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Melanoma: HELP
Articles by Arnaud de la Fouchardiere
Based on 50 articles published since 2009
(Why 50 articles?)
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Between 2009 and 2019, A. De La Fouchardière wrote the following 50 articles about Melanoma.
 
+ Citations + Abstracts
Pages: 1 · 2
1 Guideline French updated recommendations in Stage I to III melanoma treatment and management. 2017

Guillot, B / Dalac, S / Denis, M G / Dupuy, A / Emile, J F / De La Fouchardiere, A / Hindie, E / Jouary, T / Lassau, N / Mirabel, X / Piperno Neumann, S / De Raucourt, S / Vanwijck, R. ·Dermatology Department, CHU Montpellier. · Dermatology Department, CHU Dijon. · Laboratory of Biochemistry, CHU Nantes. · Dermatology Department, CHU Rennes. · Laboratory of Pathology, AP-HP Ambroise Paré Hospital, Boulogne, France. · Laboratory of Pathology, Centre Léon Bérard Lyon. · Department of Nuclear medicine, CHU Bordeaux. · Dermatology Department, CH Pau. · Department of Radiology, Institut Gustave Roussy Villejuif. · Department of Radiotherapy, Centre Oscar Lambret Lille. · Institut Curie, Paris, France. · 1 Avenue du 6 Juin, 1945, 14000 Caen, France. · Louvain Catholic University, Brussels, Belgium. ·J Eur Acad Dermatol Venereol · Pubmed #28120528.

ABSTRACT: As knowledge continues to develop, regular updates are necessary concerning recommendations for practice. The recommendations for the management of melanoma stages I to III were drawn up in 2005. At the request of the Société Française de Dermatologie, they have now been updated using the methodology for recommendations proposed by the Haute Autorité de Santé in France. In practice, the principal recommendations are as follows: for staging, it is recommended that the 7th edition of AJCC be used. The maximum excision margins have been reduced to 2 cm. Regarding adjuvant therapy, the place of interferon has been reduced and no validated emerging medication has yet been identified. Radiotherapy may be considered for patients in Stage III at high risk of relapse. The sentinel lymph node technique remains an option. Initial examination includes routine ultrasound as of Stage II, with other examinations being optional in stages IIC and III. A shorter strict follow-up period (3 years) is recommended for patients, but with greater emphasis on imaging.

2 Guideline [Update to the recommendations for management of melanoma stages I to III]. 2016

Guillot, B / Dalac, S / Denis, M G / Dupuy, A / Emile, J-F / De La Fouchardière, A / Hindie, E / Jouary, T / Lassau, N / Mirabel, X / Piperno Neumann, S / De Raucourt, S / Vanwijck, R. ·Département de dermatologie, hôpital Saint-Éloi, CHU de Montpellier, 34295 Montpellier cedex 5, France. Electronic address: b-guillot@chu-montpellier.fr. · Service de dermatologie, hôpital du Bocage sud, CHU de Dijon, BP 1542, 21079 Dijon cedex, France. · Laboratoire de biochimie, institut de biologie, 9, quai Moncousu, 44093 Nantes cedex, France. · Service de dermatologie, CHU de Rennes, Rennes, France. · Service d'anatomie pathologique, CHU Ambroise-Paré-Boulogne, 92104 Boulogne cedex, France. · Centre anticancéreux Léon-Bérard, 28, rue Laennec, 69008 Lyon, France. · Service de médecine nucléire Sud et Pellegrin, CHU de Bordeaux, Bordeaux, France. · Service de médecine, centre hospitalier de Pau, 64000 Pau, France. · Service d'imagerie médicale, institut Gustave-Roussy, 94800 Villejuif, France. · Centre Oscar-Lambret, 3, rue Fréderic-Combemale, 59000 Lille, France. · Institut Curie, 26, rue d'Ulm, 75005 Paris, France. · 1, avenue du 6-Juin, 14000 Caen, France. · Université catholique de Louvain, 10, avenue Hippocrate, 1200 Bruxelles, Belgique. ·Ann Dermatol Venereol · Pubmed #27527567.

ABSTRACT: As knowledge continues to develop, regular updates are necessary concerning recommendations for practice. The recommendations for the management of melanoma stages I to III were drawn up in 2005. At the request of the Société Française de Dermatologie, they have now been updated using the methodology for recommendations proposed by the Haute Autorité de Santé. In practice, the principal recommendations are as follows: for staging, it is recommended that the 7th edition of AJCC be used. The maximum excision margins have been reduced to 2cm. Regarding adjuvant therapy, the place of interferon has been reduced and no validated emerging medication has yet been identified. Radiotherapy may be considered for patients in stage III at high risk of relapse. The sentinel lymph node technique remains an option. Initial examination includes routine ultrasound as of stage II, with other examinations being optional in stages IIC and III. A shorter strict follow-up period (3years) is recommended for patients, but with greater emphasis on imaging.

3 Guideline [Guidelines for stage I to III melanoma]. 2016

Guillot, Bernard / Dalac, Sophie / Denis, Marc / Dupuy, Alain / Emile, Jean François / De La Fouchardiere, Arnaud / Hindie, Elif / Jouary, Thomas / Lassau, Nathalie / Mirabel, Xavier / Piperno Neumann, Sophie / De Raucourt, Sixtine / Vanwijck, Romain. ·Département de dermatologie, hôpital Saint-Eloi, CHU de Montpellier, 34295 Montpellier cedex 5, France. Electronic address: b-guillot@chu-montpellier.fr. · Service de dermatologie, hôpital du Bocage sud, CHU de Dijon, BP 1542, 21079 Dijon cedex, France. · Laboratoire de biochimie, institut de biologie, 9, quai Moncousu, 44093 Nantes cedex, France. · Service de dermatologie, CHU de Rennes, Rennes, France. · Service d'anatomie pathologique, CHU Ambroise-Paré Boulogne, 92104 Boulogne cedex, France. · Centre anticancéreux Léon-Bérard, 28, rue Laennec, 69008 Lyon, France. · Service de médecine nucléire sud et pellegrin, CHU de Bordeaux, Bordeaux, France. · Service de médecine, CH de Pau, 64000 Pau, France. · Service d'imagerie médicale, institut Gustave-Roussy, 94800 Villejuif, France. · Centre Oscar-Lambret, 3, rue Fréderic-Combemale, 59000 Lille, France. · Institut Curie, 26, rue d'Ulm, 75005 Paris, France. · Sixtine, 1, avenue du 6 juin, 14000 Caen, France. · Université catholique de Louvain, avenue Hippocrate, 10 B-1200 Bruxelles, Belgique. ·Bull Cancer · Pubmed #27456259.

ABSTRACT: -- No abstract --

4 Review Comprehensive Study of the Clinical Phenotype of Germline BAP1 Variant-Carrying Families Worldwide. 2018

Walpole, Sebastian / Pritchard, Antonia L / Cebulla, Colleen M / Pilarski, Robert / Stautberg, Meredith / Davidorf, Frederick H / de la Fouchardière, Arnaud / Cabaret, Odile / Golmard, Lisa / Stoppa-Lyonnet, Dominique / Garfield, Erin / Njauw, Ching-Ni / Cheung, Mitchell / Turunen, Joni A / Repo, Pauliina / Järvinen, Reetta-Stiina / van Doorn, Remco / Jager, Martine J / Luyten, Gregorius P M / Marinkovic, Marina / Chau, Cindy / Potrony, Miriam / Höiom, Veronica / Helgadottir, Hildur / Pastorino, Lorenza / Bruno, William / Andreotti, Virginia / Dalmasso, Bruna / Ciccarese, Giulia / Queirolo, Paola / Mastracci, Luca / Wadt, Karin / Kiilgaard, Jens Folke / Speicher, Michael R / van Poppelen, Natasha / Kilic, Emine / Al-Jamal, Rana'a T / Dianzani, Irma / Betti, Marta / Bergmann, Carsten / Santagata, Sandro / Dahiya, Sonika / Taibjee, Saleem / Burke, Jo / Poplawski, Nicola / O'Shea, Sally J / Newton-Bishop, Julia / Adlard, Julian / Adams, David J / Lane, Anne-Marie / Kim, Ivana / Klebe, Sonja / Racher, Hilary / Harbour, J William / Nickerson, Michael L / Murali, Rajmohan / Palmer, Jane M / Howlie, Madeleine / Symmons, Judith / Hamilton, Hayley / Warrier, Sunil / Glasson, William / Johansson, Peter / Robles-Espinoza, Carla Daniela / Ossio, Raul / de Klein, Annelies / Puig, Susana / Ghiorzo, Paola / Nielsen, Maartje / Kivelä, Tero T / Tsao, Hensin / Testa, Joseph R / Gerami, Pedram / Stern, Marc-Henri / Paillerets, Brigitte Bressac-de / Abdel-Rahman, Mohamed H / Hayward, Nicholas K. ·QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia. · University of Queensland, Brisbane, QLD, Australia. · The University of the Highlands and Islands, Inverness, UK. · Department of Ophthalmology and Visual Science, The Ohio State University, Columbus, OH. · Division of Human Genetics, Department of Internal Medicine and Comprehensive Cancer Center, The Ohio State University, Columbus, OH. · Département of Biopathology, Centre Leon Bérard, Lyon, France. · Département de Biopathologie, Gustave Roussy, Université Paris-Saclay, Villejuif, France. · Département De Biologie Des Tumeurs, Institut Curie, Paris, France. · Institut Curie, PSL Research University, INSERM U830, DNA Repair and Uveal Melanoma (D.R.U.M.), Equipe labellisée par la Ligue Nationale contre le Cancer, Paris, France. · Sorbonne Paris Cité, University Paris-Descartes, Paris, France. · Department of Dermatology, Feinberg School of Medicine, Northwestern University, Chicago, IL. · Department of Dermatology, Wellman Center for Photomedicine, Massachusetts General Hospital, Boston, MA. · Cancer Biology Program, Fox Chase Cancer Center, Philadelphia, PA. · Folkhälsan Institute of Genetics, Helsinki, Finland. · Department of Ophthalmology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland. · Department of Dermatology, LUMC, Leiden, The Netherlands. · Department of Ophthalmology, LUMC, Leiden, The Netherlands. · Dermatology Department, Melanoma Unit, Hospital Clinic de Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Universitat de Barcelona, Barcelona, Spain. · Centro de Investigación Biomédica en Red (CIBER) de Enfermedades Raras, Instituto de Salud Carlos III, Barcelona, Spain. · Department of Oncology-Pathology, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden. · Department of Internal Medicine and Medical Specialties and Genetics of Rare Cancers, University of Genoa, Ospedale Policlinico San Martino, Genoa, Italy. · Medical Oncology Unit, Ospedale Policlinico San Martino, Genoa, Italy. · Department of Surgical and Diagnostic Sciences, Pathology Unit, University of Genoa and Ospedale Policlinico San Martino, Genoa, Italy. · Department of Clinical Genetics, University Hospital of Copenhagen, Copenhagen, Denmark. · Department of Ophthalmology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark. · Institute of Human Genetics, Diagnostic and Research Center for Molecular Biomedicine, Medical University of Graz, Graz, Austria. · Department of Ophthalmology. · Department of Clinical Genetics, Erasmus University Medical Center, Rotterdam, the Netherlands. · Department of Ophthalmology, Ocular Oncology Service, Helsinki University Central Hospital, Helsinki, Finland. · Department of Health Sciences, Università del Piemonte Orientale, Novara, Italy. · Bioscientia Center for Human Genetics, Ingelheim, Germany. · Department of Medicine IV, Faculty of Medicine, Medical Center-University of Freiburg, University of Freiburg, Freiburg, Germany. · Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA. · Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO. · Department of Dermatology, Dorset County Hospital NHS Foundation Trust, Dorchester, UK. · Tasmanian Clinical Genetics Service, Royal Hobart Hospital, TAS, Australia. · Adult Genetics Unit, Medicine Directorate, Royal Adelaide Hospital, Adelaide, SA, Australia. · University Department of Paediatrics, University of Adelaide, Adelaide, SA, Australia. · Dermatology Department, Mater Private Hospital Cork, Citygate, Mahon, Cork, Ireland. · Yorkshire Regional Genetics Service, Chapel Allerton Hospital, Leeds Teaching Hospitals NHS Trust, Leeds, UK. · Experimental Cancer Genetics, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Cambridge, UK. · Department of Ophthalmology, Ocular Melanoma Center and Retina Service, Massachusetts Eye and Ear, Harvard Medical School, Boston, MA. · Department of Anatomical Pathology, Flinders University and SA Pathology at Flinders Medical Centre, Adelaide, SA, Australia. · Impact Genetics, Bowmanville, Ontario, Canada. · Bascom Palmer Eye Institute, Sylvester Comprehensive Cancer Center and Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, Miami, FL. · Laboratory of Translational Genomics, National Cancer Institute, Bethesda, MD. · Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY. · Queensland Ocular Oncology Service, The Terrace Eye Centre, Brisbane, QLD, Australia. · Laboratorio Internacional de Investigación sobre el Genoma Humano, Universidad Nacional Autónoma de México, Juriquilla, Santiago de Querétaro, Mexico. · Department of Clinical Genetics, LUMC, Leiden, The Netherlands. · Massachusetts General Hospital Cancer Center, Boston, MA. · The Robert H. Lurie Cancer Center, Northwestern University, Chicago, IL. · INSERM UMR 1186, Integrative Tumor Immunology and Genetic Oncology, Gustave Roussy, EPHE, PSL, Faculté de Médecine, Université Paris-Sud, Université Paris-Saclay, Villejuif, France. · Department of Pathology, Menoufiya University, Shebin El-Kom, Egypt. ·J Natl Cancer Inst · Pubmed #30517737.

ABSTRACT: Background: The BRCA1-associated protein-1 (BAP1) tumor predisposition syndrome (BAP1-TPDS) is a hereditary tumor syndrome caused by germline pathogenic variants in BAP1 encoding a tumor suppressor associated with uveal melanoma, mesothelioma, cutaneous melanoma, renal cell carcinoma, and cutaneous BAP1-inactivated melanocytic tumors. However, the full spectrum of tumors associated with the syndrome is yet to be determined. Improved understanding of the BAP1-TPDS is crucial for appropriate clinical management of BAP1 germline variant carriers and their families, including genetic counseling and surveillance for new tumors. Methods: We collated germline variant status, tumor diagnoses, and information on BAP1 immunohistochemistry or loss of somatic heterozygosity on 106 published and 75 unpublished BAP1 germline variant-positive families worldwide to better characterize the genotypes and phenotypes associated with the BAP1-TPDS. Tumor spectrum and ages of onset were compared between missense and null variants. All statistical tests were two-sided. Results: The 181 families carried 140 unique BAP1 germline variants. The collated data confirmed the core tumor spectrum associated with the BAP1-TPDS and showed that some families carrying missense variants can exhibit this phenotype. A variety of noncore BAP1-TPDS -associated tumors were found in families of variant carriers. Median ages of onset of core tumor types were lower in null than missense variant carriers for all tumors combined (P < .001), mesothelioma (P < .001), cutaneous melanoma (P < .001), and nonmelanoma skin cancer (P < .001). Conclusions: This analysis substantially increases the number of pathogenic BAP1 germline variants and refines the phenotype. It highlights the need for a curated registry of germline variant carriers for proper assessment of the clinical phenotype of the BAP1-TPDS and pathogenicity of new variants, thus guiding management of patients and informing areas requiring further research.

5 Review Unclassified sclerosing malignant melanomas with AKAP9-BRAF gene fusion: a report of two cases and review of BRAF fusions in melanocytic tumors. 2018

Perron, Emilie / Pissaloux, Daniel / Neub, Angela / Hohl, Daniel / Tartar, Marie Dominique / Mortier, Laurent / Alberti, Laurent / de la Fouchardiere, Arnaud. ·Département de Biopathologie, Centre Leon Bérard, Lyon, France. emilie.perron.1@ulaval.ca. · Département de Biologie médicale, Service d'anatomopathologie, Centre hospitalier universitaire de Québec-Université Laval, 11 Côte du Palais, Québec, QC, G1R 2J6, Canada. emilie.perron.1@ulaval.ca. · Département de Biologie Moléculaire, de Biochimie Médicale et de Pathologie, Faculté de Médecine de l'Université Laval, Québec, Canada. emilie.perron.1@ulaval.ca. · Département de Biopathologie, Centre Leon Bérard, Lyon, France. · Service de Dermatologie et Vénérologie, Centre hospitalier universitaire vaudois (CHUV), Lausanne, Switzerland. · Service de Pathologie, Hôpital Jean Bernard, Valenciennes, France. · Service de Dermatologie, Université de Lille, INSERM U 1189, CHU Lille, F-59000, Lille, France. ·Virchows Arch · Pubmed #29464327.

ABSTRACT: The current classification of melanocytic tumors includes clinical, pathological, and molecular data. A subset of lesions remains difficult to classify according to these complex multilayer schemes. We report two cases of deeply infiltrating melanomas with a sclerosing background. The first case occurred on the back of a middle-aged man appearing clinically as a dermatofibroma. The architectural and cytological aspects resembled those of a desmoplastic melanoma but the strong expression of both melanA and HMB45, two stainings usually reported as negative in this entity, raised the question of an alternate diagnosis. The second case was a large, slowly growing, perivulvar tumor in a middle-aged woman. The morphology was complex with a central junctional spitzoid pattern associating an epidermal hyperplasia with large nests of large spindled melanocytes. The dermal component was made of deeply invasive strands and nests of nevoid unpigmented melanocytes surrounded by fibrosis; a perineural invasion was present at the periphery of the lesion. In both cases, aCGH found, among many other anomalies, a chromosomal breakpoint at the BRAF locus. RNA sequencing identified in both an AKAP9-BRAF gene fusion. A complementary resection was performed and no relapses have been observed in the respectively 15 and 6 months of follow-up. Both of these melanomas remained unclassified. We further review the variety of melanocytic tumors associated with such BRAF fusions.

6 Review [Gallbladder metastasis of melanoma: Immunohistochemical and molecular data of a case and review of the literature]. 2017

Tauziède-Espariat, Arnault / Raffoul, Johnny / Sun, Shan-Rong / Monnin, Christine / de la Fouchardière, Arnaud / Lassabe, Catherine. ·Service d'anatomie et cytologie pathologiques, centre hospitalier Belfort-Montbéliard, 2, rue du Docteur-Flamand, 25200 Montbéliard, France. Electronic address: arnault.tauziedeespariat@gmail.com. · Service d'anatomie et cytologie pathologiques, centre hospitalier Belfort-Montbéliard, 2, rue du Docteur-Flamand, 25200 Montbéliard, France. · Département de biopathologie, centre Léon-Bérard, 28, rue Laennec, 69008 Lyon, France. ·Ann Pathol · Pubmed #29153887.

ABSTRACT: We report the case of a 57-year-old man, who is hospitalized for the surgery of a gallbladder mass associated by an increase in fluorodeoxyglucose-activity on positron emission tomography/computed tomography scan. This is an incidental finding occurring during monitoring of a skin melanoma. A cholecystectomy is performed. Microscopic examination identified an infiltration of the gallbladder wall by a proliferation of atypical pigmented spindled melanocytes with numerous mitoses. The immunohistochemical analysis confirmed the melanocytic nature of this proliferation with the staining of HMB-45, S100 protein and Melan-A. A complementary immunohistochemical (p16, desmin and BRAFV600E) and molecular (BRAF sequencing) study is performed. The results are consistent with the hypothesis of a gallbladder metastasis of a cutaneous melanoma is proposed. Gallbladder metastases of melanoma are exceptional. The aim of our work is to describe a new case with immunohistochemical and molecular characterization, to review the literature on this topic and to consider the main differential diagnosis (primary malignant melanoma of the gallbladder).

7 Review [Cutaneous melanocytic tumors. Case 4]. 2016

de la Fouchardière, Arnaud. ·Département de biopathologie, centre Léon-Bérard, 28, rue Laennec, 69008 Lyon, France. Electronic address: arnaud.delafouchardiere@lyon.unicancer.fr. ·Ann Pathol · Pubmed #27641820.

ABSTRACT: -- No abstract --

8 Article CRTC1-TRIM11 fusion defined melanocytic tumors: A series of four cases. 2019

Ko, Jennifer S / Wang, Lin / Billings, Steven D / Pissaloux, Daniel / Tirode, Franck / Berry, Ryan / De La Fouchardiere, Arnaud. ·Department of Pathology, Cleveland Clinic, Cleveland, Ohio. · Department of Pathobiology, Centre Léon Bérard, Lyon, France. · Univ Lyon, Université Claude Bernard Lyon 1, Research Cancer Center of Lyon, Lyon, France. ·J Cutan Pathol · Pubmed #31237704.

ABSTRACT: A cutaneous melanocytic tumor with morphologic overlap with clear cell sarcoma, but defined by CRTC1-TRIM11 gene fusion, was recently described in a series of five adult patients. Here, we expand the clinicopathologic features of this entity by four additional cases which include pediatric presentation, exophytic growth, and propensity to occur on the head. Patients (2F; 2M) had a median age of 41 years (range 11-59). Sites of involvement included leg, ear, and face. Tumors were circumscribed, unencapsulated, mostly limited to the dermis, and varied from 5 to 35 mm. One case was exophytic. Lesional cells were arranged in nests and fascicles, and were monomorphic and fusiform with moderate pale to clear cytoplasm, occasional nuclear pseudo-inclusions, and small to prominent nucleoli. Mitotic rate was variable (rare to 12/10 HPF, median 3/10 HPF). The pediatric case showed increased nuclear pleomorphism, tumor necrosis, and mitotic figures. All cases showed strong, diffuse nuclear staining for SOX10, but were negative or focal for S100 protein, HMB45 and Melan-A expression. Cases were positive by FISH technique and/or RNA sequencing for a TRIM11 rearrangement/fusion, and negative for EWSR1 rearrangement. This series is presented to aid in further characterization of this novel melanocytic tumor.

9 Article CYSLTR2-mutant Cutaneous Melanocytic Neoplasms Frequently Simulate "Pigmented Epithelioid Melanocytoma," Expanding the Morphologic Spectrum of Blue Tumors: A Clinicopathologic Study of 7 Cases. 2019

Goto, Keisuke / Pissaloux, Daniel / Paindavoine, Sandrine / Tirode, Franck / de la Fouchardière, Arnaud. ·Department of Pathology, Tokyo Metropolitan Cancer and Infectious Disease Center Komagome Hospital. · Department of Pathology, Itabashi Central Clinical Laboratory, Tokyo. · Department of Diagnostic Pathology, Shizuoka Cancer Center Hospital, Nagaizumi. · Department of Diagnostic Pathology and Cytology, Osaka International Cancer Institute, Osaka. · Department of Dermatology, Hyogo Cancer Center, Akashi, Japan. · Department of Biopathology, Center Le[Combining Acute Accent]on Be[Combining Acute Accent]rard, Lyon, France. · University of Lyon, Claude Bernard Lyon1 University, INSERM 1052, CNRS 5286, Léon Bérard Cancer Care Center, Cancer Research Center of Lyon, Ligue Contre Le Cancer Labellised Team, Lyon, France. ·Am J Surg Pathol · Pubmed #31162285.

ABSTRACT: Recurrent activating Gαq mutations in the spectrum of blue nevi have been well studied. However, the clinicopathologic characteristics of the recently described CYSLTR2-mutant and PLCB4-mutant blue nevi remain limited, owing to their rarity. Herein, we present 7 CYSLTR2-mutant melanocytic neoplasms, including 1 cellular blue nevus, 4 atypical cellular blue nevi, and 2 blue nevus-like melanomas. They occurred on the scalp, breast, flank, forearm, thigh, leg, and ankle of 3 male patients and 4 female patients, with a median age of 43 (25 to 81) years at diagnosis. Five exhibited an exophytic growth, and 6 were heavily pigmented. A fascicular arrangement of medium to large spindle melanocytes was seen in 6 cases, but epithelioid cytology was present in only 2 cases, one of them being focal. A junctional component was present in 3 cases. Immunoreactivity for HMB45 was diffusely present, except in 1 cellular blue nevus. BAP1 nuclear immunoexpression was lost in 1 melanoma case. A canonical CYSLTR2 L129Q hotspot mutation was present in all cases. Altogether, these histopathologic findings suggest that CYSLTR2-mutant melanocytic blue neoplasms frequently exhibit a heavily pigmented exophytic tumor with a silhouette resembling "pigmented epithelioid melanocytoma" rather than usual cellular blue nevus. Moreover, most of these tumors were not clinically recognized as blue nevi and not located in the classic topography of cellular blue nevus aside from the scalp. However, a fascicular arrangement of medium to large-sized spindled melanocytes, as well as a lack of epithelioid or nevoid melanocytes, could be potential diagnostic clues to morphologically distinguish CYSLTR2-mutant tumors from "pigmented epithelioid melanocytoma."

10 Article β-Catenin nuclear expression discriminates deep penetrating nevi from other cutaneous melanocytic tumors. 2019

de la Fouchardière, Arnaud / Caillot, Claire / Jacquemus, Julien / Durieux, Emeline / Houlier, Aurélie / Haddad, Véronique / Pissaloux, Daniel. ·Departement de Biopathologie, Centre Léon Bérard, 28, rue Laennec, 69008, Lyon, France. arnaud.delafouchardiere@lyon.unicancer.fr. · Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Centre Léon Bérard, Cancer Research Center of Lyon, Equipe Labellisée Ligue contre le Cancer, Université de Lyon, Lyon, France. arnaud.delafouchardiere@lyon.unicancer.fr. · Departement de Biopathologie, Centre Léon Bérard, 28, rue Laennec, 69008, Lyon, France. · Department of Pathology, Centre Hospitalier Lyon-Sud, 69310, Lyon, France. · Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Centre Léon Bérard, Cancer Research Center of Lyon, Equipe Labellisée Ligue contre le Cancer, Université de Lyon, Lyon, France. ·Virchows Arch · Pubmed #30756182.

ABSTRACT: Recent advances in genomics have improved the molecular classification of cutaneous melanocytic tumors. Among them, deep penetrating nevi (DPN) and plexiform nevi have been linked to joint activation of the MAP kinase and dysregulation of the β-catenin pathways. Immunohistochemical studies have confirmed cytoplasmic and nuclear expression of β-catenin and its downstream effector cyclin D1 in these tumors. We assessed nuclear β-catenin immunohistochemical expression in a large group of DPN as well as in the four most frequent differential diagnoses of DPN: "blue" melanocytic tumors, Spitz tumors, nevoid and SSM melanomas, and pigmented epithelioid melanocytomas (PEM). Nuclear β-catenin expression was positive in 98/100 DPN and 2/16 of melanomas (one SSM and one nevoid melanoma with a plexiform clone) and was negative in all 30 Spitz, 26 blue, and 6 PEM lesions. In 41% DPN, β-catenin expression was positive in more than 30% nuclei. No differences were observed in cytoplasmic and nuclear cyclin D1 expression between these tumor groups, suggesting alternate, β-catenin-independent, activation pathways. We have subsequently studied nuclear β-catenin expression in a set of 13 tumors with an ambiguous diagnosis, for which DPN was part of the differential diagnosis. The three out of four patients showing canonical DPN mutation profiles were the only β-catenin-positive cases. We conclude that nuclear β-catenin expression, independently from CCND1 expression, in a dermal melanocytic tumor is an argument for its classification as DPN. In ambiguous cases and in early combined DPN lesions, this antibody can be helpful as a screening tool. β-Catenin is also potentially expressed in a subset of malignant melanomas with CTNNB1 mutations.

11 Article Tspan8-β-catenin positive feedback loop promotes melanoma invasion. 2019

El Kharbili, Manale / Agaësse, Gweltaz / Barbollat-Boutrand, Laetitia / Pommier, Roxane M / de la Fouchardière, Arnaud / Larue, Lionel / Caramel, Julie / Puisieux, Alain / Berthier-Vergnes, Odile / Masse, Ingrid. ·Université de Lyon, F-69003, Lyon, France. · Université Lyon 1, Lyon, F-69003, France. · CNRS, UMR5534, Centre de Génétique et de Physiologie Moléculaires et Cellulaires, Villeurbanne, F-69622, France. · Department of Dermatology, University of Colorado Anschutz Medical Campus, 12800 E. 19th Avenue, P18-8132, Aurora, CO, 80045, USA. · Centre de Recherche en Cancérologie de Lyon, CNRS UMR5286, Inserm U1052, Université de Lyon, Université Lyon 1, 69000, Lyon, France. · Département de Biopathologie, Centre Leon Bérard, Lyon, France. · Institut Curie, PSL Research University, INSERM U1021, Normal and Pathological Development of Melanocytes, Orsay, France. · Univ Paris-Sud, Univ Paris-Saclay, CNRS UMR 3347, Orsay, France. · Equipe Labellisée Ligue Contre le Cancer, Orsay, France. · Université de Lyon, F-69003, Lyon, France. ingrid.masse@univ-lyon1.fr. · Université Lyon 1, Lyon, F-69003, France. ingrid.masse@univ-lyon1.fr. · CNRS, UMR5534, Centre de Génétique et de Physiologie Moléculaires et Cellulaires, Villeurbanne, F-69622, France. ingrid.masse@univ-lyon1.fr. · Centre de Recherche en Cancérologie de Lyon, CNRS UMR5286, Inserm U1052, Université de Lyon, Université Lyon 1, 69000, Lyon, France. ingrid.masse@univ-lyon1.fr. ·Oncogene · Pubmed #30679790.

ABSTRACT: Due to its high proclivity to metastasize, and despite the recent development of targeted and immune therapy strategies, melanoma is still the deadliest form of skin cancer. Therefore, understanding the molecular mechanisms underlying melanoma invasion remains crucial. We previously characterized Tspan8 for its ability to prompt melanoma cell detachment from their microenvironment and trigger melanoma cell invasiveness, but the signaling events by which Tspan8 regulates the invasion process still remain unknown. Here, we demonstrated that β-catenin stabilization is a molecular signal subsequent to the onset of Tspan8 expression, and that, in turn, β-catenin triggers the direct transcriptional activation of Tspan8 expression, leading to melanoma invasion. Moreover, we showed that β-catenin activation systematically correlates with a high expression of Tspan8 protein in melanoma lesions from transgenic Nras; bcat* mice, as well as in deep penetrating naevi, a type of human pre-melanoma neoplasm characterized by a combined activation of β-catenin and MAP kinase signaling. Overall, our data suggest that β-catenin and Tspan8 are part of a positive feedback loop, which sustains a high Tspan8 expression level, conferring to melanoma cells the invasive properties required for tumor progression and dissemination.

12 Article Clinical and dermoscopic features of cutaneous BAP1-inactivated melanocytic tumors: Results of a multicenter case-control study by the International Dermoscopy Society. 2019

Yélamos, Oriol / Navarrete-Dechent, Cristián / Marchetti, Michael A / Rogers, Tova / Apalla, Zoe / Bahadoran, Philippe / Blázquez-Sánchez, Nuria / Busam, Klaus / Carrera, Cristina / Dusza, Stephen W / de la Fouchardière, Arnaud / Ferrara, Gerardo / Gerami, Pedram / Kittler, Harald / Lallas, Aimilios / Malvehy, Josep / Millán-Cayetano, José F / Nelson, Kelly C / Quan, Victor Li / Puig, Susana / Stevens, Howard / Thomas, Luc / Marghoob, Ashfaq A. ·Dermatology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York; Dermatology Department, Hospital Clínic, Institut d'Investigacions Biomediques August Pi i Sunyer, Universitat de Barcelona, and CIBER de Enfermedades Raras, Instituto de Salud Carlos III, Barcelona, Spain. Electronic address: oyelamos@gmail.com. · Dermatology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York; Department of Dermatology, Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile. · Dermatology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York. · First Department of Dermatology, Aristotle University, Thessaloniki, Greece. · Dermatology Department, Centre Hospitalier Universitaire de Nice, Nice, France. · Dermatology Department, Hospital Costa del Sol, Marbella, Spain. · Pathology Department, Memorial Sloan Kettering Cancer Center, New York, New York. · Dermatology Department, Hospital Clínic, Institut d'Investigacions Biomediques August Pi i Sunyer, Universitat de Barcelona, and CIBER de Enfermedades Raras, Instituto de Salud Carlos III, Barcelona, Spain. · Département de Biopathologie, Centre Léon Bérard, Lyon, France. · Anatomic Pathology Unit, Hospital of Macerata, Macerata, Italy. · Dermatology Department, Feinberg School of Medicine, Northwestern University, Chicago, Illinois. · Department of Dermatology, Medical University of Vienna, Vienna, Austria. · Dermatology Department, The University of Texas MD Anderson Cancer Center, Houston, Texas. · Skin Care Network, Barnet, London, United Kingdom. · Department of Dermatology, Lyon 1 University, Centre Hospitalier Lyon Sud and Lyon's Cancer Research Center INSERM U1052 - CNRS UMR5286, Lyon, France. ·J Am Acad Dermatol · Pubmed #30244062.

ABSTRACT: BACKGROUND: Multiple BRCA1-associated protein 1 (BAP1)-inactivated melanocytic tumors (BIMTs) have been associated with a familial cancer syndrome involving germline mutations in BAP1. OBJECTIVES: We sought to describe the clinical and dermoscopic features of BIMTs. METHODS: This was a retrospective, multicenter, case-control study. Participating centers contributed clinical data, dermoscopic images, and histopathologic data of biopsy-proven BIMTs. We compared the dermoscopic features between BIMTs and control patients. RESULTS: The dataset consisted of 48 BIMTs from 31 patients (22 women; median age 37 years) and 80 control patients. Eleven patients had a BAP1 germline mutation. Clinically, most BIMTs presented as pink, dome-shaped papules (n = 24). Dermoscopically, we identified 5 patterns: structureless pink-to-tan with irregular eccentric dots/globules (n = 14, 29.8%); structureless pink-to-tan with peripheral vessels (n = 10, 21.3%); structureless pink-to-tan (n = 7, 14.9%); a network with raised, structureless, pink-to-tan areas (n = 7, 14.9%); and globular pattern (n = 4, 8.5%). The structureless with eccentric dots/globules pattern and network with raised structureless areas pattern were only identified in BIMT and were more common in patients with BAP1 germline mutations (P < .0001 and P = .001, respectively). LIMITATIONS: Limitations included our small sample size, retrospective design, the absence of germline genetic testing in all patients, and inclusion bias toward more atypical-looking BIMTs. CONCLUSIONS: Dome-shaped papules with pink-to-tan structureless areas and peripheral irregular dots/globules or network should raise the clinical suspicion for BIMT.

13 Article The Ectodysplasin receptor EDAR acts as a tumor suppressor in melanoma by conditionally inducing cell death. 2019

Vial, Jonathan / Royet, Amélie / Cassier, Philippe / Tortereau, Antonin / Dinvaut, Sarah / Maillet, Denis / Gratadou-Hupon, Lise / Creveaux, Marion / Sadier, Alexa / Tondeur, Garance / Léon, Sophie / Depaepe, Lauriane / Pantalacci, Sophie / de la Fouchardière, Arnaud / Micheau, Olivier / Dalle, Stéphane / Laudet, Vincent / Mehlen, Patrick / Castets, Marie. ·Dependence Receptors, Cancer and Development Laboratory - Equipe labellisée 'La Ligue', LabEx DEVweCAN, Centre de Cancérologie de Lyon, INSERM U1052-CNRS UMR5286, Université de Lyon, Centre Léon Bérard, 69008, Lyon, France. · National Veterinary School, F-69280 Marcy L'Etoile, Lyon, France. · UnivLyon, ENS de Lyon, Université de Lyon, CNRS UMR5239, INSERM U1210, Lyon, France. · Department of Dermatology, Centre Hospitalier Lyon Sud, Pierre Bénite, France. · Anatomopathology service, Centre Léon Bérard, 69008, Lyon, France. · Institut National de la Santé et de la Recherche Médicale, UMR866, F-21079, Dijon, France. · Observatoire Océanologique de Banyuls-sur-Mer, 1, avenue du Fontaulé, 66650, Banyuls-sur-Mer, France. · Dependence Receptors, Cancer and Development Laboratory - Equipe labellisée 'La Ligue', LabEx DEVweCAN, Centre de Cancérologie de Lyon, INSERM U1052-CNRS UMR5286, Université de Lyon, Centre Léon Bérard, 69008, Lyon, France. patrick.mehlen@lyon.unicancer.fr. · Dependence Receptors, Cancer and Development Laboratory - Equipe labellisée 'La Ligue', LabEx DEVweCAN, Centre de Cancérologie de Lyon, INSERM U1052-CNRS UMR5286, Université de Lyon, Centre Léon Bérard, 69008, Lyon, France. marie.castets@lyon.unicancer.fr. ·Cell Death Differ · Pubmed #29855541.

ABSTRACT: Ectodysplasin receptor EDAR is seen as a typical Tumor Necrosis Factor receptor (TNFR) family member known to interact with its ligand Eda-A1, and signaling mainly through the nuclear factor-kappaB (NF-κB) and c-jun N-terminal kinases pathways. Mutations in genes that encode proteins involved in EDAR transduction cascade cause anhidrotic ectodermal dysplasia. Here, we report an unexpected pro-apoptotic activity of EDAR when unbound to its ligand Eda-A1, which is independent of NF-κB pathway. Contrarily to other death receptors, EDAR does recruit caspase-8 to trigger apoptosis but solely upon ligand withdrawal, thereby behaving as the so-called dependence receptors. We propose that pro-apoptotic activity of unbound EDAR confers it a tumor suppressive activity. Along this line, we identified loss-of-pro-apoptotic function mutations in EDAR gene in human melanoma. Moreover, we show that the invalidation of EDAR in mice promotes melanoma progression in a B-Raf mutant background. Together, these data support the view that EDAR constrains melanoma progression by acting as a dependence receptor.

14 Article Primary malignant melanoma of the esophagus, treated with immunotherapy: a case report. 2018

Rochefort, Pauline / Roussel, Juliette / de la Fouchardière, Arnaud / Sarabi, Matthieu / Desseigne, Françoise / Guibert, Pierre / Cattey-Javouhey, Anne / Mastier, Charles / Neidhardt-Berard, Eve-Marie / de la Fouchardière, Christelle. ·Department of Medical Oncology, Centre Leon Berard, Claude Bernard University, Lyon, France. · Department of Biopathology, Centre Leon Berard, Claude Bernard University, Lyon, France. · Departement of Radiology, Centre Leon Berard, Claude Bernard University, Lyon, France. ·Immunotherapy · Pubmed #30073896.

ABSTRACT: Primary malignant melanoma of the esophagus is rare, accounting for less than 0.1-0.2% of all esophageal malignancies. It is associated with a poor outcome due to late detection and high metastatic potential. Here, we report a case of esophageal cancer, which was initially diagnosed as an adenocarcinoma and finally was confirmed as a primary malignant melanoma. This 75-year-old Caucasian male had a history of dysphagia and recent lingering abdominal pain. First biopsy showed a poorly-differentiated adenocarcinoma. He was then treated with neoadjuvant radiochemotherapy. Biopsies were repeated because of an incomplete tumor response, evaluated by endoscopic and imaging studies. The final diagnosis was a malignant melanoma. The patient has been treated with immune-checkpoint inhibitor, nivolumab, an anti-PD1 antibody.

15 Article Expression of the serotonin receptor 2B in uveal melanoma and effects of an antagonist on cell lines. 2018

Weidmann, Cindy / Bérubé, Julie / Piquet, Léo / de la Fouchardière, Arnaud / Landreville, Solange. ·Axe Médecine régénératrice and Centre Universitaire d'Ophtalmologie (CUO)-Recherche, Centre de recherche du CHU de Québec, Quebec City, QC, Canada. · Centre de recherche sur le cancer de l'Université Laval, Quebec City, QC, Canada. · Centre de recherche en organogénèse expérimentale de l'Université Laval/LOEX, Quebec City, QC, Canada. · Département d'ophtalmologie, Faculté de médecine, Université Laval, Quebec City, QC, Canada. · Département de biopathologie, Centre Léon Bérard, Lyon, France. · Axe Médecine régénératrice and Centre Universitaire d'Ophtalmologie (CUO)-Recherche, Centre de recherche du CHU de Québec, Quebec City, QC, Canada. Solange.Landreville@fmed.ulaval.ca. · Centre de recherche sur le cancer de l'Université Laval, Quebec City, QC, Canada. Solange.Landreville@fmed.ulaval.ca. · Centre de recherche en organogénèse expérimentale de l'Université Laval/LOEX, Quebec City, QC, Canada. Solange.Landreville@fmed.ulaval.ca. · Département d'ophtalmologie, Faculté de médecine, Université Laval, Quebec City, QC, Canada. Solange.Landreville@fmed.ulaval.ca. ·Clin Exp Metastasis · Pubmed #29696577.

ABSTRACT: Uveal melanoma (UM) is the most common primary tumor in the adult, and disseminates to the liver in half of patients. A 15-gene expression profile prognostic assay allows to determine the likelihood of metastasis in patients using their ocular tumor DNA, but a cure still remains to be discovered. The serotonin receptor 2B represents the discriminant gene of this molecular signature with the greatest impact on the prognosis of UM. However, its contribution to the metastatic potential of UM remains unexplored. The purpose of this study was to investigate the effects of a selective serotonin receptor 2B antagonist on cellular and molecular behaviours of UM cells. UM cell lines expressing high level of serotonin receptor 2B proteins were selected by Western blotting. The selective serotonin receptor 2B antagonist PRX-08066 was evaluated for its impact on UM cells using viability assays, phosphorylated histone H3 immunostainings, clonogenic assays, migration assays, invasion assays and membrane-based protein kinase phosphorylation antibody arrays. The pharmacological inhibition of the serotonin receptor 2B reduced the viability of UM cells and the population in mitosis, and impaired their clonogenicity and potential of migration. It also decreased the phosphorylation of kinases from signaling pathways classically activated by the serotonin receptor 2B, as well as kinases β-catenin, Proline-rich tyrosine kinase 2, and Signal transducer and activator of transcription 5. Our findings support a role for the serotonin receptor 2B in the proliferation and migration of UM cells, through activation of many signaling pathways such as WNT, Focal adhesion kinase and Janus kinase/STAT.

16 Article Melanocytic Myxoid Spindle Cell Tumor With ALK Rearrangement (MMySTAR): Report of 4 Cases of a Nevus Variant With Potential Diagnostic Challenge. 2018

Perron, Emilie / Pissaloux, Daniel / Charon Barra, Celine / Karanian, Marie / Lamant, Laurence / Parfait, Sophie / Alberti, Laurent / de la Fouchardière, Arnaud. ·Departement of Biopathology, Centre Leon Bérard, Lyon. · Department of Pathology, Centre Hospitalier Universitaire de Québec-Université Laval. · Department of Molecular Biology and Medical Biochemistry, Faculté de médecine de l'Université Laval, Québec City, QC, Canada. · Centre George François Leclerc, Dijon. · Department of Histopathology, University Hospitals of Toulouse, Toulouse. · Pathology Laboratory of Auxerre, Auxerre, France. ·Am J Surg Pathol · Pubmed #29635259.

ABSTRACT: Melanocytic tumors rarely display extensive dermal myxoid deposits except in the myxoid variant of melanoma. We describe in 4 patients the unusual association of morphologic and genetic features. All cases occurred in males and were located on the limbs or proximal girdle area. Age at diagnosis ranged from 8 to 47 years. Size ranged from 6 to 11 mm. Microscopic analysis showed compound, but mainly dermal melanocytic nevi, all presenting a deep dermal expansion with fascicules of amelanotic spindled cells floating in a myxoid background. Cytologic atypia and mitotic activity were low. The superficial portion was either of spitzoid or nevoid cytology with a limited junctional component. In the initial case, the dermal myxoid component was predominant with rare, barely visible, superficial melanocytic nests. This peculiar morphology was responsible for a delayed diagnostic, which required an extensive panel of antibodies ruling out most, potentially myxoid, soft tissue tumors. We later observed the presence of similar, but more limited, dermal morphologic features in 3 other cases. Immunohistochemistry in the deep myxoid areas was melanA, ALK, SOX10, and MiTF. Molecular studies confirmed the ALK rearrangement by an ALK break-apart fluorescence in situ hybridization technique and by RNA sequencing. The latter identified 4 different 5'-fusion partners. Two gene fusions were undescribed: FBXO28(e2)-ALK(e19) and NPAS2(e2)-ALK(e19), and 2 previously described: TPM3(e7)-ALK(e20) and PPFIBP1(e9)-ALK(e19). No relapse or metastatic evolution was seen during follow-up (3 to 24 mo). We denominated this potentially challenging new variant of compound nevus linked to a kinase fusion: Melanocytic Myxoid Spindle Cell Tumor with ALK Rearrangement.

17 Article Atypical cutaneous melanocytic tumours arising in two patients with Li-Fraumeni syndrome. 2017

Jacquemus, Julien / Perron, Emilie / Pissaloux, Daniel / Alberti, Laurent / de la Fouchardière, Arnaud. ·Département of Biopathology, Centre Leon Bérard, Lyon, France. · Département of Biopathology, Centre Leon Bérard, Lyon, France; Service d'anatomopathologie, Centre Hospitalier Universitaire de Québec-Université Laval, Canada; Département de Biologie Moléculaire, de Biochimie Médicale et de Pathologie, Faculté de Médecine, Université Laval, Québec, Canada. · Département of Biopathology, Centre Leon Bérard, Lyon, France. Electronic address: arnaud.delafouchardiere@lyon.unicancer.fr. ·Pathology · Pubmed #29108654.

ABSTRACT: -- No abstract --

18 Article Combined activation of MAP kinase pathway and β-catenin signaling cause deep penetrating nevi. 2017

Yeh, Iwei / Lang, Ursula E / Durieux, Emeline / Tee, Meng Kian / Jorapur, Aparna / Shain, A Hunter / Haddad, Veronique / Pissaloux, Daniel / Chen, Xu / Cerroni, Lorenzo / Judson, Robert L / LeBoit, Philip E / McCalmont, Timothy H / Bastian, Boris C / de la Fouchardière, Arnaud. ·Department of Dermatology, University of California, San Francisco, 94143, CA, USA. Iwei.Yeh@ucsf.edu. · Department of Pathology, University of California, San Francisco, 94143, CA, USA. Iwei.Yeh@ucsf.edu. · Department of Pathology, University of California, San Francisco, 94143, CA, USA. · Department of Pathology, Centre Hospitalier Lyon-Sud, Lyon, 69310, France. · Department of Dermatology, University of California, San Francisco, 94143, CA, USA. · Department of Biopathology, Centre Léon Bérard, Lyon, 69008, France. · Department of Dermatology, Medical University of Graz, Graz, 8036, Austria. ·Nat Commun · Pubmed #28935960.

ABSTRACT: Deep penetrating nevus (DPN) is characterized by enlarged, pigmented melanocytes that extend through the dermis. DPN can be difficult to distinguish from melanoma but rarely displays aggressive biological behavior. Here, we identify a combination of mutations of the β-catenin and mitogen-activated protein kinase pathways as characteristic of DPN. Mutations of the β-catenin pathway change the phenotype of a common nevus with BRAF mutation into that of DPN, with increased pigmentation, cell volume and nuclear cyclin D1 levels. Our results suggest that constitutive β-catenin pathway activation promotes tumorigenesis by overriding dependencies on the microenvironment that constrain proliferation of common nevi. In melanoma that arose from DPN we find additional oncogenic alterations. We identify DPN as an intermediate stage in the step-wise progression from nevus to melanoma. In summary, we delineate specific genetic alterations and their sequential order, information that can assist in the diagnostic classification and grading of these distinctive neoplasms.Deep penetrating nevi (DPN) are unusual melanocytic neoplasms with unknown genetic drivers. Here the authors show that majority of DPN harbor activating mutations in the β-catenin and the MAP-kinase pathways; this characteristic can help in the classification and grading of these distinctive neoplasms.

19 Article A large-scale RNAi screen identifies LCMR1 as a critical regulator of Tspan8-mediated melanoma invasion. 2017

Agaësse, G / Barbollat-Boutrand, L / Sulpice, E / Bhajun, R / El Kharbili, M / Berthier-Vergnes, O / Degoul, F / de la Fouchardière, A / Berger, E / Voeltzel, T / Lamartine, J / Gidrol, X / Masse, I. · ·Oncogene · Pubmed #28628117.

ABSTRACT: This corrects the article DOI: 10.1038/onc.2016.219.

20 Article Germline 2017

Jouenne, Fanélie / Chauvot de Beauchene, Isaure / Bollaert, Emeline / Avril, Marie-Françoise / Caron, Olivier / Ingster, Olivier / Lecesne, Axel / Benusiglio, Patrick / Terrier, Philippe / Caumette, Vincent / Pissaloux, Daniel / de la Fouchardière, Arnaud / Cabaret, Odile / N'Diaye, Birama / Velghe, Amélie / Bougeard, Gaelle / Mann, Graham J / Koscielny, Serge / Barrett, Jennifer H / Harland, Mark / Newton-Bishop, Julia / Gruis, Nelleke / Van Doorn, Remco / Gauthier-Villars, Marion / Pierron, Gaelle / Stoppa-Lyonnet, Dominique / Coupier, Isabelle / Guimbaud, Rosine / Delnatte, Capucine / Scoazec, Jean-Yves / Eggermont, Alexander M / Feunteun, Jean / Tchertanov, Luba / Demoulin, Jean-Baptiste / Frebourg, Thierry / Bressac-de Paillerets, Brigitte. ·Département de Biologie et Pathologie Médicales, Gustave Roussy, Université Paris-Saclay, Villejuif, France. · INSERM, U1186, Université Paris-Saclay, Villejuif, France. · Department of Physics T38, Technical University of Munich, Garching, Germany. · De Duve Institute, Université Catholique de Louvain, Brussels, Belgium. · Department of Dermatology, Assistance Publique-Hopitaux de Paris, Hopital Cochin Tarnier, Paris, France. · Faculté de Médecine, Paris 5 Descartes, Paris, France. · Département de Médecine Oncologique, Gustave Roussy, Université Paris-Saclay, Villejuif, France. · Service de Génétique Médicale, CHU d'Angers, Angers, France. · Department of Pathology, Centre Leon Bérard, Lyon, Rhône-Alpes, France. · Faculty of Medicine, INSERM U1079, Normandy University, Rouen, France. · Department of Genetics, Rouen University Hospital, Normandy Centre for Genomic and personalized Medicine, Rouen, Haute-Normandie, France. · Centre for Cancer Research, Weastmead Institute for Medical Research and Melanoma Institute, Sydney, New South Wales, Australia. · Service de Biostatistiques et d'Epidemiologie, Gustave Roussy, Villejuif, France. · INSERM U1018, CESP, Université Paris-Sud, Université Paris-Saclay, Villejuif, France. · Section of Epidemiology and Biostatistics, Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, UK. · Department of Dermatology, Leiden University Medical Center, Leiden, The Netherlands. · Institut Curie Hospital Group, Service de Génétique, Paris, France. · Hopital Arnaud de Villeneuve, Service de Génétique Médicale et Oncogénétique, CHU de Montpellier, Montpellier, France. · CRCM Val d'Aurellle, INSERM U896, Montpellier, France. · Toulouse University Hospital, Toulouse, France. · Unité d'Oncogénétique, Centre René Gauducheau, Nantes Saint Herblain, France. · INSERM U1015 and Faculté de médecine, Gustave Roussy, Université Paris-Saclay, Villejuif, France. · CNRS UMR8200, Gustave Roussy, Université Paris-Saclay, Villejuif, France. · Centre de Mathématiques et de leurs applications, Ecole Normale Supérieure de Cachan, Université Paris-Saclay, Cachan, France. ·J Med Genet · Pubmed #28592523.

ABSTRACT: BACKGROUND: Sarcomas are rare mesenchymal malignancies whose pathogenesis is poorly understood; both environmental and genetic risk factors could contribute to their aetiology. METHODS AND RESULTS: We performed whole-exome sequencing (WES) in a familial aggregation of three individuals affected with soft-tissue sarcoma (STS) without TP53 mutation (Li-Fraumeni-like, LFL) and found a shared pathogenic mutation in CONCLUSION: Germline mutations in

21 Article Occurrence of BAP1 germline mutations in cutaneous melanocytic tumors with loss of BAP1-expression: A pilot study. 2017

Cabaret, Odile / Perron, Emilie / Bressac-de Paillerets, Brigitte / Soufir, Nadem / de la Fouchardière, Arnaud. ·Gustave Roussy, Service de Génétique, Villejuif, France. · Département of Biopathology, Centre Leon Bérard, Lyon, France. · Service d'anatomopathologie, Centre Hospitalier Universitaire de Québec-Université Laval, Canada. · Département de biologie moléculaire, de biochimie médicale et de pathologie, Faculté de médecine, Université Laval, Québec, Canada. · INSERM, U976 & AP-HP, Hôpital Bichat Claude Bernard, Paris, France. ·Genes Chromosomes Cancer · Pubmed #28560743.

ABSTRACT: Melanocytic BAP1-associated intradermal tumors (MBAITs) can either be sporadic or associated with a cancer-predisposition syndrome. In this study we explored the clinical status of 136 patients in which at least one MBAIT was found. 49/136 (36%) of them gave their signed consent for an oncogenetic BAP1 blood test. 28/136 patients (20%) diagnosed with an MBAIT had other MBAITs and/or a personal or familial history of BAP1-related cancers that could clinically designate them as potential carriers of a BAP1 germline mutation. 17 of these 28 patients underwent oncogenetic testing. A deleterious mutation of BAP1 was confirmed in 12/17 cases. 4/17 cases were wild-type; all had a single MBAIT and a history of skin melanoma. A variant of unknown significance was found in one case with multiple MBAITs. Among the 12 mutated cases, multiple MBAITs were present in 10/12 cases and were the only clinical sign in 4/12 cases. The remaining 32/49 blood-tested cases with an isolated MBAIT were wild type for BAP1 in 25/32 cases or showed a variant of unknown significance in 7/32 cases. We recommend, following the diagnosis of a MBAIT, performing a BAP1 immunohistochemistry in all other cutaneous melanocytic tumors removed previously or simultaneously and all skin melanomas. This screening could help clinicians prioritize which patients would most benefit from oncogenetic testing.

22 Article Tetraspanin 8 is a novel regulator of ILK-driven β1 integrin adhesion and signaling in invasive melanoma cells. 2017

El Kharbili, Manale / Robert, Clément / Witkowski, Tiffany / Danty-Berger, Emmanuelle / Barbollat-Boutrand, Laetitia / Masse, Ingrid / Gadot, Nicolas / de la Fouchardière, Arnaud / McDonald, Paul C / Dedhar, Shoukat / Le Naour, François / Degoul, Françoise / Berthier-Vergnes, Odile. ·Université de Lyon, Lyon, France. · Université Lyon 1, Lyon, France. · CNRS, UMR5534, Centre de Génétique et de Physiologie Moléculaire et Cellulaire, Villeurbanne, France. · Current address: Department of Dermatology, University of Colorado, Aurora, Colorado, USA. · Clermont Université, Université d'Auvergne, Imagerie Moléculaire et Thérapie Vectorisée, Clermont-Ferrand, France. · Inserm, U990, Clermont-Ferrand, France. · Laboratoire CarMeN (INSERM 1060, INRA1397, INSA), Université Lyon 1, Lyon, France. · Université Lyon 1, Fédération de Recherche Santé Lyon-Est, ANIPATH, Faculté Laennec, Lyon, France. · Département de Biopathologie, Centre Léon Bérard, Lyon, France. · Department of Integrative Oncology, British Columbia Cancer Research Center, Vancouver, Canada. · INSERM U602, Villejuif, France. · Current address: INSERM U1193, Hôpital Paul Brousse, Villejuif, France. ·Oncotarget · Pubmed #28188308.

ABSTRACT: Melanoma is well known for its propensity for lethal metastasis and resistance to most current therapies. Tumor progression and drug resistance depend to a large extent on the interplay between tumor cells and the surrounding matrix. We previously identified Tetraspanin 8 (Tspan8) as a critical mediator of melanoma invasion, whose expression is absent in healthy skin. The present study investigated whether Tspan8 may influence cell-matrix anchorage and regulate downstream molecular pathways leading to an aggressive behavior. Using silencing and ectopic expression strategies, we showed that Tspan8-mediated invasion of melanoma cells resulted from defects in cell-matrix anchorage by interacting with β1 integrins and by interfering with their clustering, without affecting their surface or global expression levels. These effects were associated with impaired phosphorylation of integrin-linked kinase (ILK) and its downstream target Akt-S473, but not FAK. Specific blockade of Akt or ILK activity strongly affected cell-matrix adhesion. Moreover, expression of a dominant-negative form of ILK reduced β1 integrin clustering and cell-matrix adhesion. Finally, we observed a tumor-promoting effect of Tspan8 in vivo and a mutually exclusive expression pattern between Tspan8 and phosphorylated ILK in melanoma xenografts and human melanocytic lesions. Altogether, the in vitro, in vivo and in situ data highlight a novel regulatory role for Tspan8 in melanoma progression by modulating cell-matrix interactions through β1 integrin-ILK axis and establish Tspan8 as a negative regulator of ILK activity. These findings emphasize the importance of targeting Tspan8 as a means of switching from low- to firm-adhesive states, mandatory to prevent tumor dissemination.

23 Article A large-scale RNAi screen identifies LCMR1 as a critical regulator of Tspan8-mediated melanoma invasion. 2017

Agaësse, G / Barbollat-Boutrand, L / Sulpice, E / Bhajun, R / El Kharbili, M / Berthier-Vergnes, O / Degoul, F / de la Fouchardière, A / Berger, E / Voeltzel, T / Lamartine, J / Gidrol, X / Masse, I. ·Université de Lyon, Lyon, France. · Université Lyon 1, Lyon, France. · CNRS, UMR5534, Centre de Génétique et de Physiologie Moléculaires et Cellulaires, Villeurbanne, France. · Université Grenoble-Alpes, Grenoble, France. · CEA, BIG-BGE, Biomics, Grenoble, France. · Inserm, BGE, Grenoble, France. · Clermont Université, Université d'Auvergne, Imagerie Moléculaire et Thérapie Vectorisée, BP, Clermont-Ferrand, France. · Inserm, U 990, Clermont-Ferrand, France. · Département de Biopathologie, Centre Léon Bérard, Lyon, France. · Laboratoire CarMeN (INSERM 1060, INRA 1397, INSA), Université de Lyon, Lyon, France. · Centre de Recherche en Cancérologie de Lyon, CNRS UMR5286, Inserm U1052, Université de Lyon, Université Lyon 1, Lyon, France. ·Oncogene · Pubmed #27375018.

ABSTRACT: Melanoma is the deadliest form of skin cancer owing to its proclivity to metastasise, and recently developed therapies have not yielded the expected results, because almost all patients relapse. Therefore, understanding the molecular mechanisms that underlie early invasion by melanoma cells is crucial to improving patient survival. We have previously shown that, whereas the Tetraspanin 8 protein (Tspan8) is undetectable in normal skin and benign lesions, its expression arises with the progression of melanoma and is sufficient to increase cell invasiveness. Therefore, to identify Tspan8 transcriptional regulators that could explain the onset of Tspan8 expression, thereby conferring an invasive phenotype, we performed an innovative RNA interference-based screen, which, for the first time, identified several Tspan8 repressors and activators, such as GSK3β, PTEN, IQGAP1, TPT1 and LCMR1. LCMR1 is a recently identified protein that is overexpressed in numerous carcinomas; its expression and role, however, had not previously been studied in melanoma. The present study identified Tspan8 as the first LCMR1 target that could explain its function in carcinogenesis. LCMR1 modulation was sufficient to positively regulate endogenous Tspan8 expression, with concomitant in vitro phenotypic changes such as loss of melanoma cell-matrix adherence and increase in invasion, and Tspan8 expression promoted tumourigenicity in vivo. Moreover, LCMR1 and Tspan8 overexpression were shown to correlate in melanoma lesions, and both proteins could be downregulated in vitro by vemurafenib. In conclusion, this study highlights the importance of Tspan8 and its regulators in the control of early melanoma invasion and suggests that they may be promising new therapeutic targets downstream of the RAF-MEK-ERK signalling pathway.

24 Article Effects of Long-term Serial Passaging on the Characteristics and Properties of Cell Lines Derived From Uveal Melanoma Primary Tumors. 2016

Mouriaux, Frédéric / Zaniolo, Karine / Bergeron, Marjorie-Allison / Weidmann, Cindy / De La Fouchardière, Arnaud / Fournier, Frédéric / Droit, Arnaud / Morcos, Mohib W / Landreville, Solange / Guérin, Sylvain L. ·Centre universitaire d'ophtalmologie-Recherche (CUO-Recherche), Axe médecine régénératrice, Hôpital du Saint-Sacrement, Centre de Recherche FRQS du CHU de Québec-Université Laval, Québec, Canada 2Département d'ophtalmologie, Faculté de Médecine, Université Laval, Québec, Canada 3CNRS, UMR 6301 ISTCT, CERVOxy. GIP CYCERON, Caen, France 4CHU de Rennes, Service d'Ophtalmologie, France. · Centre universitaire d'ophtalmologie-Recherche (CUO-Recherche), Axe médecine régénératrice, Hôpital du Saint-Sacrement, Centre de Recherche FRQS du CHU de Québec-Université Laval, Québec, Canada 5Centre de recherche en organogénèse expérimentale de l'Université Laval/LOEX, Québec, Canada. · Département de biopathologie, Centre Léon Bérard, Lyon, France. · Département de médecine moléculaire, CHUL, Centre de Recherche FRQS du CHU de Québec-Université Laval, Québec, Canada. · Centre de recherche en organogénèse expérimentale de l'Université Laval/LOEX, Québec, Canada 8Service de pathologie, Hôpital du Saint-Sacrement, Centre de Recherche FRQS du CHU de Québec-Université Laval, Québec, Canada. · Centre universitaire d'ophtalmologie-Recherche (CUO-Recherche), Axe médecine régénératrice, Hôpital du Saint-Sacrement, Centre de Recherche FRQS du CHU de Québec-Université Laval, Québec, Canada 2Département d'ophtalmologie, Faculté de Médecine, Université Laval, Québec, Canada 5Centre de recherche en organogénèse expérimentale de l'Université Laval/LOEX, Québec, Canada. ·Invest Ophthalmol Vis Sci · Pubmed #27723895.

ABSTRACT: Purpose: Development of liver metastasis remains the most common cause of mortality in uveal melanoma (UM). A few cell lines cultured from primary UM tumors have been used widely to investigate the pathobiology of UM. However, the translation of basic knowledge to the clinic for the treatment of the metastatic disease has remained incremental at best. In this study, we examined whether the properties of UM cell lines at various passages were similar to their corresponding primary tumors. Methods: Gene expression profiling by microarray was performed on UM primary tumors and derived cell lines cultured at varying passages. Expression of UM protein markers was monitored by immunohistochemical analyses and Western blotting. The in vivo tumorigenic properties of UM cultures were evaluated using athymic nude mice. Results: Cell passaging severely reduced the expression of genes encoding markers typical of UM, including those of the prognostic gene signature. Marked differences between gene expression profiles of primary tumors and cell lines could be linked to the infiltrating immune and stromal cells in situ. In addition, the tumorigenic properties of UM cell lines also increased with cell passaging in culture as evaluated by their subcutaneous injection into athymic mice. Conclusions: Together, these findings demonstrate that the short-term UM primary cultures exhibit molecular features that resemble the respective surgical material and, thus, represent the best model for in vitro-assessed cancer treatments.

25 Article ZEB1-mediated melanoma cell plasticity enhances resistance to MAPK inhibitors. 2016

Richard, Geoffrey / Dalle, Stéphane / Monet, Marie-Ambre / Ligier, Maud / Boespflug, Amélie / Pommier, Roxane M / de la Fouchardière, Arnaud / Perier-Muzet, Marie / Depaepe, Lauriane / Barnault, Romain / Tondeur, Garance / Ansieau, Stéphane / Thomas, Emilie / Bertolotto, Corine / Ballotti, Robert / Mourah, Samia / Battistella, Maxime / Lebbé, Céleste / Thomas, Luc / Puisieux, Alain / Caramel, Julie. ·Cancer Research Center of Lyon, INSERM U1052, Lyon, France Cancer Research Center of Lyon, CNRS UMR 5286, Lyon, France Université de Lyon, Lyon, France ISPB Université Lyon 1, Lyon, France Centre Léon Bérard, Lyon, France. · Cancer Research Center of Lyon, INSERM U1052, Lyon, France Cancer Research Center of Lyon, CNRS UMR 5286, Lyon, France Université de Lyon, Lyon, France ISPB Université Lyon 1, Lyon, France Centre Léon Bérard, Lyon, France Dermatology Unit, Hospices Civils de Lyon CH Lyon Sud, Pierre Bénite Cedex, France. · Cancer Research Center of Lyon, INSERM U1052, Lyon, France Cancer Research Center of Lyon, CNRS UMR 5286, Lyon, France Université de Lyon, Lyon, France ISPB Université Lyon 1, Lyon, France Centre Léon Bérard, Lyon, France Department of Biopathology, Centre Léon Bérard, Lyon, France. · Department of Biopathology, Hospices Civils de Lyon CH Lyon Sud, Pierre-Bénite Cedex, France. · Fondation Synergie Lyon Cancer, Centre Léon Bérard, Lyon, France. · INSERM U1065 Equipe 1 Biologie et pathologies des mélanocytes: de la pigmentation cutanée au mélanome Equipe labellisée Ligue 2013 Centre Méditerranéen de Médecine Moléculaire, Nice, France Université de Nice Sophia-Antipolis UFR Médecine, Nice, France CHU Nice Service de Dermatologie, Nice, France. · APHP INSERM U976 Saint Louis Hospital Pharmacology-Genetic Laboratory Paris, Paris, France. · Department of Pathology, INSERM U1165 Université Paris Diderot AP-HP Hôpital Saint-Louis, Paris, France. · Department of Dermatology, APHP Saint Louis Hospital, Paris, France INSERM U976 University Paris 7 Diderot, Paris, France. · Cancer Research Center of Lyon, INSERM U1052, Lyon, France Cancer Research Center of Lyon, CNRS UMR 5286, Lyon, France Université de Lyon, Lyon, France ISPB Université Lyon 1, Lyon, France Centre Léon Bérard, Lyon, France Institut Universitaire de France, Paris, France alain.puisieux@lyon.unicancer.fr julie.caramel@lyon.unicancer.fr. · Cancer Research Center of Lyon, INSERM U1052, Lyon, France Cancer Research Center of Lyon, CNRS UMR 5286, Lyon, France Université de Lyon, Lyon, France ISPB Université Lyon 1, Lyon, France Centre Léon Bérard, Lyon, France alain.puisieux@lyon.unicancer.fr julie.caramel@lyon.unicancer.fr. ·EMBO Mol Med · Pubmed #27596438.

ABSTRACT: Targeted therapies with MAPK inhibitors (MAPKi) are faced with severe problems of resistance in BRAF-mutant melanoma. In parallel to the acquisition of genetic mutations, melanoma cells may also adapt to the drugs through phenotype switching. The ZEB1 transcription factor, a known inducer of EMT and invasiveness, is now considered as a genuine oncogenic factor required for tumor initiation, cancer cell plasticity, and drug resistance in carcinomas. Here, we show that high levels of ZEB1 expression are associated with inherent resistance to MAPKi in BRAF

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