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1. SAR442085, a novel anti-CD38 antibody with enhanced antitumor activity against multiple myeloma

Author

Alain Fournier, Marielle Chiron, Nadège Carrié, Sukhvinder Sidhu, Marine Cuisinier, Sahar Kassem, Dmitri Wiederschain, Hélène Bonnevaux, Jean-Luc Teillaud, Ludovic Martinet, Helgi van de Velde, Jill Corre, Isabelle Arnould, Béré K. Diallo, Nizar El-Murr, Céline Nicolazzi, Angela Virone-Oddos, Hervé Avet-Loiseau, and Alexandre Tang

Subjects
medicine.drug_class, Immunology, Bone Marrow Cells, Mice, Transgenic, CD38, Monoclonal antibody, Biochemistry, Antineoplastic Agents, Immunological, Cell Line, Tumor, medicine, Animals, Humans, Receptor, Isatuximab, Antibody-dependent cell-mediated cytotoxicity, Membrane Glycoproteins, biology, Chemistry, Degranulation, Daratumumab, Cell Biology, Hematology, ADP-ribosyl Cyclase 1, Xenograft Model Antitumor Assays, Neoplasm Proteins, HEK293 Cells, Cancer research, biology.protein, Antibody, Multiple Myeloma
Abstract

Anti-CD38 monoclonal antibodies (mAbs) represent a breakthrough in the treatment of multiple myeloma (MM), yet some patients fail to respond or progress quickly with this therapy, highlighting the need for novel approaches. In this study we compared the preclinical efficacy of SAR442085, a next-generation anti-CD38 mAb with enhanced affinity for activating Fcγ receptors (FcγR), with first-generation anti-CD38 mAb daratumumab and isatuximab. In surface plasmon resonance and cellular binding assays, we found that SAR442085 had higher binding affinity than daratumumab and isatuximab for FcγRIIa (CD32a) and FcγRIIIa (CD16a). SAR442085 also exhibited better in vitro antibody-dependent cellular cytotoxicity (ADCC) against a panel of MM cells expressing variable CD38 receptor densities including MM patients’ primary plasma cells. The enhanced ADCC of SAR442085 was confirmed using NK-92 cells bearing low and high affinity FcγRIIIa (CD16a)-158F/V variants. Using MM patients’ primary bone marrow cells, we confirmed that SAR442085 had an increased ability to engage FcγRIIIa, resulting in higher natural killer (NK) cell activation and degranulation against primary plasma cells than preexisting Fc wild-type anti-CD38 mAbs. Finally, using huFcgR transgenic mice that express human Fcγ receptors under the control of their human regulatory elements, we demonstrated that SAR442085 had higher NK cell-dependent in vivo antitumor efficacy and better survival than daratumumab and isatuximab against EL4 thymoma or VK*MYC myeloma cells overexpressing human CD38. These results highlight the preclinical efficacy of SAR442085 and support the current evaluation of this next-generation anti-CD38 antibody in phase I clinical development in patients with relapsed/refractory MM.

Published
2022
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2. Overexpression of microRNAs-155 and 21 targeting mismatch repair proteins in inflammatory bowel diseases

Author

Kristell Wanherdrick, Nizar El-Murr, Magali Svrcek, Emmanuel Tiret, Jean-Frederic Colombel, Alex Duval, Thécla Lesuffleur, Jean-François Fléjou, Jacques Cosnes, Sylvie Dumont, Laurent Beaugerie, Université Pierre et Marie Curie - Paris 6 (UPMC), Service de Gastroentérologie et nutrition [CHU Saint-Antoine], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Service d'Hépato-gastroentérologie, Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Service d'anatomie et cytologie pathologiques [CHU Saint-Antoine], Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Saint-Antoine [AP-HP], Instabilité des microsatellites et cancers [CHU Saint-Antoine], Centre de Recherche Saint-Antoine (CR Saint-Antoine), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Saint-Antoine [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)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Saint-Antoine [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), CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Instabilité des microsatellites et cancers [CRSA], Centre de Recherche Saint-Antoine (CRSA), and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)

Subjects
Adult, Male, congenital, hereditary, and neonatal diseases and abnormalities, Cancer Research, medicine.medical_specialty, Biology, DNA Mismatch Repair, Gastroenterology, Young Adult, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, microRNA, medicine, Humans, In patient, Intestinal Mucosa, Young adult, neoplasms, Aged, 030304 developmental biology, Aged, 80 and over, 0303 health sciences, [CHIM.ORGA]Chemical Sciences/Organic chemistry, Cancer, Microsatellite instability, Inflammatory Bowel Diseases, General Medicine, Middle Aged, medicine.disease, digestive system diseases, 3. Good health, MicroRNAs, Real-time polymerase chain reaction, 030220 oncology & carcinogenesis, Female, Microsatellite Instability, DNA mismatch repair, Colorectal Neoplasms
Abstract

Microsatellite instability (MSI) due to mismatch repair (MMR) deficiency is reported in 5-10% of colorectal cancers (CRCs) complicating inflammatory bowel diseases (IBD). The molecular mechanisms underlying MMR deficiency may be different in IBD CRCs, and in sporadic and hereditary MSI tumors. Here, we hypothesize that overexpression of miR-155 and miR-21, two inflammation-related microRNAs that target core MMR proteins, may constitute a pre-neoplastic event for the development of MSI IBD CRCs. We studied miR-155 and miR-21 expression using real-time quantitative PCR in MSI (n = 10) and microsatellite stable (n = 10) IBD CRCs, and in MSI (n = 32) and microsatellite stable (n = 30) non-IBD CRCs. We also screened colonic samples from IBD patients without cancer (n = 18) and used healthy colonic mucosa as controls (n = 20). MiR-155 and miR-21 appeared significantly overexpressed not only in the colonic mucosa of IBD subjects without CRC but also in neoplastic tissues of IBD patients compared with non-IBD controls (P < 0.001). Importantly, in patients with IBD CRCs, miR-155 and miR-21 overexpression extended to the distant non-neoplastic mucosa (P < 0.001). Ratios of expressions in tumors versus matched distant mucosa revealed a nearly significant association between miR-155 overexpression and MSI in IBDs (P = 0.057). These results show a strong deregulation of both MMR-targeting microRNAs in IBD subjects with or without cancer. MiR-155 overexpression being particularly associated to MSI IBD CRCs and extending to distant non-neoplastic mucosa, strongly suggests that a pre-neoplastic miR-155 field defect may promote MSI-driven transformation of the colonic mucosa. The detection and monitoring of miR-155 field defect may, therefore, have implications for the prevention and treatment of MSI IBD CRCs.

Published
2013
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3. HSP110 T17 simplifies and improves the microsatellite instability testing in patients with colorectal cancer

Author

Coralie Dorard, Richard Hamelin, Kristell Wanherdrick, Magali Svrcek, Anne-Marie Bouvier, Pascale Cervera, Mouna Chouchène, Yann Parc, Anaïs Lagrange, Chrystelle Colas, Florence Coulet, Richie Soong, Carmen Garrido, Jérémie H. Lefevre, Janick Selves, Alex Duval, Erell Guillerm, Olivier Lascols, Sahra Bodo, Thierry André, Laetitia Marisa, Jean-François Fléjou, Ada Collura, Côme Lepage, Olivier Buhard, Kerryn Garrett, Caroline Chapusot, Marie-Pierre Gaub, A’dem Bokhari, Barry Iacopetta, Malorie Greene, Isabelle Sourouille, Agathe Guilloux, Martine Muleris, Hélène Blanché, Nizar El-Murr, Centre de Recherche Saint-Antoine (UMRS893), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), École polytechnique (X), (le programme) Cartes d'identité des tumeurs (CIT), Ligue Nationales Contre le Cancer (LNCC), Université Pierre et Marie Curie - Paris 6 (UPMC), CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Fondation Jean Dausset CEPH, Registre Bourguignon des Cancers Digestifs, Lipides - Nutrition - Cancer (U866) (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA)-Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA)-Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), National University of Singapore (NUS), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA), Développement et physiopathologie de l'intestin et du pancréas, Institut National de la Santé et de la Recherche Médicale (INSERM), St John God HealthCare, The University of Western Australia (UWA), Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER, Service de Pathologie [CHU Saint-Antoine], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Service d'anatomie et cytologie pathologiques [CHU Saint-Antoine], Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Saint-Antoine [AP-HP], Service de chirurgie générale et digestive [CHU Saint-Antoine], National University of Singapore - Cancer Science Institute of Singapore, Laboratoire commun de biologie et génétique moléculaires [CHU Saint-Antoine], Service d'Oncologie Médicale [CHU Saint -Antoine], Centre de Recherche Saint-Antoine ( CR Saint-Antoine ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), École polytechnique ( X ), (le programme) Cartes d'identité des tumeurs ( CIT ), Université Pierre et Marie Curie - Paris 6 ( UPMC ), Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Saint-Antoine [APHP], Service d'anatomie et cytologie pathologiques, Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Saint-Antoine [APHP], Lipides - Nutrition - Cancer (U866) ( LNC ), Université de Bourgogne ( UB ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon ( ENSBANA ) -Université de Bourgogne ( UB ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon ( ENSBANA ) -Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ), National University of Singapore ( NUS ), Université de Bourgogne ( UB ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon ( ENSBANA ), Institut National de la Santé et de la Recherche Médicale ( INSERM ), The University of Western Australia ( UWA ), and Centre Régional de Lutte contre le cancer - Centre Georges-François Leclerc ( CRLCC - CGFL )

Subjects
0301 basic medicine, Oncology, medicine.medical_specialty, Genotype, Colorectal cancer, Population, Mismatch Repair, Biology, Guidelines, Bioinformatics, DNA Mismatch Repair, Colon-Cancer, 03 medical and health sciences, 0302 clinical medicine, Molecular genetics, Internal medicine, Diagnostic-Tests, Genetics, medicine, Biomarkers, Tumor, Humans, Chemotherapy, HSP110 Heat-Shock Proteins, education, [ SDV.GEN.GH ] Life Sciences [q-bio]/Genetics/Human genetics, Genotyping, neoplasms, Genetics (clinical), Tumors, education.field_of_study, Pentaplex Pcr, Microsatellite instability, DNA, medicine.disease, Colorectal Neoplasms, Hereditary Nonpolyposis, Lynch syndrome, digestive system diseases, 3. Good health, Mononucleotide Repeats, 030104 developmental biology, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, 030220 oncology & carcinogenesis, DNA mismatch repair, Microsatellite Instability, Lynch-Syndrome, Colorectal Neoplasms, Mutations
Abstract

IF 5.65; International audience; Background Every colorectal cancer (CRC) patient should be tested for microsatellite instability (MSI, a marker for defective DNA mismatch repair) as a first screen for Lynch syndrome (LS). In this study, we investigated whether it may be possible to improve the detection of MSI in CRC. We examined whether the HT17 DNA repeat (critical for correct splicing of the chaperone HSP110) might constitute a superior marker for diagnosis of the MSI phenotype in patients with CRC compared with the standard panel of markers (pentaplex).Methods The HT17 polymorphism was analysed in germline DNA from 1037 multi-ethnic individuals. We assessed its sensitivity and specificity for detecting MSI in a multicentre, population-based cohort of 685 patients with CRC and an additional series of 70 patients with CRC considered to be at-risk of LS. All cases were screened earlier for MSI using pentaplex markers. Cases showing discordant HT17/pentaplex results were further examined for the expression of mismatch repair proteins.Results HT17 status was analysed independently and blinded to previous results from pentaplex genotyping. HT17 showed no germline allelic variation outside a very narrow range. Compared with the pentaplex panel, HT17 showed better sensitivity (0.984 (95% CI 0.968 to 0.995) vs 0.951 (95% CI 0.925 to 0.972)) and similar specificity (0.997 (95% CI 0.989 to 1.000) for both) for the detection of MSI. Furthermore, HT17 alone correctly classified samples judged to be uncertain with the pentaplex panel and showed excellent ability to detect MSI in patients with LS.Conclusions HT17 simplifies and improves the current standard molecular methods for detecting MSI in CRC.

Published
2016
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4. A Vulnerability of a Subset of Colon Cancers with Potential Clinical Utility

Author

Giovanni D'Ario, Sjors G J G In 't Veld, Cornelia Rumpf-Kienzl, Sabine C. Linn, Cor Lieftink, Alberto Villanueva, Andreas Schlicker, Roderick L. Beijersbergen, Christophe Henry, Jonne A. Raaijmakers, Lodewyk F. A. Wessels, Marielle Chiron, René Bernards, Jacco van Rheenen, Sara Mainardi, Mariangela Russo, Alice Bartolini, Loredana Vecchione, Cecile Combeau, Mauro Delorenzi, David G. Molleví, Iris Simon, Ramon Salazar, Federica Di Nicolantonio, Alberto Bardelli, Sabine Tejpar, René H. Medema, Céline Nicolazzi, Evelyne Beerling, Arianna Fumagalli, Valentina Gambino, Loreley Calvet, Nizar El-Murr, Sun Tian, and Hubrecht Institute for Developmental Biology and Stem Cell Research

Subjects
Genetics and Molecular Biology (all), 0301 basic medicine, endocrine system diseases, Mutant, BRAF-like colon cancer, medicine.disease_cause, Microtubules, Biochemistry, Small hairpin RNA, Mice, 0302 clinical medicine, Non-U.S. Gov't, skin and connective tissue diseases, Cells, Cultured, Mutation, Research Support, Non-U.S. Gov't, 3. Good health, targeted treatment, 030220 oncology & carcinogenesis, Colonic Neoplasms, Heterografts, functional genomics, Proto-Oncogene Proteins B-raf, Mice, Nude, Biology, Vinblastine, Research Support, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, Microtubule, medicine, Journal Article, Animals, Humans, Gene silencing, Mitosis, neoplasms, Biochemistry, Genetics and Molecular Biology(all), fungi, Antineoplastic Agents, Phytogenic, digestive system diseases, Nuclear Pore Complex Proteins, vinorelbine, RANBP2, Biochemistry, Genetics and Molecular Biology (all), 030104 developmental biology, Cancer research, Neoplasm Transplantation, V600E, Molecular Chaperones, Genetics and Molecular Biology(all), Genetic screen
Abstract

BRAF(V600E) mutant colon cancers (CCs) have a characteristic gene expression signature that is also found in some tumors lacking this mutation. Collectively, they are referred to as "BRAF-like" tumors and represent some 20% of CCs. We used a shRNA-based genetic screen focused on genes upregulated in BRAF(V600E) CCs to identify vulnerabilities of this tumor subtype that might be exploited therapeutically. Here, we identify RANBP2 (also known as NUP358) as essential for survival of BRAF-like, but not for non-BRAF-like, CC cells. Suppression of RANBP2 results in mitotic defects only in BRAF-like CC cells, leading to cell death. Mechanistically, RANBP2 silencing reduces microtubule outgrowth from the kinetochores, thereby inducing spindle perturbations, providing an explanation for the observed mitotic defects. We find that BRAF-like CCs display far greater sensitivity to the microtubule poison vinorelbine both in vitro and in vivo, suggesting that vinorelbine is a potential tailored treatment for BRAF-like CCs.

Published
2016

5. Small Bowel Adenocarcinomas Complicating Crohn's Disease Are Associated With Dysplasia: A Pathological and Molecular Study

Author

Pascale Cervera, Jean-François Rahier, Severine Vermeire, Gottfried Novacek, Dominique Cazals-Hatem, Sandro Ardizzone, Monique Delos, Guillaume Cadiot, Laurent Beaugerie, Paolo Fociani, Olivier Lascols, Nizar El-Murr, Sylvie Dumont, Jean-François Fléjou, Magali Svrcek, Fritz Wrba, Yoram Bouhnik, Florence Le Pessot, Marie-Danièle Diebold, Franck Carbonnel, Aurelie Scriva, Gaël Piton, Karel Geboes, Antoinette Lemoine, Emmanuelle Leteurtre, Jacques Cosnes, Guillaume Savoye, Jean-Frederic Colombel, Service de gastro-entérologie, Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Université Pierre et Marie Curie - Paris 6 (UPMC), CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Microenvironnement et Physiopathologie de la Differenciation, Université Paris-Sud - Paris 11 (UP11)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche Saint-Antoine (UMRS893), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'Hépato-Gastroentérologie [CHU Rouen], Hôpital Charles Nicolle [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Service d'Hépato-gastroentérologie, Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U837 (JPArc), Université Lille Nord de France (COMUE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Pole des maladies de l'appareil digestif, gastroentérologie et assistance nutritive, Hôpital Beaujon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service d'Anatomo-Pathologie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7)-Hôpital Beaujon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université de Reims Champagne-Ardenne (URCA), Laboratoire d'Anatomopathologie, Centre hospitalier Universitaire, UCL Mont Godinne, Hépatogastroentérologie, CHU de Bicêtre, Service de Gastroentérologie et nutrition [CHU Saint-Antoine], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Service d'anatomie et cytologie pathologiques [CHU Saint-Antoine], Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Saint-Antoine [AP-HP], Hôpital Charles Nicolle [Rouen]-Université de Rouen Normandie (UNIROUEN), Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U1172 Inserm - U837 (JPArc), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Lille Nord de France (COMUE)-Université de Lille, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), Centre Hospitalier Régional Universitaire [Besançon] (CHRU Besançon)-Hôpital Jean Minjoz, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Saint-Antoine [APHP], Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Saint-Antoine [APHP], Centre de Recherche Saint-Antoine (CR Saint-Antoine), Hepato Gastroenterology, Hospital and University of Rouen, Service d'Hépato-Gastroentérologie [Rouen], Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Hôpital Charles Nicolle [Rouen]-CHU Rouen, Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer (JPArc - U837 Inserm), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Université Lille 2 - Faculté de Médecine, AP-HP Hôpital Beaujon, and Hôpital Beaujon-Université Paris Diderot - Paris 7 (UPD7)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)

Subjects
Adult, Male, Pathology, medicine.medical_specialty, Colorectal cancer, Fibromuscular dysplasia, Adenocarcinoma, Gastroenterology, Young Adult, 03 medical and health sciences, 0302 clinical medicine, Crohn Disease, Risk Factors, Internal medicine, Intestine, Small, medicine, Fibromuscular Dysplasia, Humans, Immunology and Allergy, Survival rate, neoplasms, Inflammation, Crohn's disease, business.industry, [CHIM.ORGA]Chemical Sciences/Organic chemistry, Cancer, Middle Aged, Prognosis, medicine.disease, Ulcerative colitis, digestive system diseases, 3. Good health, Survival Rate, Dysplasia, 030220 oncology & carcinogenesis, Female, 030211 gastroenterology & hepatology, Colorectal Neoplasms, business, Follow-Up Studies
Abstract

International audience; BACKGROUND:: Crohn's disease (CD) is associated with an increased risk of small bowel adenocarcinoma (SBA). However, there are no guidelines for the screening and early diagnosis of SBA. Colorectal cancer associated with chronic colitis arises from dysplasia. High-risk patients benefit from surveillance colonoscopies aimed to detect dysplasia. The dysplasia-carcinoma sequence remains poorly documented in CD-associated SBA. Moreover, molecular data about SBA complicating CD and associated dysplasia are very limited. We therefore assessed dysplasia and several key molecular markers of carcinogenesis in SBA and dysplasia developed in patients with CD. METHODS:: Forty-five SBA complicating CD and 4 specimens with dysplasia without SBA were screened. In SBA, we looked for dysplasia and determined their pathological characteristics (type, grade, distribution). We also stained for mismatch repair proteins (MLH1, MSH2, MSH6, PMS2), p53, β-catenin, and p16 and looked for KRAS, BRAF and PIK3CA mutations. RESULTS:: All neoplastic lesions, except 1 lesion, were found in inflamed mucosal areas. Dysplasia was found in 20 of 41 patients with SBA (49%). Dysplasia was flat or raised, low grade or high grade, and adjacent or distant to concomitant SBA. Molecular markers of SBA carcinogenesis complicating CD were similar to those observed in chronic colitis-related colorectal cancer (KRAS, BRAF, p53, MSI), although differences were observed for β-catenin and p16. No PIK3CA mutations were observed. CONCLUSIONS:: These results suggest that there is an inflammation-dysplasia-adenocarcinoma sequence in at least half of CD-related SBA, similar to what is observed in chronic colitis-related colorectal cancer and may have implications for the prevention and treatment of this cancer.

Published
2014
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6. MiRNA Genes Constitute New Targets for Microsatellite Instability in Colorectal Cancer

Author

Alex Duval, Richard C. Hamelin, Magali Svrcek, Jean-François Fléjou, Zoulira Abidi, Marie-Pierre Gaub, Nizar El-Murr, Kristell Wanherdrick, and Thécla Lesuffleur

Subjects
Mutation rate, DNA Mutational Analysis, Biophysics, lcsh:Medicine, Gastroenterology and Hepatology, Biology, medicine.disease_cause, MiRBase, Mutation Rate, Nucleic Acids, Molecular Cell Biology, Gastrointestinal Tumors, microRNA, Genetics, medicine, Humans, lcsh:Science, Gene, Likelihood Functions, Mutation, Multidisciplinary, lcsh:R, Cancers and Neoplasms, Microsatellite instability, DNA, medicine.disease, digestive system diseases, MicroRNAs, Cell Transformation, Neoplastic, Oncology, Medicine, Microsatellite, Microsatellite Instability, lcsh:Q, Colorectal Neoplasms, Carcinogenesis, Research Article
Abstract

Mismatch repair-deficient colorectal cancers (CRC) display widespread instability at DNA microsatellite sequences (MSI). Although MSI has been reported to commonly occur at coding repeats, leading to alterations in the function of a number of genes encoding cancer-related proteins, nothing is known about the putative impact of this process on non-coding microRNAs. In miRbase V15, we identified very few human microRNA genes with mono- or di-nucleotide repeats (n = 27). A mutational analysis of these sequences in a large series of MSI CRC cell lines and primary tumors underscored instability in 15 of the 24 microRNA genes successfully studied at variable frequencies ranging from 2.5% to 100%. Following a maximum likelihood statistical method, microRNA genes were separated into two groups that differed significantly in their mutation frequencies and in their tendency to represent mutations that may or may not be under selective pressures during MSI tumoral progression. The first group included 21 genes that displayed no or few mutations in CRC. The second group contained three genes, i.e., hsa-mir-1273c, hsa-mir-1303 and hsa-mir-567, with frequent (≥ 80%) and sometimes bi-allelic mutations in MSI tumors. For the only one expressed in colonic tissues, hsa-mir-1303, no direct link was found between the presence or not of mono- or bi-allelic alterations and the levels of mature miR expression in MSI cell lines, as determined by sequencing and quantitative PCR respectively. Overall, our results provide evidence that DNA repeats contained in human miRNA genes are relatively rare and preserved from mutations due to MSI in MMR-deficient cancer cells. Functional studies are now required to conclude whether mutated miRNAs, and especially the miR-1303, might have a role in MSI tumorigenesis.

Published
2012
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7. NRAS Mutation Is the Sole Recurrent Somatic Mutation in Large Congenital Melanocytic Nevi

Author

C Charbel, Selim Aractingi, Gabriel G. Malouf, Jörg Tost, Sarah Guégan, Natacha Kadlub, Xiaoping Su, Aurore Coulomb-L'Hermine, Nizar El-Murr, Alexandre How-Kit, Arnaud Picard, Samia Mourah, and Romain H. Fontaine

Subjects
Male, Proto-Oncogene Proteins B-raf, Risk, Neuroblastoma RAS viral oncogene homolog, Pathology, medicine.medical_specialty, Genotype, DNA Mutational Analysis, Dermatology, Biology, medicine.disease_cause, Polymerase Chain Reaction, Polymorphism, Single Nucleotide, Biochemistry, GTP Phosphohydrolases, 03 medical and health sciences, 0302 clinical medicine, Germline mutation, Congenital melanocytic nevus, medicine, Humans, Nevus, Exome, Child, Molecular Biology, Exome sequencing, Cell Proliferation, 030304 developmental biology, Nevus, Pigmented, 0303 health sciences, Mutation, Melanoma, Infant, Membrane Proteins, Cell Biology, medicine.disease, Genes, ras, Phenotype, Child, Preschool, 030220 oncology & carcinogenesis, Melanocytes, Female
Abstract

Congenital melanocytic nevus (CMN) is a particular melanocytic in utero proliferation characterized by an increased risk of melanoma transformation during infancy or adulthood. NRAS and BRAF mutations have consistently been reported in CMN samples, but until recently results have been contradictory. We therefore studied a series of large and giant CMNs and compared them with small and medium CMNs using Sanger sequencing, pyrosequencing, high-resolution melting analysis, and mutation enrichment by an enhanced version of ice-COLD-PCR. Large-giant CMNs displayed NRAS mutations in 94.7% of cases (18/19). At that point, the role of additional mutations in CMN pathogenesis had to be investigated. We therefore performed exome sequencing on five specimens of large-giant nevi. The results showed that NRAS mutation was the sole recurrent somatic event found in such melanocytic proliferations. The genetic profile of small-medium CMNs was significantly different, with 70% of cases bearing NRAS mutations and 30% showing BRAF mutations. These findings strongly suggest that NRAS mutations are sufficient to drive melanocytic benign proliferations in utero.

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