primary, Molecular Medicine, Female, Artificial intelligence, Gene Fusion, Transcriptome, business
Abstract

International audience; Cancers of unknown primary (CUP) are metastatic cancers for which the primary tumor is not found despite thorough diagnostic investigations. Multiple molecular assays have been proposed to identify the tissue of origin (TOO) and inform clinical care; however, none has been able to combine accuracy, interpretability, and easy access for routine use. We developed a classifier tool based on the training of a variational autoencoder to predict tissue of origin based on RNA-sequencing data. We used as training data 20,918 samples corresponding to 94 different categories, including 39 cancer types and 55 normal tissues. The TransCUPtomics classifier was applied to a retrospective cohort of 37 CUP patients and 11 prospective patients. TransCUPtomics exhibited an overall accuracy of 96% on reference data for TOO prediction. The TOO could be identified in 38 (79%) of 48 CUP patients. Eight of 11 prospective CUP patients (73%) could receive first-line therapy guided by TransCUPtomics prediction, with responses observed in most patients. The variational autoencoder added further utility by enabling prediction interpretability, and diagnostic predictions could be matched to detection of gene fusions and expressed variants. TransCUPtomics confidently predicted TOO for CUP and enabled tailored treatments leading to significant clinical responses. The interpretability of our approach is a powerful addition to improve the management of CUP patients. Copyright

Published
2021
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29. Stratégie diagnostique des sarcomes des tissus mous de l’enfant et adolescent

Author

Gaëlle Pierron, Arnaud Gauthier, Benoit Dumont, Hervé Brisse, Charlotte Collignon, Aurélia Alimi, Camille Cordero, Daniel Orbach, Aphaia Roussel, Lauriane Lemelle, Liesbeth Cardoen, Lucie Rouffiange, Institut Curie [Paris], Hôpital Robert Debré, and CCSD, Accord Elsevier

Subjects
0301 basic medicine, Cancer Research, medicine.medical_specialty, Percutaneous, Sarcomes des parties molles, Pediatric cancer, Diagnostic guidelines, Pédiatrie, [SDV]Life Sciences [q-bio], Disease, Adolescents, 03 medical and health sciences, 0302 clinical medicine, Biopsy, medicine, Soft tissue mass, Radiology, Nuclear Medicine and imaging, Diagnostic, Soft part sarcomas, medicine.diagnostic_test, business.industry, Cancer, Soft tissue, Hematology, General Medicine, medicine.disease, Predictive value, 3. Good health, [SDV] Life Sciences [q-bio], 030104 developmental biology, Oncology, 030220 oncology & carcinogenesis, Recommandations de prise en charge, Surgical biopsy, Radiology, business
Abstract

International audience; Soft tissue sarcomas in children are rare tumor, representing around 6 to 7% of children cancer. They spread mostly sporadically (90%) and therefore are rarely associated to an underlying constitutional genetic disease (10%). About half of those sarcomas are rhabdomyosarcomas and the others are a very heterogenous histologic group with various bio-pathologies and prognosis. Clinical presentation is mainly a soft tissue lump often difficult to distinguish from more frequent benign causes (malformative, infectious, benign, or pseudotumor). Inappropriate initial diagnosis work-up has a strong impact on soft tissue sarcomas' prognosis. Adapted complementary investigations (first ultrasound and MRI) are important to compile arguments for a malign origin and to indicate a biopsy. However, predictive value of imaging exams still remains imperfect, and histological analysis by percutaneous image-guided biopsy and sometimes by surgical biopsy is often necessary. Authors realize an update on optimal diagnostic pathway including molecular tests in presence of a soft tissue mass in a child.

Published
2020
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30. A subset of epithelioid and spindle cell rhabdomyosarcomas is associated with TFCP2 fusions and common ALK upregulation

Author

Benjamin Bonhomme, Cleofe Romagosa, Gaëlle Pierron, Anne Moreau, Jean Michel Coindre, Arjen H.G. Cleven, Irma Ramos-Oliver, François Le Loarer, Sophie Le Guellec, Corinne Bouvier, Sébastien Salas, Anne Gomez-Brouchet, Virginie Audard, Marie Pierre Castex, Frédérique Larousserie, Anand Sherwood, Anne-Marie Cleton-Jansen, Dilara C. Savci-Heijink, Camille Laurent, Franck Tirode, Judith V.M.G. Bovée, Daniel Pissaloux, Jessica Baud, Antoine Giraud, Herman M. Kroon, Institut Bergonié [Bordeaux], UNICANCER, Université de Bordeaux (UB), Actions for OnCogenesis understanding and Target Identification in ONcology (ACTION), UNICANCER-UNICANCER-Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale (INSERM), Leiden University Medical Center (LUMC), Département de pathologie [CHU La Timone, Marseille], Hôpital de la Timone [CHU - APHM] (TIMONE), Département d'oncologie pédiatrique [CHU Toulouse], CHU Toulouse [Toulouse], Vall d'Hebron University Hospital [Barcelona], Service de Pathologie [CHU Nantes], Centre hospitalier universitaire de Nantes (CHU Nantes), Service d’Oncologie Médicale [Hôpital de la Timone - APHM], Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Institut Universitaire du Cancer de Toulouse - Oncopole (IUCT Oncopole - UMR 1037), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Pathologie [AP-HP Hôpital Cochin], Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre d'Investigation Clinique - Epidemiologie Clinique / Essais Cliniques Bordeaux, Institut National de la Santé et de la Recherche Médicale (INSERM), Academic Medical Center - Academisch Medisch Centrum [Amsterdam] (AMC), University of Amsterdam [Amsterdam] (UvA), Centre Léon Bérard [Lyon], Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Département de Biologie des Tumeurs, Institut Curie [Paris], Department of Conservative Dentistry and Endodontics [CSI College of Dental Sciences, Madurai, India], Sercice Hématologie, immunologie et oncologie pédiatrique [CHU Toulouse], Pôle Enfants [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and TIRODE, Franck

Subjects
Male, 0301 basic medicine, Pathology, [SDV.BBM.BM] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Fusion gene, 0302 clinical medicine, CDKN2A, Rhabdomyosarcoma, Anaplastic Lymphoma Kinase, Prospective Studies, Child, Exome, Aged, 80 and over, medicine.diagnostic_test, Epithelioid Cells, Soft tissue, Middle Aged, Prognosis, Immunohistochemistry, Up-Regulation, 3. Good health, DNA-Binding Proteins, Phenotype, Molecular Diagnostic Techniques, 030220 oncology & carcinogenesis, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Female, Sarcoma, Gene Fusion, Adult, medicine.medical_specialty, Adolescent, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, Pathology and Forensic Medicine, Young Adult, 03 medical and health sciences, [SDV.CAN] Life Sciences [q-bio]/Cancer, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Biomarkers, Tumor, medicine, Humans, Genetic Predisposition to Disease, Craniofacial, Retrospective Studies, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, medicine.disease, 030104 developmental biology, Transcription Factors, Fluorescence in situ hybridization
Abstract

International audience; Rhabdomyosarcomas with TFCP2 fusions represent an emerging subtype of tumors, initially discovered by RNA-sequencing. We report herein the clinicopathological, transcriptional, and genomic features of a series of 14 cases. Cases were retrospectively and prospectively recruited and studied by immunohistochemistry (MYF4, MYOD1, S100, AE1/E3, ALK), fluorescence in situ hybridization with TFCP2 break-apart probe (n = 10/14), array-comparative genomic hybridization (Agilent), whole RNA-sequencing (Truseq Exome, Illumina), or anchored multiplex PCR-based targeted next-generation sequencing (Archer® FusionPlex® Sarcoma kit). Patient's age ranged between 11 and 86 years, including 5 pediatric cases. Tumors were located in the bone (n = 12/14) and soft tissue (n = 2/14). Most bone tumors invaded surrounding soft tissue. Craniofacial bones were over-represented (n = 8/12). Median survival was 8 months and five patients are currently alive with a median follow-up of 20 months. Most tumors displayed a mixed spindle cell and epithelioid pattern with frequent vesicular nuclei. All tumors expressed keratins and showed a rhabdomyogenic phenotype (defined as expression of MYF4 and/or MYOD1). ALK was overexpressed in all but three cases without underlying ALK fusion on break-apart FISH (n = 5) nor next-generation sequencing (n = 14). ALK upregulation was frequently associated with an internal deletion at genomic level. TFCP2 was fused in 5' either to EWSR1 (n = 6) or FUS (n = 8). EWSR1 was involved in both soft tissue cases. FISH with TFCP2 break-apart probe was positive in all tested cases (n = 8), including one case with unbalanced signal. On array-CGH, all tested tumors displayed complex genetic profiles with genomic indexes ranging from 13 to 107.55 and recurrent CDKN2A deletions. FET-TFCP2 rhabdomyosarcomas clustered together and distinctly from other rhabdomyosarcomas subgroups. Altogether, our data confirm and expand the spectrum of the new family of FET-TFCP2 rhabdomyosarcomas, which are associated with a predilection for the craniofacial bones, an aggressive course, and recurrent pathological features. Their association with ALK overexpression might represent a therapeutic vulnerability.

Published
2020
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31. Low-frequency variation near common germline susceptibility loci are associated with risk of Ewing sarcoma

Author

Sakina Zaidi, Didier Surdez, Javier Alonso, Gregory T. Armstrong, Gaëlle Pierron, Nadège Corradini, Nathaniel Rothman, Markus Metzler, Valérie Laurence, Kathleen Wyatt, Kristine Jones, Heinrich Kovar, Brian D. Carter, Eve Lapouble, Weiyin Zhou, Leslie L. Robison, Rebeca Alba Rubio, Thomas Kirchner, Wendy M. Leisenring, David G. Cox, Manuela Krumbholz, Lisa Mirabello, Smita Bhatia, Olivier Delattre, Casey L. Dagnall, Lindsay M. Morton, Neal D. Freedman, Stéphanie Reynaud, Stelly Ballet, Udo Kontny, Thomas Meitinger, Sandrine Grossetête-Lalami, Robert N. Hoover, Shu-Hong Lin, Ana Patiño-García, Joshua N. Sampson, Margaret A. Tucker, Laurie Burdett, Olivier Mirabeau, Perrine Marec Bérard, Mitchell J. Machiela, Jeremy A. Miller, Stephen J. Chanock, Thomas G. P. Grunewald, Jennifer Kriebel, Jean Michon, Meredith Yeager, Uta Dirksen, Wolfgang Hartmann, Andreas E. Kulozik, Javed Khan, Konstantin Strauch, Franck Tirode, Eric Karlins, Anna González-Neira, Michelle Manning, NIH - National Cancer Institute (NCI) (Estados Unidos), Agence Nationale de la Recherche (Francia), Unión Europea. Comisión Europea. 7 Programa Marco, Deutsche Forschungsgemeinschaft (Alemania), Instituto de Salud Carlos III, Comunidad Foral de Navarra (España), National Cancer Institute (United States), Agence Nationale de la Recherche (France), 7º Programa Marco - Comisión Europea, Deutsche Forschungsgemeinschaft, Instituto de Salud Carlos III - ISCIII, and Gobierno de Navarra

Subjects
0301 basic medicine, Heredity, Epidemiology, Medizin, Genome-wide association study, Linkage Disequilibrium, 0302 clinical medicine, Medizinische Fakultät, Medicine and Health Sciences, Odds Ratio, Genetics, Multidisciplinary, Cancer Risk Factors, Prostate Cancer, Prostate Diseases, Sarcoma, Genomics, Genetic Mapping, Oncology, 030220 oncology & carcinogenesis, Medicine, Research Article, Urology, Science, Ewing Sarcoma, Locus (genetics), Variant Genotypes, Sarcoma, Ewing, Biology, Polymorphism, Single Nucleotide, 03 medical and health sciences, Genetic variation, Genome-Wide Association Studies, Humans, Genetic Predisposition to Disease, ddc:610, Allele, Alleles, Genetic association, Colorectal Cancer, Haplotype, Cancers and Neoplasms, Biology and Life Sciences, Computational Biology, Genetic Variation, Human Genetics, Genome Analysis, Minor allele frequency, Genitourinary Tract Tumors, 030104 developmental biology, Germ Cells, Genetic Loci, Medical Risk Factors, Chromosome 20, Genome-Wide Association Study
Abstract

PLOS ONE 15(9), e0237792 (2020). doi:10.1371/journal.pone.0237792, Published by PLOS, San Francisco, California, US

Published
2020
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32. VOPP1 promotes breast tumorigenesis by interacting with the tumor suppressor WWOX

Author

Rosette Lidereau, François Lallemand, Karim Taouis, Jacques Camonis, Laetitia Fuhrmann, Zakia Tariq, Gaëlle Pierron, Etienne Formstecher, Anne Vincent-Salomon, Ivan Bièche, Khadija Ait Rais, Ambre Petitalot, Paula Azorin, Florian Bonin, Nadège Bouteille, Sebastien Nola, Sophie Vacher, Sandrine Tury, Keltouma Driouch, Pharmacogenomics Unit [Paris], Department of Genetics [Paris], Institut Curie [Paris]-Institut Curie [Paris], Somatic Genetics Unit [Paris], Pathology [Paris], Department of Tumor Biology [Paris], Hybrigenics Services [Paris], Unité de génétique et biologie des cancers (U830), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), This work was supported by La Ligue Contre le Cancer (N°2FI10655MMGF), the GEFLUC, and a GenHomme Network Grant (02490-6088) to Hybrigenics and Institut Curie. F. Bonin and Z. Tariq are supported by a grant from the Breast Cancer Research Foundation (BCRF, USA, BCRF-16-096)., and Bodescot, Myriam

Subjects
0301 basic medicine, WWOX, Physiology, Regulator, Breast Neoplasms, [SDV.CAN]Life Sciences [q-bio]/Cancer, Plant Science, Biology, medicine.disease_cause, General Biochemistry, Genetics and Molecular Biology, law.invention, 03 medical and health sciences, 0302 clinical medicine, Breast cancer, [SDV.CAN] Life Sciences [q-bio]/Cancer, Structural Biology, law, Cell Line, Tumor, medicine, Humans, Breast tumors, lcsh:QH301-705.5, Ecology, Evolution, Behavior and Systematics, VOPP1, Oncogene, Tumor Suppressor Proteins, Cancer, [SDV.BBM.MN]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular Networks [q-bio.MN], Cell Biology, medicine.disease, 3. Good health, Cell Transformation, Neoplastic, 030104 developmental biology, WW Domain-Containing Oxidoreductase, [SDV.BBM.MN] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular Networks [q-bio.MN], lcsh:Biology (General), Apoptosis, 030220 oncology & carcinogenesis, Cancer research, Suppressor, Female, General Agricultural and Biological Sciences, Carcinogenesis, Transcription Factors, Research Article, Developmental Biology, Biotechnology
Abstract

Background The WW domain-containing oxidoreductase (WWOX) gene, frequently altered in breast cancer, encodes a tumor suppressor whose function is mediated through its interactions with cancer-related proteins, such as the pro-apoptotic protein p73α. Results To better understand the involvement of WWOX in breast tumorigenesis, we performed a yeast two-hybrid screen and co-immunoprecipitation assays to identify novel partners of this protein. We characterized the vesicular overexpressed in cancer pro-survival protein 1 (VOPP1) as a new regulator of WWOX. In breast cancer cells, VOPP1 sequestrates WWOX in lysosomes, impairs its ability to associate with p73α, and inhibits WWOX-dependent apoptosis. Overexpressed VOPP1 potentiates cellular transformation and enhances the growth of transplanted tumors in vivo. VOPP1 is overexpressed in breast tumors, especially in tumors that retain WWOX. Moreover, increased expression of VOPP1 is associated with reduced survival of patients with WWOX-positive, but not with WWOX-negative, tumors. Conclusions These findings emphasize the importance of the sequestration of WWOX by VOPP1 in addition to WWOX loss in breast tumors and define VOPP1 as a novel oncogene promoting breast carcinogenesis by inhibiting the anti-tumoral effect of WWOX. Electronic supplementary material The online version of this article (10.1186/s12915-018-0576-6) contains supplementary material, which is available to authorized users.

Published
2018
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33. Brain tumor with an ATXN1-NUTM1 fusion gene expands the histologic spectrum of NUTM1-rearranged neoplasia

Author

Charlotte Dubucs, Aurore Siegfried, Emmanuelle Uro-Coste, Gaëlle Pierron, I. Catalaa, Marion Gambart, Julien Masliah-Planchon, Badreddine Mohand-Oumoussa, Franck Tirode, Sarah Péricart, Franck Bourdeaut, Franck-Emmanuel Roux, Delphine Larrieu-Ciron, Yvan Nicaise, Département de Pathologie [CHU Toulouse], CHU Toulouse [Toulouse], Centre de Recherches en Cancérologie de Toulouse (CRCT), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Unité de génétique et biologie des cancers (U830), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie-Institut National de la Santé et de la Recherche Médicale (INSERM), Unité de Génétique Somatique, Institut Curie, Plateforme Post-génomique de la Pitié-Salpêtrière (P3S), UMS omique (OMIQUE), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Centre de Recherche en Cancérologie de Lyon (CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), TIRODE, Franck, Service Anatomie et cytologie pathologiques [CHU Toulouse], Pôle Biologie [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Curie [Paris], Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), and Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)

Subjects
medicine.medical_specialty, Pathology, Neurology, CIC-ATXN1-ATXN1L axis, DNA methylation-based classification, Central nervous system, Brain tumor, Oncogenic gene fusions, CIC-ATXN1-ATXN1L axis, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, [SDV.BBM.BM] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, lcsh:RC346-429, Pathology and Forensic Medicine, Fusion gene, 03 medical and health sciences, Cellular and Molecular Neuroscience, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], ATXN1, medicine, Letter to the Editor, lcsh:Neurology. Diseases of the nervous system, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, 0303 health sciences, NUTM1-rearranged neoplasia, RNA sequencing, NUTM1, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, medicine.disease, Oncogenic gene fusions, medicine.anatomical_structure, 030220 oncology & carcinogenesis, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Neurology (clinical)
Abstract

International audience

Published
2019
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34. Genome-wide association study identifies multiple new loci associated with Ewing sarcoma susceptibility

Author

Ana Patiño-García, Thomas G. P. Grunewald, David G. Cox, Lindsay M. Morton, Michelle Manning, Sandrine Grossetête-Lalami, Gaëlle Pierron, Nadège Corradini, Stephen J. Chanock, Kathleen Wyatt, Udo Kontny, Gregory T. Armstrong, Jean Michon, Sakina Zaidi, Didier Surdez, Wolfgang Hartmann, Heinrich Kovar, Olivier Delattre, Jennifer Kriebel, Nathalie Gaspar, Perrine Marec Bérard, Valérie Laurence, Casey L. Dagnall, Thomas Kirchner, Stéphanie Reynaud, Uta Dirksen, Nathaniel Rothman, Konstantin Strauch, Margaret A. Tucker, Lisa Mirabello, Smita Bhatia, Markus Metzler, Laurie Burdett, Neal D. Freedman, Rebeca Alba Rubio, Franck Tirode, Andreas E. Kulozik, Meredith Yeager, Kristine Jones, Javier Alonso, Stelly Ballet, Olivier Mirabeau, Eve Lapouble, Robert N. Hoover, Weiyin Zhou, Wendy M. Leisenring, Leslie L. Robison, Piero Picci, Javed Khan, Thomas Meitinger, Anna González-Neira, Eric Karlins, Mitchell J. Machiela, Unión Europea, TIRODE, Franck, Clinical Genetics Branch, Division of Cancer Epidemiology & Genetics, National Institutes of Health [Bethesda] (NIH)-National Cancer Institute [Bethesda] (NCI-NIH), National Institutes of Health [Bethesda] (NIH), Laboratory for Pediatric Sarcoma Biology [Munich, Germany], Ludwig-Maximilian-Universität München Pathologisches Institut [Germany], German Cancer Consortium [Heidelberg] (DKTK), German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ), Unité de Génétique Somatique, Institut Curie [Paris], Unité de génétique et biologie des cancers (U830), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Département d'Oncologie Médicale [Institut Curie, Paris], Cancer Genomics Research Laboratory, Division of Cancer Epidemiology and Genetics, Frederick National Laboratory for Cancer Research (FNLCR), Unité de Génétique Somatique [Institut Curie, Paris], Children’s Cancer Research Institute [Vienna, Austria], Département de cancérologie de l'enfant et de l'adolescent [Gustave Roussy], Institut Gustave Roussy (IGR), Division of Pediatric Hematology, Oncology and Stem Cell Transplantation [Aechen, Germany], Genotyping Unit (CeGen), Human Cancer Genetics Programme, Spanish National Cancer Research Centre, Istituto Ortopedico Rizzoli [Bologna, Italy], Unidad de Tumores Sólidos Infantiles – Unidad de Investigación Biomédica [Madrid, Spain], Instituto de Salud Carlos III [Madrid] (ISC)- Instituto de Investigación en Enfermedades Raras (IIER), Center for Applied Medical Research [Plamplona] (CIMA), Universidad de Navarra [Pamplona] (UNAV), Institut d'hématologie et d'oncologie pédiatrique [CHU - HCL] (IHOPe), Hospices Civils de Lyon (HCL), Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Clinical Genetics Branch, National Cancer Institute [Bethesda] (NCI-NIH), National Institutes of Health [Bethesda] (NIH)-National Institutes of Health [Bethesda] (NIH), Department of Epidemiology and Cancer Control [Memphis, TN, USA], Cancer Prevention and Clinical Statistics Program [Seattle, WA, USA], Institute for Cancer Outcomes and Survivorship [Birmingham, AL, USA], University Children's Hospital of Heidelberg [Heidelberg, Germany], Research Unit of Molecular Biology [Neuherberg, Germany], Institute of Epidemiology [Neuherberg] (EPI), German Research Center for Environmental Health - Helmholtz Center München (GmbH), German Center for Diabetes Diseases [Neuherberg, Germany] (DZD), Institute of Human Genetics [Neuherberg] (IHG), Helmholtz Zentrum München = German Research Center for Environmental Health, Institute of Human Genetics [Munich, Germany], Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM), Pediatric Oncology and Hematology [Erlangen, Germany], University Hospital Erlangen = Uniklinikum Erlangen, Gerhard-Domagk-Institute of Pathology, Westfälische Wilhelms-Universität Münster = University of Münster (WWU), Institute of Genetic Epidemiology [Neuherberg, Germany], Chair of Genetic Epidemiology [Munich, Germany] (IBE), Institute of Pathology [Munich, Germany], University Children's Hospital of Essen [Essen, Germany], This work was supported by the Intramural Research Program of the U.S. NationalCancer Institute and the Intramural Research Program of the American Cancer Society.This work was supported by grants from the Institut Curie, the Inserm, the LigueNationale Contre le Cancer (Equipe labellisée, Carte d’Identité des Tumeurs programand Recherche Epidémiologique 2009 program), the ANR-10-EQPX-03 from the AgenceNationale de la Recherche, the European PROVABES (ERA-649 NET TRANSCAN JTC2011), and ASSET (FP7-HEALTH-2010-259348) projects. This research was supportedby FP7 grant 'EURO EWING Consortium' No. 602856 and the following associations:Courir pour Mathieu, Dans les pas du Géant, Les Bagouzamanon, Enfants et Santé, M lavie avec Lisa, Lulu et les petites bouilles de lune, les Amis de Claire, l’Etoile de Martin andthe Société Française de lutte contre les Cancers et les leucémies de l’Enfant et del’adolescent. The laboratory of T. G. P. Grünewald is supported by grants from the‘Verein zur Förderung von Wissenschaft und Forschung an der Medizinischen Fakultätder LMU München (WiFoMed)’, by LMU Munich’s Institutional Strategy LMU excellentwithin the framework of the German Excellence Initiative, the ‘Mehr LEBEN für krebskranke Kinder—Bettina-Bräu-Stiftung’, the Walter Schulz Foundation, the WilhelmSander-Foundation (2016.167.1), and by the German Cancer Aid (DKH-111886 andDKH-70112257). D. Surdez is supported by SiRIC (Grant « INCa-DGOS-4654). Wethank the following clinicians for providing samples used in this study: C. Alenda, F.Almazán, D. Ansoborlo, L. Aymerich, L. Benboukbher, C. Beléndez, C. Berger, C. Bergeron, P. Biron, J.Y. Blay, E. Bompas, H. Bonnefoi, P. Boutard, B. Bui-Nguyen, D.Chauveaux, C. Calvo, A. Carboné, C. Clement, T. Contra, N. Corradini, A.S. Defachelles,V. Gandemer-Delignieres, A. Deville, A. Echevarria, J. Fayette, M. Fraga, D. Frappaz, J.L.Fuster, P. García-Miguel, J.C. Gentet, P. Kerbrat, V. Laithier, V. Laurence, P. Leblond, O.Lejars, R. López-Almaraz, B. López-Ibor, P. Lutz, J.F. Mallet, L. Mansuy, P. Marec Bérard,G. Margueritte, A. Marie Cardine, C. Melero, L. Mignot, F. Millot, O. Minckes, G.Margueritte, C. Mata, M.E. Mateos, M. Melo, C. Moscardó, M. Munzer, B. Narciso, A.Navajas, D. Orbach, C. Oudot, H. Pacquement, C. Paillard, Y. Perel, T. Philip, C. Piguet,M.I. Pintor, D. Plantaz, E. Plouvier, S. Ramirez-Del-Villar, I. Ray-Coquard, Y. Reguerre,M. Rios, P. Rohrlich, H. Rubie, A. Sastre, G. Schleiermacher, C. Schmitt, P. Schneider, L.Sierrasesumaga, C. Soler, N. Sirvent, S. Taque, E. Thebaud, A. Thyss, R. Tichit, J.J. Uriz, J.P. Vannier, F. Watelle-Pichon. This work was supported by the Instituto de SaludCarlos III (PI16CIII/00026) and the Asociación Pablo Ugarte, Fundación Sonrisa deAlex, ASION-La Hucha de Tomás, Sociedad Española de Hematología y OncologíaPediátricas. The Childhood Cancer Survivor Study is supported by the NationalCancer Institute (CA55727, G.T. Armstrong, Principal Investigator), with funding forgenotyping from the Intramural Research Program of the National Institutes ofHealth, National Cancer Institute. The KORA study was initiated and financed by theHelmholtz Zentrum München—German Research Center for Environmental Health,which is funded by the German Federal Ministry of Education and Research (BMBF) andby the State of Bavaria. Furthermore, KORA research was supported within the MunichCenter of Health Sciences (MC-Health), Ludwig-Maximilians-Universität, as part ofLMUinnovativ, Helmholtz-Zentrum München (HZM), University Hospital Erlangen [Germany], Westfälische Wilhelms-Universität Münster (WWU), Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5), and Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
0301 basic medicine, Candidate gene, Oncogene Proteins, Fusion, Medizin, General Physics and Astronomy, Genome-wide association study, Cell Cycle Proteins, [SDV.BBM.BM] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, lcsh:Science, Genetics, Multidisciplinary, Nuclear Proteins, 3. Good health, DNA-Binding Proteins, Gene Expression Regulation, Neoplastic, Homeobox Protein Nkx-2.2, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Quality Control, Risk, Genotype, Science, European Continental Ancestry Group, Quantitative Trait Loci, Single-nucleotide polymorphism, Locus (genetics), [SDV.CAN]Life Sciences [q-bio]/Cancer, Sarcoma, Ewing, Biology, Quantitative trait locus, Polymorphism, Single Nucleotide, Article, White People, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, [SDV.CAN] Life Sciences [q-bio]/Cancer, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Humans, Genetic Predisposition to Disease, Allele, Alleles, Cell Proliferation, Homeodomain Proteins, Proto-Oncogene Protein c-fli-1, Gene Expression Profiling, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, General Chemistry, Zebrafish Proteins, Pediatric cancer, 030104 developmental biology, Expression quantitative trait loci, lcsh:Q, RNA-Binding Protein EWS, Transcription Factors, Genome-Wide Association Study
Abstract

Ewing sarcoma (EWS) is a pediatric cancer characterized by the EWSR1-FLI1 fusion. We performed a genome-wide association study of 733 EWS cases and 1346 unaffected individuals of European ancestry. Our study replicates previously reported susceptibility loci at 1p36.22, 10q21.3 and 15q15.1, and identifies new loci at 6p25.1, 20p11.22 and 20p11.23. Effect estimates exhibit odds ratios in excess of 1.7, which is high for cancer GWAS, and striking in light of the rarity of EWS cases in familial cancer syndromes. Expression quantitative trait locus (eQTL) analyses identify candidate genes at 6p25.1 (RREB1) and 20p11.23 (KIZ). The 20p11.22 locus is near NKX2-2, a highly overexpressed gene in EWS. Interestingly, most loci reside near GGAA repeat sequences and may disrupt binding of the EWSR1-FLI1 fusion protein. The high locus to case discovery ratio from 733 EWS cases suggests a genetic architecture in which moderate risk SNPs constitute a significant fraction of risk., Ewing sarcoma (EWS) is a rare pediatric bone cancer typically involving the EWSR1-FLI1 fusion. Here the authors perform a genome-wide association study and report three new EWS risk loci that reside near GGAA repeat sequences, and identify candidate genes (RREB1 and KIZ) from eQTL analysis.

Published
2018
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35. Genomic complexity in pediatric synovial sarcomas (Synobio study): the European pediatric soft tissue sarcoma group (EpSSG) experience

Author

Camille Chakiba, Gianni Bisogno, Daniel Orbach, Veronique Minard-Colin, Véronique Mosseri, Andrea Ferrari, Anna Kelsey, Frédéric Chibon, Daniel Pissaloux, Bernadette Brennan, Gian Luca De Salvo, Dominique Ranchère-Vince, Gaëlle Pierron, and Nadège Corradini

Subjects
0301 basic medicine, Adult, Male, Cancer Research, medicine.medical_specialty, Pediatric Soft Tissue Sarcoma, Multivariate analysis, Adolescent, EpSSG, comparative genomic hybridization, genomic index, synovial sarcoma, Gastroenterology, 03 medical and health sciences, Sarcoma, Synovial, Young Adult, 0302 clinical medicine, Internal medicine, medicine, Humans, Radiology, Nuclear Medicine and imaging, Young adult, Neoplasm Metastasis, Child, Original Research, Cancer Biology, Neoplasm Staging, Comparative Genomic Hybridization, Tumor size, business.industry, Age Factors, Genetic Variation, Genomics, medicine.disease, Synovial sarcoma, Europe, 030104 developmental biology, Oncology, 030220 oncology & carcinogenesis, Relative risk, Child, Preschool, Cohort, Female, Neoplasm Grading, business, Comparative genomic hybridization
Abstract

A genomic index (GI) tool using array comparative genomic hybridization (aCGH) on tumor cells has emerged as independent prognostic factor associated with the risk of metastatic relapse in synovial sarcoma (SS). The aim was to assess GI in pediatric patients with SS, to determine its value as a prognostic factor. All pediatric/adolescent/young adults’ (

Published
2018

36. Patient Derived Xenografts (PDX) Models as an Avatar to Assess Personalized Therapy Options in Uveal Melanoma: A Feasibility Study

Author

Fariba Nemati, Leanne de Koning, David Gentien, Franck Assayag, Emilie Henry, Khadija Ait Rais, Gaelle Pierron, Odette Mariani, Michèle Nijnikoff, Gabriel Champenois, André Nicolas, Didier Meseure, Sophie Gardrat, Nicolas Servant, Philippe Hupé, Maud Kamal, Christophe Le Tourneau, Sophie Piperno-Neumann, Manuel Rodrigues, Sergio Roman-Roman, Didier Decaudin, Pascale Mariani, and Nathalie Cassoux

Subjects
patient-derived xenografts (PDXs), uveal melanoma, avatar, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Uveal melanoma is the most common primary intraocular malignancy in adults. Up to 50% of UM patients develop metastatic disease, usually in the liver. When metastatic, the prognosis is poor, and few treatment options exist. Here, we investigated the feasibility of establishing patient-derived xenografts (PDXs) from a patient’s tumor in order to screen for therapies that the patient could benefit from. Samples obtained from 29 primary tumors and liver metastases of uveal melanoma were grafted into SCID mice. PDX models were successfully established for 35% of primary patient tumors and 67% of liver metastases. The tumor take rate was proportional to the risk of metastases. PDXs showed the same morphology, the same GNAQ/11, BAP1, and SF3B1 mutations, and the same chromosome 3 and 8q status as the corresponding patient samples. Six PDX models were challenged with two compounds for 4 weeks. We show that, for 31% of patients with high or intermediate risk of metastasis, the timing to obtain efficacy results on PDX models derived from their primary tumors was compatible with the selection of the therapy to treat the patient after relapse. PDXs could thus be a valid tool (“avatar”) to select the best personalized therapy for one third of patients that are most at risk of relapse.

Published
2023
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37. Imaging and multi-omics datasets converge to define different neural progenitor origins for ATRT-SHH subgroups

Author

María-Jesús Lobón-Iglesias, Mamy Andrianteranagna, Zhi-Yan Han, Céline Chauvin, Julien Masliah-Planchon, Valeria Manriquez, Arnault Tauziede-Espariat, Sandrina Turczynski, Rachida Bouarich-Bourimi, Magali Frah, Christelle Dufour, Thomas Blauwblomme, Liesbeth Cardoen, Gaelle Pierron, Laetitia Maillot, Delphine Guillemot, Stéphanie Reynaud, Christine Bourneix, Célio Pouponnot, Didier Surdez, Mylene Bohec, Sylvain Baulande, Olivier Delattre, Eliane Piaggio, Olivier Ayrault, Joshua J. Waterfall, Nicolas Servant, Kevin Beccaria, Volodia Dangouloff-Ros, and Franck Bourdeaut

Subjects
Science
Abstract

Abstract Atypical teratoid rhabdoid tumors (ATRT) are divided into MYC, TYR and SHH subgroups, suggesting diverse lineages of origin. Here, we investigate the imaging of human ATRT at diagnosis and the precise anatomic origin of brain tumors in the Rosa26-CreERT2::Smarcb1flox/flox model. This cross-species analysis points to an extra-cerebral origin for MYC tumors. Additionally, we clearly distinguish SHH ATRT emerging from the cerebellar anterior lobe (CAL) from those emerging from the basal ganglia (BG) and intra-ventricular (IV) regions. Molecular characteristics point to the midbrain-hindbrain boundary as the origin of CAL SHH ATRT, and to the ganglionic eminence as the origin of BG/IV SHH ATRT. Single-cell RNA sequencing on SHH ATRT supports these hypotheses. Trajectory analyses suggest that SMARCB1 loss induces a de-differentiation process mediated by repressors of the neuronal program such as REST, ID and the NOTCH pathway.

Published
2023
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38. Sequential genomic analysis using a multisample/multiplatform approach to better define rhabdomyosarcoma progression and relapse

Author

Henry de Traux de Wardin, Josephine K. Dermawan, Marie-Sophie Merlin, Leonard H. Wexler, Daniel Orbach, Fabio Vanoli, Gudrun Schleiermacher, Birgit Geoerger, Stelly Ballet, Delphine Guillemot, Eléonore Frouin, Stacy Cyrille, Olivier Delattre, Gaelle Pierron, and Cristina R. Antonescu

Subjects
Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Abstract The genomic spectrum of rhabdomyosarcoma (RMS) progression from primary to relapse is not fully understood. In this pilot study, we explore the sensitivity of various targeted and whole-genome NGS platforms in order to assess the best genomic approach of using liquid biopsy in future prospective clinical trials. Moreover, we investigate 35 paired primary/relapsed RMS from two contributing institutions, 18 fusion-positive (FP-RMS) and 17 fusion-negative RMS (FN-RMS) by either targeted DNA or whole exome sequencing (WES). In 10 cases, circulating tumor DNA (ctDNA) from multiple timepoints through clinical care and progression was analyzed for feasibility of liquid biopsy in monitoring treatment response/relapse. ctDNA alterations were evaluated using a targeted 36-gene custom RMS panel at high coverage for single-nucleotide variation and fusion detection, and a shallow whole-genome sequencing for copy number variation. FP-RMS have a stable genome with relapse, with common secondary alterations CDKN2A/B, MYCN, and CDK4 present at diagnosis and impacting survival. FP-RMS lacking major secondary events at baseline acquire recurrent MYCN and AKT1 alterations. FN-RMS acquire a higher number of new alterations, most commonly SMARCA2 missense mutations. ctDNA analyses detect pathognomonic variants in all RMS patients within our collection at diagnosis, regardless of type of alterations, and confirmed at relapse in 86% of FP-RMS and 100% FN-RMS. Moreover, a higher number of fusion reads is detected with increased disease burden and at relapse in patients following a fatal outcome. These results underscore patterns of tumor progression and provide rationale for using liquid biopsy to monitor treatment response.

Published
2023
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39. A biobank of pediatric patient-derived-xenograft models in cancer precision medicine trial MAPPYACTS for relapsed and refractory tumors

Author

Maria Eugénia Marques Da Costa, Sakina Zaidi, Jean-Yves Scoazec, Robin Droit, Wan Ching Lim, Antonin Marchais, Jerome Salmon, Sarah Cherkaoui, Raphael J. Morscher, Anouchka Laurent, Sébastien Malinge, Thomas Mercher, Séverine Tabone-Eglinger, Isabelle Goddard, Francoise Pflumio, Julien Calvo, Francoise Redini, Natacha Entz-Werlé, Aroa Soriano, Alberto Villanueva, Stefano Cairo, Pascal Chastagner, Massimo Moro, Cormac Owens, Michela Casanova, Raquel Hladun-Alvaro, Pablo Berlanga, Estelle Daudigeos-Dubus, Philippe Dessen, Laurence Zitvogel, Ludovic Lacroix, Gaelle Pierron, Olivier Delattre, Gudrun Schleiermacher, Didier Surdez, and Birgit Geoerger

Subjects
Biology (General), QH301-705.5
Abstract

Abstract Pediatric patients with recurrent and refractory cancers are in most need for new treatments. This study developed patient-derived-xenograft (PDX) models within the European MAPPYACTS cancer precision medicine trial (NCT02613962). To date, 131 PDX models were established following heterotopical and/or orthotopical implantation in immunocompromised mice: 76 sarcomas, 25 other solid tumors, 12 central nervous system tumors, 15 acute leukemias, and 3 lymphomas. PDX establishment rate was 43%. Histology, whole exome and RNA sequencing revealed a high concordance with the primary patient’s tumor profile, human leukocyte-antigen characteristics and specific metabolic pathway signatures. A detailed patient molecular characterization, including specific mutations prioritized in the clinical molecular tumor boards are provided. Ninety models were shared with the IMI2 ITCC Pediatric Preclinical Proof-of-concept Platform (IMI2 ITCC-P4) for further exploitation. This PDX biobank of unique recurrent childhood cancers provides an essential support for basic and translational research and treatments development in advanced pediatric malignancies.

Published
2023
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40. Evolutionary Routes in Metastatic Uveal Melanomas Depend on MBD4 Alterations

Author

Rémi Dendale, Monique K van der Kooij, Sarah Tick, Khadija Aït Raïs, Vincent Servois, Raymond L. Barnhill, Marc Putterman, Sophie Piperno-Neumann, Samar Alsafadi, Alexandre Houy, Sergio Roman-Roman, Joshua J. Waterfall, Gaëlle Pierron, Benjamin Marande, Sieta Gassama, Ellen Kapiteijn, Manuel Rodrigues, Nathalie Cassoux, Odette Mariani, Marc-Henri Stern, Sophie Gardrat, Sylvain Baulande, Lenha Mobuchon, and Pascale Mariani

Subjects
0301 basic medicine, Cancer Research, Mutation, Monosomy, biology, Genetic heterogeneity, business.industry, Melanoma, medicine.disease_cause, medicine.disease, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, Oncology, 030220 oncology & carcinogenesis, Genotype, Genetic variation, medicine, Cancer research, GNAS complex locus, biology.protein, Allele, business
Abstract

Purpose: Uveal melanomas (UM) are genetically simple tumors carrying few copy number alterations (CNA) and a low mutation burden, except in rare MBD4-deficient, hypermutated cases. The genomics of uveal melanoma metastatic progression has not been described. We assessed the genetic heterogeneity of primary and metastatic MBD4-proficient and -deficient uveal melanomas. Experimental Design: We prospectively collected 75 metastatic and 16 primary samples from 25 consecutive uveal melanoma patients, and performed whole-exome sequencing. Results: MBD4-proficient uveal melanomas contained stable genomes at the nucleotide level, acquiring few new single nucleotide variants (SNVs; 16 vs. 13 in metastases and primary tumors, respectively), and no new driver mutation. Five CNAs were recurrently acquired in metastases (losses of 1p, 6q, gains of 1q, 8q, and isodisomy 3). In contrast, MBD4-deficient uveal melanomas carried more than 266 SNVs per sample, with high genetic heterogeneity and TP53, SMARCA4, and GNAS new driver mutations. SNVs in MBD4-deficient contexts were exploited to unveil the timeline of oncogenic events, revealing that metastatic clones arose early after tumor onset. Surprisingly, metastases were not enriched in monosomy 3, a previously defined metastatic risk genomic feature. Monosomy 3 was associated with shorter metastatic-free interval compared with disomy 3 rather than higher rate of relapse. Conclusions: MBD4-proficient uveal melanomas are stable at the nucleotide level, without new actionable alterations when metastatic. In contrast, MBD4 deficiency is associated with high genetic heterogeneity and acquisition of new driver mutations. Monosomy 3 is associated with time to relapse rather than rate of relapse, thus opening avenues for a new genetic prognostic classification of uveal melanomas.

Published
2019

41. Iterative treatment with surgery and radiofrequency ablation of uveal melanoma liver metastasis: Retrospective analysis of a series of very long-term survivors

Author

Romain Foucher, Vincent Servois, Carla Da Costa, Gaëlle Pierron, Sylvain Dureau, Alexia Savignoni, Pascale Mariani, Nathalie Cassoux, Toufik Bouhadiba, Mohamed Maher Almubarak, and Université Paris sciences et lettres (PSL)

Subjects
Adult, Male, Uveal Neoplasms, 0301 basic medicine, medicine.medical_specialty, Percutaneous, Radiofrequency ablation, [SDV]Life Sciences [q-bio], law.invention, Resection, Metastasis, 03 medical and health sciences, 0302 clinical medicine, law, Retrospective analysis, medicine, Hepatectomy, Humans, Melanoma, First Recurrence, Aged, Retrospective Studies, business.industry, Liver Neoplasms, General Medicine, Middle Aged, medicine.disease, 3. Good health, Surgery, 030104 developmental biology, Oncology, 030220 oncology & carcinogenesis, Catheter Ablation, Female, Metastasectomy, business
Abstract

Background After treatment of primary ocular uveal melanoma (UM), up to 50% of patients will develop metastases, mostly in the liver. Systemic treatments do not provide any overall survival benefit for these patients and surgery remains the most effective therapy for selected patients. Radiofrequency ablation (RFA) alone or in combination with surgery is frequently used to spare hepatic parenchyma. When patients relapse after treatment of their first metastases, and when the liver recurrence is limited, new local liver treatment is questionable. Methods A total of 14 patients with liver metastases from uveal melanoma (LMUM) were retrospectively evaluated. All patients had a complete first liver resection and a second treatment with RFA. Overall survival, recurrence-free interval after the first and the second treatment was evaluated. Results Treatment of hepatic recurrence was percutaneous RFA for ten patients and per-operative RFA for four patients associated with new metastasectomy. The median time to onset of LMUMs after ocular UM treatment was 50 months, and the median time to recurrence of hepatic metastasis after the first liver treatment was 20 months. The overall survival was 70% at five years and 35% at ten years. The recurrence-free interval was 50% and 56% at two years after the first and the second treatment, respectively. Conclusion Prolonged survival can be achieved by exclusive and iterative local treatment combining surgery and RFA in a small proportion of patients with a first recurrence of isolated LMUM.

Published
2019
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42. SHH medulloblastoma in a young adult with a TCF4 germline pathogenic variation

Author

Lydie Burglen, Olivier Ayrault, Irina Giurgea, Maud Blanluet, Franck Bielle, François Doz, David Gentien, Audrey Rapinat, Julien Masliah-Planchon, Olivier Delattre, Badreddine Mohand Oumoussa, Diane Doummar, Gaëlle Pierron, Christine Bourneix, Stéphane Clemenceau, Elodie Girard, Franck Bourdeaut, Celio Pouponnot, Mamy Andrianteranagna, UNIROUEN - UFR Santé (UNIROUEN UFR Santé), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU), Genetique et Biotherapies des Maladies Degeneratives et Proliferatives du Systeme Nerveux (Inserm U745), Institut des sciences du Médicament -Toxicologie - Chimie - Environnement (IFR71), Institut National de la Santé et de la Recherche Médicale (INSERM)-Ecole Nationale Supérieure de Chimie de Paris- Chimie ParisTech-PSL (ENSCP)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Ecole Nationale Supérieure de Chimie de Paris- Chimie ParisTech-PSL (ENSCP)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Paris Descartes - Paris 5 (UPD5)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Mondor de recherche biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Laboratoire de Neuropathologie Raymond Escourolle, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP]-Sorbonne Université (SU), École supérieure du professorat et de l'éducation - Académie de Grenoble (ESPE Grenoble), Université Savoie Mont Blanc (USMB [Université de Savoie] [Université de Chambéry])-Université Grenoble Alpes (UGA), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [APHP]-Centre National de la Recherche Scientifique (CNRS), Laboratoire de neurogénétique moléculaire, CHU Trousseau [APHP], Service: neuropédiatrie pathologie du développement, Université Pierre et Marie Curie - Paris 6 (UPMC), Signalisation cellulaire et neurobiologie (SNC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Curie-Centre National de la Recherche Scientifique (CNRS), Signalisation normale et pathologique de l'embryon aux thérapies innovante des cancers, Institut Curie-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Département de recherche translationnelle, Institut Curie, Service de Génétique Oncologique, Unité de génétique et biologie des cancers (U830), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie-Institut National de la Santé et de la Recherche Médicale (INSERM), Unité de Génétique Somatique, Institut National de la Santé et de la Recherche Médicale (INSERM)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Paris Descartes - Paris 5 (UPD5)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Physiopathologie des maladies génétiques d'expression pédiatrique (UMRS_933), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de Neuropathologie [CHU Pitié Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Grenoble Alpes - École supérieure du professorat et de l'éducation - Académie de Grenoble (UGA ESPE Grenoble), Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-CHU Pitié-Salpêtrière [AP-HP], UMS omique (OMIQUE), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Plateforme Post-génomique de la Pitié-Salpêtrière (P3S), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Sorbonne Université (SU), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Curie [Paris]-Centre National de la Recherche Scientifique (CNRS), Signalisation normale et pathologique de l'embryon aux thérapies innovantes des cancers, Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut Curie [Paris], Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5), Université Grenoble Alpes (UGA)-Université Savoie Mont Blanc (USMB [Université de Savoie] [Université de Chambéry]), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-CHU Pitié-Salpêtrière [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Recherche pour le Développement (IRD)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Maladies génétiques d'expression pédiatrique (U933), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Trousseau [APHP], and Département de Recherche Translationnelle

Subjects
Medulloblastoma, 0303 health sciences, Pathology, medicine.medical_specialty, [SDV]Life Sciences [q-bio], [SDV.CAN]Life Sciences [q-bio]/Cancer, TCF4, Biology, medicine.disease, Germline, Pathology and Forensic Medicine, 03 medical and health sciences, Cellular and Molecular Neuroscience, 0302 clinical medicine, Variation (linguistics), medicine, Neurology (clinical), Young adult, 030217 neurology & neurosurgery, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology
Abstract

International audience

Published
2019
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43. A large collection of integrated genomically characterized patient‐derived xenografts highlighting the heterogeneity of triple‐negative breast cancer

Author

Cécile Laurent, Gaëlle Pierron, Marion Lavigne, Pierre Painsec, Ivan Bièche, Elisabetta Marangoni, Cécile Reyes, Ahmed Dahmani, Bérengère Ouine, David Gentien, Leanne De Koning, Laura Sourd, Elodie Montaudon, Anne Vincent-Salomon, Ludivine Morisset, Florence Coussy, Samia Melaabi, Franck Assayag, Thibaut Larcher, Sylvain Baulande, Elodie Girard, Céline Callens, Léa Huguet, Sophie Chateau-Joubert, Virginie Bernard, Véronique Diéras, Jean-Luc Servely, Rania El Botty, Anais Boulai, Sophie Vacher, Institut Curie, Institut Curie Research Center (Laboratory of Preclinical Investigation, Department of Translational Research), Translational Research Department, RPPA Platform, Institut Curie Research Center, Department of Biopathology, Università degli Studi di Roma Tor Vergata [Roma], Unit of Pharmacogenomics, Department of Genetics, Laboratory of Preclinical Investigation, Department of Translational Research, aboratory of Preclinical Investigation, Department of Translational Research, BioPôle Alfort, École nationale vétérinaire d'Alfort (ENVA), Développement et Pathologie du Tissu Musculaire (DPTM), Ecole Nationale Vétérinaire de Nantes-Institut National de la Recherche Agronomique (INRA), Translational Research Department, Genomics Platform, U900, Institut National de la Santé et de la Recherche Médicale (INSERM), Unit of Somatic Genomics, Department of Genetics, Rt2 Lab, Genomics of Excellence (ICGex) Platform, Institut Curie Research, Department of Medical Oncology, Humanitas Centro Catanese di Oncologia, Inserm U1016, Paris Descartes University, Institut Curie [Paris], Physiopathologie Animale et bioThérapie du muscle et du système nerveux (PAnTher), Institut National de la Recherche Agronomique (INRA)-Ecole Nationale Vétérinaire, Agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS), Cancer et génome: Bioinformatique, biostatistiques et épidémiologie d'un système complexe, MINES ParisTech - École nationale supérieure des mines de Paris, and Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
Neuroblastoma RAS viral oncogene homolog, endocrine system, Cancer Research, Combination therapy, Class I Phosphatidylinositol 3-Kinases, [SDV]Life Sciences [q-bio], Gene Dosage, Triple Negative Breast Neoplasms, Biology, GTP Phosphohydrolases, Genetic Heterogeneity, Mice, 03 medical and health sciences, 0302 clinical medicine, Breast cancer, medicine, Animals, Humans, Gene Regulatory Networks, Molecular Targeted Therapy, Precision Medicine, Biomarker discovery, skin and connective tissue diseases, Gene, PI3K/AKT/mTOR pathway, Triple-negative breast cancer, Gene Expression Profiling, High-Throughput Nucleotide Sequencing, Membrane Proteins, Middle Aged, medicine.disease, 3. Good health, Gene Expression Regulation, Neoplastic, Oncology, 030220 oncology & carcinogenesis, Cancer research, Immunohistochemistry, Female, Tumor Suppressor Protein p53, Neoplasm Transplantation, Signal Transduction
Abstract

Triple-negative breast cancer (TNBC) represents 10% of all breast cancers and is a very heterogeneous disease. Globally, women with TNBC have a poor prognosis, and the development of effective targeted therapies remains a real challenge. Patient-derived xenografts (PDX) are clinically relevant models that have emerged as important tools for the analysis of drug activity and predictive biomarker discovery. The purpose of this work was to analyze the molecular heterogeneity of a large panel of TNBC PDX (n = 61) in order to test targeted therapies and identify biomarkers of response. At the gene expression level, TNBC PDX represent all of the various TNBC subtypes identified by the Lehmann classification except for immunomodulatory subtype, which is underrepresented in PDX. NGS and copy number data showed a similar diversity of significantly mutated gene and somatic copy number alteration in PDX and the Cancer Genome Atlas TNBC patients. The genes most commonly altered were TP53 and oncogenes and tumor suppressors of the PI3K/AKT/mTOR and MAPK pathways. PDX showed similar morphology and immunohistochemistry markers to those of the original tumors. Efficacy experiments with PI3K and MAPK inhibitor monotherapy or combination therapy showed an antitumor activity in PDX carrying genomic mutations of PIK3CA and NRAS genes. TNBC PDX reproduce the molecular heterogeneity of TNBC patients. This large collection of PDX is a clinically relevant platform for drug testing, biomarker discovery and translational research.

Published
2019
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44. Novel KHDRBS1-NTRK3 Rearrangement in a Congenital Pediatric CD34-Positive Skin Tumor: A Case Report

Author

Marie-Christine Machet, Anne Jourdain, Aurélien Binet, Stéphanie Reynaud, Annabel Maruani, Gaëlle Pierron, Daniel Orbach, Sylvie Fraitag, Matthias Tallegas, Paediatric Onco-Hematology Unit, Hopital de Clocheville, MethodS in Patients-centered outcomes and HEalth ResEarch (SPHERE), Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR des Sciences Pharmaceutiques et Biologiques, Université de Nantes (UN)-Université de Nantes (UN), and Université de Tours-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR des Sciences Pharmaceutiques et Biologiques

Subjects
0301 basic medicine, Pathology, Skin Neoplasms, Biopsy, [SDV]Life Sciences [q-bio], Antigens, CD34, 0302 clinical medicine, Neoplasms, Diagnosis, Gene Rearrangement, Tumor, Spindle-cell, Adaptor Proteins, RNA-Binding Proteins, General Medicine, Dermal Fibroma, Magnetic Resonance Imaging, Immunohistochemistry, 3. Good health, DNA-Binding Proteins, Phenotype, Molecular Diagnostic Techniques, 030220 oncology & carcinogenesis, trkC, Female, Gene Fusion, Infantile Fibrosarcoma, Receptor, medicine.medical_specialty, Malignancy, Pathology and Forensic Medicine, Diagnosis, Differential, 03 medical and health sciences, Predictive Value of Tests, medicine, Dermatofibrosarcoma protuberans, Biomarkers, Tumor, Humans, Receptor, trkC, Genetic Predisposition to Disease, Antigens, Molecular Biology, Connective tissue nevus, Adaptor Proteins, Signal Transducing, business.industry, Signal Transducing, Infant, Cell Biology, Gene rearrangement, medicine.disease, stomatognathic diseases, 030104 developmental biology, Cutaneous, Differential, CD34, Differential diagnosis, Lipofibromatosis, business, Biomarkers
Abstract

International audience; Cutaneous spindle-cell neoplasms in adults as well as children represent a frequent dilemma for pathologists. Along this neoplasm spectrum, the differential diagnosis with CD34-positive proliferations can be challenging, particularly concerning neoplasms of fibrohistiocytic and fibroblastic lineages. In children, cutaneous and superficial soft-tissue neoplasms with CD34-positive spindle cells are associated with benign to intermediate malignancy potential and include lipofibromatosis, plaque-like CD34-positive dermal fibroma, fibroblastic connective tissue nevus, and congenital dermatofibrosarcoma protuberans. Molecular biology has been valuable in showing dermatofibrosarcoma protuberans and infantile fibrosarcoma that are characterized by COL1A1-PDGFB and ETV6-NTRK3 rearrangements respectively. We report a case of congenital CD34-positive dermohypodermal spindle-cell neoplasm occurring in a female infant and harboring a novel KHDRBS1-NTRK3 fusion. This tumor could belong to a new subgroup of pediatric cutaneous spindle-cell neoplasms, be an atypical presentation of a plaque-like CD34-positive dermal fibroma, of a fibroblastic connective tissue nevus, or represent a dermatofibrosarcoma protuberans with an alternative gene rearrangement.

Published
2019
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45. Clinical characteristics and outcomes for children, adolescents and young adults with 'CIC‐fused' or 'BCOR‐rearranged' soft tissue sarcomas: A multi‐institutional European retrospective analysis

Author

Monika Sparber‐Sauer, Nadège Corradini, Maria Carmen Affinita, Giuseppe Maria Milano, Gaelle Pierron, Matthieu Carton, Franck Tirode, Daniel Pissaloux, Rita Alaggio, Christian Vokuhl, Gianni Bisogno, Pablo Berlanga, Andrea Ferrari, and Daniel Orbach

Subjects
BCOR rearrangement, CIC‐DUX fusion transcript, pediatric/adolescent oncology, soft tissue sarcoma, YWHAE fusion transcript, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Abstract Background In certain rare undifferentiated small round cell sarcomas new specific molecular CIC‐DUX4/other partner, BCOR‐CCNB3/other partner, YWHAE fusions, or BCOR‐ITD (internal tandem duplication) were identified. These new “CIC fused” (CIC‐fused/ATXN1::NUTM1) and “BCOR rearranged” (BCOR fused/ITD/ YWHAE) soft tissue sarcomas (STS) are not well described. Methods Multi‐institutional European retrospective analysis of young patients (0–24 years) with CIC‐fused and BCOR rearranged STS. Results Overall, out of the 60 patients selected, the fusion status was CIC‐fused (n = 29), ATXN1::NUTM1 (n = 2), BCOR::CCNB3 (n = 18), BCOR‐ITD (n = 7), and YWHAE (n = 3), MAML::BCOR STS (n = 1). The main primaries were abdomen‐pelvic (n = 23) and limbs (n = 18). Median age was 14 years (0.9–23.8) and 0.9 (0.1–19.1) for CIC‐fused and BCOR‐rearranged groups, respectively (n = 29; p 5 cm) but only six had lymph node involvement. Patients received mainly chemotherapy (n = 57), local surgery (n = 50), and/or radiotherapy (n = 34). After a median follow‐up of 47.1 months (range, 3.4–230), 33 (52%) patients had an event and 23 patients died. Three‐year event‐free survivals were 44.0% (95% CI 28.7–67.5) and 41.2% (95% CI 25.4–67.0) for CIC and BCOR groups (p = 0.97), respectively. Three‐year overall survivals were 46.3% (95% CI 29.6–72.4) and 67.1% (95% CI 50.4–89.3; p = 0.24), respectively. Conclusions Pediatric patients often present with large tumors and metastatic disease, especially CIC sarcomas. Overall outcome is dismal. New treatment options are needed.

Published
2023
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46. ATRT-10. SPATIO-TEMPORAL DELETION OF SMARCB1 DETERMINES MOUSE AT/RT SUBTYPES

Author

Paul Fréneaux, Olivier Delattre, Christine Bourneix, Gaëlle Pierron, Mamy Andrianteranagna, Franck Bourdeaut, Céline Chauvin, Zhi-Yan Han, Amaury Leruste, Pascale Varlet, Julien Masliah-Planchon, Arnault Tauziède-Espariat, and Didier Surdez

Subjects
Cancer Research, Pathology, medicine.medical_specialty, Ataxia, SMARCB1 Protein, Biology, Spinal cord, Neural stem cell, Abstracts, medicine.anatomical_structure, Oncology, Parenchyma, medicine, Neurology (clinical), medicine.symptom, SMARCB1, Tamoxifen, medicine.drug
Abstract

The cell(s) of origin of AT/RTs remains unclear. We previously developed a mouse model consisting in tamoxifen inducible system in a Smarcb1(Flox/Flox);Rosa26-Cre(ERT2) background. We obtained two subgroups of intracranial tumors, one with neuronal and the other with non-neuronal features, in keeping with the diversity observed in human AT/RTs. To investigate the potential cell(s) of origin of those various AT/RTs, we first endeavored to specify whether different time points of Smarcb1 inactivation correlated with specific anatomic location and/or molecular subgroups. Thereby, we identified that the neuronal group, mostly developing from the sub-ventricular zone and the spinal cord, was almost exclusively obtained with the earliest inactivation time point(E6-E7). In contrary, the non-neuronal group emerged after Smarcb1 inactivation at any time point(E6-E10), and showed intracranial but extra-parenchyma/meningeal origins. In order to more specifically identify the cell(s) of origin for the neuronal group, we next generated developmental stage-specific conditional knockout mice carrying Smarcb1 inactivation by restricting Cre expression upon promoters characteristic for various neural stem cells/progenitors. While Smarcb1(Flox/Flox);Atoh1Cre(ERT2) showed ataxia but failed to give rise to any tumor whatever the embryonal time point, targeting Nestin-expressing cells led to tumors with morphological rhabdoid features; these again showed some molecular diversity as observed in human AT/RTs. The study of the impact of Smarcb1 inactivation in other promoter-restricted backgrounds is ongoing. In conclusion, we show that spatio-temporal deletion of Smarcb1 determines mouse AT/RT subtypes. Our new mouse models not only give insight on the cell(s) of origin, but also provide interesting preclinical models.

Published
2018

47. Transcriptomic definition of molecular subgroups of small round cell sarcomas

Author

Delphine Guillemot, Megane Bouvet, Sarah Watson, Paul Fréneaux, Jean-Michel Coindre, Jean-Marc Guinebretière, Louise Galmiche-Rolland, Dominique Ranchère-Vince, Stéphanie Reynaud, Franck Tirode, Olivier Delattre, Frédérique Larousserie, Elisabeth Longchampt, Marie Karanian, Gaëlle Pierron, François Le Loarer, Virginie Perrin, Unité de génétique et biologie des cancers (U830), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Curie [Paris], Unité de Génétique Somatique, Institut Bergonié [Bordeaux], UNICANCER, Université de Bordeaux (UB), Centre Léon Bérard [Lyon], Hôpital René HUGUENIN (Saint-Cloud), Service de pathologie [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Paris Descartes - Paris 5 (UPD5), Hôpital Cochin [AP-HP], Hôpital Foch [Suresnes], Equipe labellisée Ligue contre le Cancer, Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and TIRODE, Franck

Subjects
0301 basic medicine, FET-TFCP2, sarcoma, Oncogene Proteins, Fusion, Muscle Proteins, Bone Neoplasms, VGLL2-NCOA2, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, [SDV.BBM.BM] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Pathology and Forensic Medicine, Transcriptome, Fusion gene, 03 medical and health sciences, 0302 clinical medicine, DUX4, [SDV.CAN] Life Sciences [q-bio]/Cancer, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Gene duplication, medicine, Round cell, Biomarkers, Tumor, Humans, FUS-NFATC2, Gene, fusion genes, EWSR1-PATZ1, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, medicine.disease, RNAseq, DNA-Binding Proteins, Repressor Proteins, 030104 developmental biology, 030220 oncology & carcinogenesis, Sarcoma, Small Cell, Cancer research, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], CIC-fused, Spindle cell sarcoma, Sarcoma, Gene Fusion, BCOR-rearranged, Transcription Factors
Abstract

Sarcoma represents a highly heterogeneous group of tumours. We report here the first unbiased and systematic search for gene fusions combined with unsupervised expression analysis of a series of 184 small round cell sarcomas. Fusion genes were detected in 59% of samples, with half of them being observed recurrently. We identified biologically homogeneous groups of tumours such as the CIC-fused (to DUX4, FOXO4 or NUTM1) and BCOR-rearranged (BCOR-CCNB3, BCOR-MAML3, ZC3H7B-BCOR, and BCOR internal duplication) tumour groups. VGLL2-fused tumours represented a more biologically and pathologically heterogeneous group. This study also refined the characteristics of some entities such as EWSR1-PATZ1 spindle cell sarcoma or FUS-NFATC2 bone tumours that are different from EWSR1-NFATC2 tumours and transcriptionally resemble CIC-fused tumour entities. We also describe a completely novel group of epithelioid and spindle-cell rhabdomyosarcomas characterized by EWSR1- or FUS-TFCP2 fusions. Finally, expression data identified some potentially new therapeutic targets or pathways. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Published
2018
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48. Clinicopathologic Features of CIC-NUTM1 Sarcomas, a New Molecular Variant of the Family of CIC-fused Sarcomas

Author

Gaëlle Pierron, François Le Loarer, Louise Galmiche-Rolland, Jean Michel Coindre, Franck Tirode, Sarah Watson, A. Michot, Daniel Pissaloux, Dominique Ranchère-Vince, Catherine Godfraind, Antoine Italiano, Laetitia Mayeur, Alexandre Vasiljevic, Karen Silva, Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Immunité et cancer, Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Clermont-Ferrand, Imagerie Moléculaire et Stratégies Théranostiques (IMoST), Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de pathologie [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CHU Necker - Enfants Malades [AP-HP], Université Paris Descartes - Paris 5 (UPD5), Laboratory of Solid Tumors Genetics, Nice University Hospital, Service de chirurgie plastique et reconstructive, CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Unité de Génétique Somatique, Institut Curie [Paris], Service de Pathologie, Hospices Civils de Lyon (HCL)-Hôpital neurologique et neurochirurgical Pierre Wertheimer [CHU - HCL], Hospices Civils de Lyon (HCL), Université de Lyon, Institut Bergonié [Bordeaux], UNICANCER, Centre de recherche de l'Institut Curie [Paris], INSERM U1218 ACTION, Université de Bordeaux (UB), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), Centre de Recherche en Cancérologie de Lyon (CRCL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre Léon Bérard [Lyon]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut Curie-Institut National de la Santé et de la Recherche Médicale (INSERM), Imagerie Moléculaire et Stratégies Théranostiques - Clermont Auvergne (IMoST), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne (UCA), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Necker - Enfants Malades [AP-HP], Institut Curie, and Institut Bergonié - CRLCC Bordeaux

Subjects
Adult, Male, 0301 basic medicine, Pathology, medicine.medical_specialty, Adolescent, Recombinant Fusion Proteins, Soft Tissue Neoplasms, [SDV.CAN]Life Sciences [q-bio]/Cancer, Pathology and Forensic Medicine, Young Adult, 03 medical and health sciences, Exon, 0302 clinical medicine, DUX4, Humans, Medicine, Child, Lung, medicine.diagnostic_test, business.industry, Breakpoint, Nuclear Proteins, Soft tissue, Sarcoma, medicine.disease, Phenotype, Neoplasm Proteins, 3. Good health, Repressor Proteins, 030104 developmental biology, medicine.anatomical_structure, Child, Preschool, 030220 oncology & carcinogenesis, Female, Surgery, Anatomy, business, Fluorescence in situ hybridization
Abstract

International audience; CIC-fused sarcomas represent an emerging family of tumors, for long connected to the Ewing family group of tumors, but underlined by distinct CIC fusions with different partners. 3' Fusion partners include DUX4, FOXO4, and, as recently emphasized, NUTM1. In this study, we report the clinicopathologic and molecular features of a series of 6 CIC-NUTM1 sarcomas. Mean age at diagnosis was 6 years (2 to 27 y), and 4 patients were male individuals. Primary tumors were located in the central nervous system (n=3), paravertebral soft tissue and epidural spaces (n=1, each), and lung (n=1). Median overall survival was 17.5 months (7 to 37 mo), and all but one patient died of disease. All tumors displayed classic features of CIC-DUX4 sarcomas with round cell to epithelioid microscopic appearance. Most tumors expressed ETV4 and NUTM1 (n=5/6 and 6/6, respectively), whereas WT1cter was positive in only 2 cases. All tested tumors were positive for break-apart fluorescence in situ hybridization for CIC and NUTM1. Apart from CIC or NUTM1 genomic breakpoints, no other recurrent copy number alteration was seen on genomic profiles. Fusion transcripts were identified by RNA-sequencing on either formalin-fixed paraffin-embedded or frozen material. CIC and NUTM1 breakpoints were located between exons 16 and 20 and exons 2 and 5, respectively. Altogether, CIC-NUTM1 sarcomas represent a new molecular variant of CIC-fused sarcomas with a predilection for the central nervous system and younger pediatric population. Its phenotype may be confused with NUT carcinomas.

Published
2018
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49. Deep intronic hotspot variant explaining rhabdoid tumor predisposition syndrome in two patients with atypical teratoid and rhabdoid tumor

Author

Pascale Varlet, Laurence Brugières, Thierry Frebourg, Annie Laquerrière, Gaëlle Pierron, Stéphanie Puget, Olivier Delattre, Julien Masliah-Planchon, Franck Bourdeaut, Damien Bodet, Christelle Dufour, Arnault Tauziède-Espariat, Emmanuèle Lechapt-Zalcman, Pascale Schneider, CH Belfort-Montbéliard, Pathologie cellulaire : aspects moléculaires et viraux / Pathologie et Virologie Moléculaire, Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS), Département de cancérologie de l'enfant et de l'adolescent [Gustave Roussy], Institut Gustave Roussy (IGR), Service de neurochirurgie pédiatrique [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre de Psychiatrie et Neurosciences (U894), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'hémato-immuno-oncologie pédiatrique [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Physiopathologie, Autoimmunité, maladies Neuromusculaires et THErapies Régénératrices (PANTHER), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'Anatomie et Cytologie Pathologique [CHU Rouen], Génomique et Médecine Personnalisée du Cancer et des Maladies Neuropsychiatriques (GPMCND), Hypoxie, physiopathologies cérébrovasculaire et tumorale (CERVOxy), Imagerie et Stratégies Thérapeutiques des pathologies Cérébrales et Tumorales (ISTCT), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)-Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), Unit of Somatic Genomics, Department of Genetics, Institut Curie [Paris], Unité de génétique et biologie des cancers (U830), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Unité de Génétique Somatique, Université Paris Diderot - Paris 7 (UPD7)-Université Paris Diderot - Paris 7 (UPD7)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de psychiatrie et neurosciences (U894 / UMS 1266), Normandie Université (NU)-Normandie Université (NU)-CHU Rouen, Centre National de la Recherche Scientifique (CNRS)-Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), and TAN, Yossan-Var

Subjects
Male, 0301 basic medicine, medicine.medical_specialty, [SDV.IMM] Life Sciences [q-bio]/Immunology, [SDV]Life Sciences [q-bio], Short Report, Biology, Bioinformatics, Germline, Rhabdoid Tumor Predisposition Syndrome, 03 medical and health sciences, 0302 clinical medicine, Germline mutation, Molecular genetics, Genetics, medicine, Humans, SMARCB1, Cells, Cultured, Germ-Line Mutation, Rhabdoid Tumor, Genetics (clinical), Teratoma, Cytogenetics, Infant, SMARCB1 Protein, Introns, Human genetics, 3. Good health, [SDV] Life Sciences [q-bio], 030104 developmental biology, 030220 oncology & carcinogenesis, Medical genetics, [SDV.IMM]Life Sciences [q-bio]/Immunology
Abstract

About one third of patients with rhabdoid tumors (RT) harbor a heterozygous germline variant in SMARCB1. Molecular diagnosis therefore keeps a crucial place in the diagnosis of RT, and genetic counseling should be systematically recommended. However, immunohistochemistry has progressively replaced molecular tools to assess the status of SMARCB1 in tumors; the necessity of analyzing SMARCB1 status in the tumor may thus be less considered by neuropathologists and pediatric neuro-oncologists. In the present manuscript as aforementioned, we report on two patients with bifocal RT in the first month of life and in whom no germline variant was initially found in the SMARCB1 coding sequence. Careful analysis of SMARCB1 status in the tumors revealed that only one of the two inactivating hits was found in the coding sequence. By sequencing the tumor cells RNA, we were able to detect an insertion with an abnormal sequence, due to the same intronic variant of SMARCB1, which led to the exonisation of the first intron. This cryptic variant was absent in the germline DNA of both patients. Of note, we previously reported one patient with the same deep intronic variant in the germline in a soft tissue RT. To our mind, this additional report on two patients clearly demonstrates that this intronic variant is a new hotspot that should now be systematically added to the germline screening of SMARCB1. We therefore recommend searching for and cautiously interpreting germline analysis if SMARCB1 has not been extensively studied in the tumor.

Published
2017
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50. Feasibility and clinical integration of molecular profiling for target identification in pediatric solid tumors

Author

Olivier Delattre, Gaëlle Pierron, Christophe Le Tourneau, Virginie Bernard, Eve Lapouble, Ivan Bièche, Paul Fréneaux, Caroline Oudot, Estelle Thebaud, Thomas Pincez, Hélène Pacquement, Isabelle Aerts, Nathalie Clément, Gudrun Schleiermacher, Cécile Vérité, Jean Michon, Maud Kamal, Sophie Taque, Irene Jiménez, Daniel Orbach, Franck Bourdeaut, François Doz, Cormac Owens, Département d'oncologie pédiatrique [Institut Curie, Paris], Institut Curie [Paris], Service de génétique, Institut Curie Paris, Unité de génétique et biologie des cancers (U830), Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Limoges, Risques cliniques et sécurité en santé des femmes et en santé périnatale (RISCQ), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Département d'Oncologie Médicale [Institut Curie, Paris], Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Annenberg Foundation Fondation Nelia et Amadeo Barletta, and This study was supported by the Annenberg Foundation, the Nelia and Amadeo Barletta Foundation (FNAB), the Associations Enfants et Sant?, Les Bagouz ? Manon, Les Amis de Claire, Hubert Gouin Enfance et Cancer and Meghanora. The authors declare that there is no conflict of interest.

Subjects
0301 basic medicine, Oncology, Adult, Male, medicine.medical_specialty, Poor prognosis, Adolescent, medicine.medical_treatment, molecular profiling, [SDV]Life Sciences [q-bio], Bioinformatics, Targeted therapy, 03 medical and health sciences, Neuroblastoma, 0302 clinical medicine, Internal medicine, medicine, Tumor board, Humans, Solid tumor, Child, Comparative Genomic Hybridization, business.industry, Refractory Disease, High-Throughput Nucleotide Sequencing, Infant, Mean age, Sarcoma, clinical trial, Hematology, Glioma, 3. Good health, Clinical trial, 030104 developmental biology, 030220 oncology & carcinogenesis, Child, Preschool, array comparative genomic hybridization, Pediatrics, Perinatology and Child Health, Female, next-generation sequencing, solid tumor, business, Comparative genomic hybridization
Abstract

International audience; Background: The role of tumor molecular profiling in directing targeted therapy utilization remains to be defined for pediatric tumors. We aimed to evaluate the feasibility of a sequencing and molecular biology tumor board (MBB) program, and its clinical impact on children with solid tumors. Procedure: We report on a single-center MBB experience of 60 pediatric patients with a poor prognosis or relapsed/refractory solid tumors screened between October 2014 and November 2015. Tumor molecular profiling was performed with panel-based next-generation sequencing and array comparative genomic hybridization. Results: Mean age was 12 ± 5.7 years (range 0.1–21.5); main tumor types were high-grade gliomas (n = 14), rare sarcomas (n = 9), and neuroblastomas (n = 8). The indication was a poor prognosis tumor at diagnosis for 16 patients and relapsed (n = 26) or refractory disease (n = 18) for the remaining 44 patients. Molecular profiling was feasible in 58 patients. Twenty-three patients (40%) had a potentially actionable finding. Patients with high-grade gliomas had the highest number of targetable alterations (57%). Six of the 23 patients subsequently received a matched targeted therapy for a period ranging from 16 days to 11 months. The main reasons for not receiving targeted therapy were poor general condition (n = 5), pursuit of conventional therapy (n = 6), or lack of pediatric trial (n = 4). Conclusions: Pediatric molecular profiling is feasible, with more than a third of patients being eligible to receive targeted therapy, yet only a small proportion were treated with these therapies. Analysis at diagnosis may be useful for children with very poor prognosis tumsors.

Published
2017
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