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21 results on '"Laboratoire de Biochimie [CHRU Nîmes]"'

1. Premature termination codons in SOD1 causing Amyotrophic Lateral Sclerosis are predicted to escape the nonsense-mediated mRNA decay

Author

Anne Polge, Claire Guissart, Jovana Kantar, Kevin Mouzat, Paul Vilquin, Cédric Raoul, Baptiste Louveau, Serge Lumbroso, Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Institut des Neurosciences de Montpellier (INM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Laboratoire de Biochimie [CHRU Nîmes], Immunologie humaine, physiopathologie & immunothérapie (HIPI (UMR_S_976 / U976)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Service de Biopathologie [CHRU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Raoul, Cédric, Institut des Neurosciences de Montpellier - Déficits sensoriels et moteurs (INM), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP)

Subjects
endocrine system diseases, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Nonsense-mediated decay, SOD1, Mutation, Missense, lcsh:Medicine, Biology, RNA decay, Article, 03 medical and health sciences, 0302 clinical medicine, Superoxide Dismutase-1, medicine, Genetics, Missense mutation, Humans, RNA, Messenger, Motor neuron disease, Amyotrophic lateral sclerosis, lcsh:Science, Gene, 030304 developmental biology, 0303 health sciences, Messenger RNA, Multidisciplinary, Molecular medicine, Amyotrophic Lateral Sclerosis, Medical genetics, lcsh:R, [SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, medicine.disease, humanities, 3. Good health, Nonsense Mediated mRNA Decay, Codon, Nonsense, Codon, Terminator, lcsh:Q, Haploinsufficiency, 030217 neurology & neurosurgery
Abstract

Amyotrophic lateral sclerosis (ALS) is the most common and severe adult-onset motoneuron disease and has currently no effective therapy. Approximately 20% of familial ALS cases are caused by dominantly-inherited mutations in the gene encoding Cu/Zn superoxide dismutase (SOD1), which represents one of the most frequent genetic cause of ALS. Despite the overwhelming majority of ALS-causing missense mutations in SOD1, a minority of premature termination codons (PTCs) have been identified. mRNA harboring PTCs are known to be rapidly degraded by nonsense-mediated mRNA decay (NMD), which limits the production of truncated proteins. The rules of NMD surveillance varying with PTC location in mRNA, we analyzed the localization of PTCs in SOD1 mRNA to evaluate whether or not those PTCs can be triggered to degradation by the NMD pathway. Our study shows that all pathogenic PTCs described in SOD1 so far can theoretically escape the NMD, resulting in the production of truncated protein. This finding supports the hypothesis that haploinsufficiency is not an underlying mechanism of SOD1 mutant-associated ALS and suggests that PTCs found in the regions that trigger NMD are not pathogenic. Such a consideration is particularly important since the availability of SOD1 antisense strategies, in view of variant treatment assignment.

Published
2020

2. The quantitative ultrasound method for assessing low bone mass in women with anorexia nervosa

Author

Laura Gaspari, Denis Mariano-Goulart, Rémi Doré, Patrick Lefebvre, Maude Seneque, Eric Renard, Philippe Courtet, Didier Laux, Sébastien Guillaume, Pascal Philibert, Laurent Maïmoun, Krishna Kunal Mahadea, Charles Sultan, Ariane Sultan, Marie Picot, Helena Huguet, Vincent Boudousq, Physiologie & médecine expérimentale du Cœur et des Muscles [U 1046] (PhyMedExp), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), MORNET, Dominique, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Hôpital Lapeyronie [Montpellier] (CHU), CIC Montpellier, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Saint Eloi (CHRU Montpellier), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Génomique Fonctionnelle (IGF), Hôpital de la Colombière, Service de Médecine Nucléaire [Nîmes], Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Université de Montpellier (UM), Institut d’Electronique et des Systèmes (IES), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Biochimie [CHRU Nîmes], Neuropsychiatrie : recherche épidémiologique et clinique (PSNREC), Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Hôpital Arnaud de Villeneuve [CHRU Montpellier], Acoustique (ACO), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Photonique et Ondes (PO), and Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)

Subjects
musculoskeletal diseases, 0301 basic medicine, medicine.medical_specialty, Heel, Areal bone mineral density (aBMD), [SDV]Life Sciences [q-bio], 030209 endocrinology & metabolism, [SDV.IB.MN]Life Sciences [q-bio]/Bioengineering/Nuclear medicine, [SDV.MHEP.GEO]Life Sciences [q-bio]/Human health and pathology/Gynecology and obstetrics, Standard score, [SDV.IB.MN] Life Sciences [q-bio]/Bioengineering/Nuclear medicine, 03 medical and health sciences, 0302 clinical medicine, Medicine, Orthopedics and Sports Medicine, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], [SDV.BBM.BC] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], ComputingMilieux_MISCELLANEOUS, [SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, 2. Zero hunger, Bone mineral, business.industry, Dual-X-ray absorptiometry (DXA), [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, 3. Good health, Quantitative ultrasound, [SDV.MHEP.GEO] Life Sciences [q-bio]/Human health and pathology/Gynecology and obstetrics, medicine.anatomical_structure, Anorexia nervosa (differential diagnoses), Orthopedic surgery, Broadband ultrasound attenuation (BUA) bone demineralization, Amenorrhea, Quantitative ultrasound (QUS), 030101 anatomy & morphology, medicine.symptom, business, Nuclear medicine, Body mass index
Abstract

International audience; This study investigated the potential role of quantitative ultrasound (QUS) to assess low bone mass in anorexia nervosa patients (AN). Bone parameters from QUS and DXA were positively correlated and significantly reduced in AN compared with controls, suggesting that QUS is a pertinent technique to assess low bone mass in these patients.Purpose: The aim of this study was to investigate the potential role of an alternative technique, quantitative ultrasound (QUS), to assess low bone mass in patients with anorexia nervosa (AN).Methods: Two hundred seven young women (134 patients with AN and 73 healthy controls) with ages ranging from 14.4 to 38.4 years participated in this observational cross-sectional study. Bone mass was concomitantly evaluated by DXA to determine areal bone mineral density (aBMD; g/cm2) at hip, lumbar spine, and radius and by QUS to determine broadband ultrasound attenuation (BUA; dB/MHz) at the heel.Results: BUA (66.5 ± 4.6 dB/MHz vs 61.0 ± 5.0 dB/MHz) and aBMD at the hip (0.916 ± 0.013 g/cm2 vs 0.806 ± 0.010 g/cm2), lumbar spine (0.966 ± 0.012 g/cm2 vs 0.886 ± 0.010 g/cm2), and radius (0.545 ± 0.005 g/cm2 vs 0.526 ± 0.04 g/cm2) were significantly decreased (p < 0.01) in patients with AN compared with controls. When patient and control data were pooled, BUA was significantly correlated with aBMD at the hip (r = 0.60, p < 0.001), lumbar spine (r = 0.48, p < 0.001), and radius (r = 0.40, p

Published
2021

3. Vancomycin Serum Concentration after 48 h of Administration: A 3-Years Survey in an Intensive Care Unit

Author

Alexandre Evrard, Caroline Boutin, Grégory Marin, Jason A. Roberts, Jean-Philippe Lavigne, Samir Jaber, Laurent Muller, Nicolas Molinari, Jeffrey Lipman, Jean-Yves Lefrant, Pierre Géraud Claret, Claire Roger, Saber Barbar, Nicolas Perin, Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Caractéristiques féminines des dysfonctions des interfaces cardio-vasculaires (EA 2992), Université Montpellier 1 (UM1)-Université de Montpellier (UM), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Institut Montpelliérain Alexander Grothendieck (IMAG), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Biochimie [CHRU Nîmes], Institut de Recherche en Cancérologie de Montpellier (IRCM - U1194 Inserm - UM), CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Virulence bactérienne et maladies infectieuses (VBMI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Royal Brisbane & Women's Hospital, University of Queensland [Brisbane], Physiologie & médecine expérimentale du Cœur et des Muscles [U 1046] (PhyMedExp), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
0301 basic medicine, Microbiology (medical), [SDV]Life Sciences [q-bio], vancomycin, 030106 microbiology, Biochemistry, Microbiology, Loading dose, Article, law.invention, 03 medical and health sciences, 0302 clinical medicine, Pharmacokinetics, Interquartile range, law, Intensive care, medicine, Pharmacology (medical), pharmacokinetic, General Pharmacology, Toxicology and Pharmaceutics, ComputingMilieux_MISCELLANEOUS, intensive care, drug monitoring, business.industry, lcsh:RM1-950, Acute kidney injury, 030208 emergency & critical care medicine, medicine.disease, Intensive care unit, infection, 3. Good health, lcsh:Therapeutics. Pharmacology, Infectious Diseases, Anesthesia, Toxicity, Vancomycin, business, medicine.drug
Abstract

The present study assessed the proportion of intensive care unit (ICU) patients who had a vancomycin serum concentration between 20 and 25 mg/L after 24&ndash, 48 h of intravenous vancomycin administration. From 2016 to 2018, adult ICU patients with vancomycin continuous infusion (CI) for any indication were included. The primary outcome was the proportion of patients with a first-available vancomycin serum concentration between 20&ndash, 25 mg/L at 24 h (D2) or 48 h (D3). Of 3894 admitted ICU patients, 179 were included. A median loading dose of 15.6 (interquartile range (IQR) = (12.5&ndash, 20.8) mg/kg) was given in 151/179 patients (84%). The median daily doses of vancomycin infusion for D1 and D2 were 2000 [(IQR (1600&ndash, 2000)) and 2000 (IQR (2000&ndash, 2500)) mg/d], respectively. The median duration of treatment was 4 (2&ndash, 7) days. At D2 or D3, the median value of first serum vancomycin concentration was 19.8 (IQR (16.0&ndash, 25.1)) with serum vancomycin concentration between 20&ndash, 25 mg/L reported in 43 patients (24%). Time spent in the ICU before vancomycin initiation was the only risk factor of non-therapeutic concentration at D2 or D3. Acute kidney injury occurred significantly more when vancomycin concentration was supra therapeutic at D2 or D3. At D28, 44 (26%) patients had died. These results emphasize the need of appropriate loading dose and regular monitoring to improve vancomycin efficacy and avoid renal toxicity.

Published
2020

4. Factors Affecting Tamoxifen Metabolism in Patients With Breast Cancer: Preliminary Results of the French PHACS Study

Author

Jacques Robert, Alicja Puszkiel, Alexandre Evrard, Etienne Chatelut, Florence Dalenc, Marc Debled, Fabienne Thomas, Caroline Delmas, Laurence Venat-Bouvet, Isabelle Sillet-Bach, Henri Roché, Thomas Filleron, Christelle Vachoux, Etienne Suc, Cécile Arellano, Jean-Christophe Boyer, Valérie Le Morvan, Melanie White-Koning, William Jacot, Centre de Recherches en Cancérologie de Toulouse (CRCT), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Biochimie [CHRU Nîmes], Centre Hospitalier Régional Universitaire de Nîmes (CHRU Nîmes), Institut de Recherche en Cancérologie de Montpellier (IRCM - U1194 Inserm - UM), CRLCC Val d'Aurelle - Paul Lamarque-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Bergonié - CRLCC Bordeaux, CRLCC Institut Claudius Regaud, Institut Universitaire du Cancer de Toulouse - Oncopole (IUCT Oncopole - UMR 1037), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'Oncologie médicale [CHU Limoges], CHU Limoges, Clinique Saint Jean Languedoc, Centre Hospitalier Brive-la-Gaillarde, Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Institut Bergonié [Bordeaux], UNICANCER, Institut Claudius Regaud, and Clinique Saint-Jean Languedoc [Toulouse] (CSJL)

Subjects
Oncology, Adult, medicine.medical_specialty, CYP2D6, CYP2B6, Antineoplastic Agents, Hormonal, Genotype, Breast Neoplasms, [SDV.CAN]Life Sciences [q-bio]/Cancer, CYP2C19, 030226 pharmacology & pharmacy, Polymorphism, Single Nucleotide, 03 medical and health sciences, 0302 clinical medicine, Breast cancer, Pharmacokinetics, Cytochrome P-450 Enzyme System, Internal medicine, medicine, Cytochrome P-450 CYP3A, Humans, Pharmacology (medical), Prospective Studies, skin and connective tissue diseases, Aged, Pharmacology, CYP3A4, business.industry, Middle Aged, medicine.disease, 3. Good health, Cytochrome P-450 CYP2B6, Tamoxifen, Cytochrome P-450 CYP2D6, Pharmacogenetics, 030220 oncology & carcinogenesis, Cytochrome P-450 CYP2C19 Inhibitors, Female, business, medicine.drug
Abstract

International audience; In addition to the effect of cytochrome P450 (CYP) 2D6 genetic polymorphisms, the metabolism of tamoxifen may be impacted by other factors with possible consequences on therapeutic outcome (efficacy and toxicity). This analysis focused on the pharmacokinetic (PK)-pharmacogenetic evaluation of tamoxifen in 730 patients with adjuvant breast cancer included in a prospective multicenter study. Plasma concentrations of tamoxifen and six major metabolites, the genotype for 63 single-nucleotide polymorphisms, and comedications were obtained 6 months after treatment initiation. Plasma concentrations of endoxifen were significantly associated with CYP2D6 diplotype (P

Published
2019

5. Shared polygenic risk and causal inferences in amyotrophic lateral sclerosis

Author

Bandres‐Ciga, S, Noyce, AJ, Hemani, G, Nicolas, A, Calvo, A, Mora, G, Arosio, A, Barberis, M, Bartolomei, I, Battistini, S, Benigni, M, Borghero, G, Brunetti, M, Cammarosano, S, Cannas, A, Canosa, A, Capasso, M, Caponnetto, C, Caredda, C, Carrera, P, Casale, F, Cavallaro, S, Chiò, A, Colletti, T, Conforti, FL, Conte, A, Corrado, L, Costantino, E, D'Alfonso, S, Fasano, A, Femiano, C, Ferrarese, C, Fini, N, Floris, G, Fuda, G, Giannini, F, Grassano, M, Ilardi, A, La Bella, V, Lattante, S, Logroscino, G, Logullo, FO, Loi, D, Lunetta, C, Mancardi, G, Mandich, P, Mandrioli, J, Manera, U, Marangi, G, Marinou, K, Marrali, G, Marrosu, MG, Mazzini, L, Melis, M, Messina, S, Moglia, C, Monsurro, MR, Mosca, L, Occhineri, P, Origone, P, Pani, C, Penco, S, Petrucci, A, Piccirillo, G, Pirisi, A, Pisano, F, Pugliatti, M, Restagno, G, Ricci, C, Rita Murru, M, Riva, N, Sabatelli, M, Salvi, F, Santarelli, M, Sideri, R, Simone, I, Spataro, R, Tanel, R, Tedeschi, G, Tranquilli, S, Tremolizzo, L, Trojsi, F, Volanti, P, Zollino, M, Abramzon, Y, Arepalli, S, Baloh, RH, Bowser, R, Brady, CB, Brice, A, Broach, J, Campbell, RH, Camu, W, Chia, R, Cooper‐Knock, J, Cusi, D, Ding, J, Drepper, C, Drory, VE, Dunckley, TL, Eicher, JD, Faghri, F, Feldman, E, Kay Floeter, M, Fratta, P, Geiger, JT, Gerhard, G, Gibbs, JR, Gibson, SB, Glass, JD, Hardy, J, Harms, MB, Heiman‐Patterson, TD, Hernandez, DG, Jansson, L, Kamel, F, Kirby, J, Kowall, NW, Laaksovirta, H, Landi, F, Le Ber, I, Lumbroso, S, MacGowan, DJL, Maragakis, NJ, Mouzat, K, Murphy, NA, Myllykangas, L, Nalls, MA, Orrell, RW, Ostrow, LW, Pamphlett, R, Pickering‐Brown, S, Pioro, E, Pliner, HA, Pulst, SM, Ravits, JM, Renton, AE, Rivera, A, Robbrecht, W, Rogaeva, E, Rollinson, S, Rothstein, JD, Salvi, E, Scholz, SW, Sendtner, M, Shaw, PJ, Sidle, KC, Simmons, Z, Singleton, AB, Stone, DC, Sulkava, R, Tienari, PJ, Traynor, BJ, Trojanowski, JQ, Troncoso, JC, Van Damme, P, Van Deerlin, VM, Van Den Bosch, L, Zinman, L, Stone, DJ, Bandres-Ciga, Sara, Noyce, Alastair J., Hemani, Gibran, Nicolas, Aude, Calvo, Andrea, Mora, Gabriele, Arosio, Alessandro, Barberis, Marco, Bartolomei, Ilaria, Battistini, Stefania, Benigni, Michele, Borghero, Giuseppe, Brunetti, Maura, Cammarosano, Stefania, Cannas, Antonino, Canosa, Antonio, Capasso, Margherita, Caponnetto, Claudia, Caredda, Carla, Carrera, Paola, Casale, Federico, Cavallaro, Sebastiano, Chiò, Adriano, Colletti, Tiziana, Conforti, Francesca L., Conte, Amelia, Corrado, Lucia, Costantino, Emanuela, D'Alfonso, Sandra, Fasano, Antonio, Femiano, Cinzia, Ferrarese, Carlo, Fini, Nicola, Floris, Gianluca, Fuda, Giuseppe, Giannini, Fabio, Grassano, Maurizio, Ilardi, Antonio, La Bella, Vincenzo, Lattante, Serena, Logroscino, Giancarlo, Logullo, Francesco O., Loi, Daniela, Lunetta, Christian, Mancardi, Gianluigi, Mandich, Paola, Mandrioli, Jessica, Manera, Umberto, Marangi, Giuseppe, Marinou, Kalliopi, Marrali, Giuseppe, Marrosu, Maria Giovanna, Mazzini, Letizia, Melis, Maurizio, Messina, Sonia, Moglia, Cristina, Monsurro, Maria Rosaria, Mosca, Lorena, Occhineri, Patrizia, Origone, Paola, Pani, Carla, Penco, Silvana, Petrucci, Antonio, Piccirillo, Giovanni, Pirisi, Angelo, Pisano, Fabrizio, Pugliatti, Maura, Restagno, Gabriella, Ricci, Claudia, Rita Murru, Maria, Riva, Nilo, Sabatelli, Mario, Salvi, Fabrizio, Santarelli, Marialuisa, Sideri, Riccardo, Simone, Isabella, Spataro, Rossella, Tanel, Raffaella, Tedeschi, Gioacchino, Tranquilli, Stefania, Tremolizzo, Lucio, Trojsi, Francesca, Volanti, Paolo, Zollino, Marcella, Abramzon, Yevgeniya, Arepalli, Sampath, Baloh, Robert H., Bowser, Robert, Brady, Christopher B., Brice, Alexi, Broach, Jame, Campbell, Roy H., Camu, William, Chia, Ruth, Cooper-Knock, John, Cusi, Daniele, Ding, Jinhui, Drepper, Carsten, Drory, Vivian E., Dunckley, Travis L., Eicher, John D., Faghri, Faraz, Feldman, Eva, Kay Floeter, Mary, Fratta, Pietro, Geiger, Joshua T., Gerhard, Glenn, Gibbs, J. Raphael, Gibson, Summer B., Glass, Jonathan D., Hardy, John, Harms, Matthew B., Heiman-Patterson, Terry D., Hernandez, Dena G., Jansson, Lilja, Kamel, Freya, Kirby, Janine, Kowall, Neil W., Laaksovirta, Hannu, Landi, Francesco, Le Ber, Isabelle, Lumbroso, Serge, Macgowan, Daniel J. L., Maragakis, Nicholas J., Mouzat, Kevin, Murphy, Natalie A., Myllykangas, Liisa, Nalls, Mike A., Orrell, Richard W., Ostrow, Lyle W., Pamphlett, Roger, Pickering-Brown, Stuart, Pioro, Erik, Pliner, Hannah A., Pulst, Stefan M., Ravits, John M., Renton, Alan E., Rivera, Alberto, Robbrecht, Wim, Rogaeva, Ekaterina, Rollinson, Sara, Rothstein, Jeffrey D., Salvi, Erika, Scholz, Sonja W., Sendtner, Michael, Shaw, Pamela J., Sidle, Katie C., Simmons, Zachary, Singleton, Andrew B., Stone, David C., Sulkava, Raimo, Tienari, Pentti J., Traynor, Bryan J., Trojanowski, John Q., Troncoso, Juan C., Van Damme, Philip, Van Deerlin, Vivianna M., Van Den Bosch, Ludo, Zinman, Lorne, Stone, David J., Van Damme, P, Bandres-Ciga, S, Noyce, A, Hemani, G, Nicolas, A, Calvo, A, Mora, G, Tienari, P, Stone, D, Nalls, M, Singleton, A, Chiò, A, Traynor, Bryan, J, Tremolizzo, L, Department of Neurosciences, Neurologian yksikkö, Clinicum, HUS Neurocenter, Translational neuroradiology unit [Bethesda], National Institute of Neurological Disorders and Stroke [Bethesda] (NINDS), National Institutes of Health [Bethesda] (NIH)-National Institutes of Health [Bethesda] (NIH), Univ Granada, Hosp Univ Granada, Inst Invest Biosanitaria Ibs GRANADA, Escuela Andaluza Salud Publ, Granada, Spain, Partenaires INRAE, Queen Mary University of London (QMUL), University College of London [London] (UCL), University of Bristol [Bristol], Département de Physique, Université de Genève, Université de Genève (UNIGE), Università degli studi di Torino (UNITO), University G. d'Annunzio, Chieti, Università degli studi 'G. d'Annunzio' Chieti-Pescara [Chieti-Pescara] (Ud'A), Department of Neurology, A.O.U. Maggiore della Carità, and IRCAD, Novara, Department of Health Sciences, UPO University, UPO University, Dipartimento di Matematica 'Ulisse Dini', Università degli Studi di Firenze = University of Florence [Firenze] (UNIFI), Department of Neurology, Università degli Studi di Milano-Bicocca [Milano] (UNIMIB), Department of Neuroscience, University of Siena, Siena, Università cattolica del Sacro Cuore [Roma] (Unicatt), Università degli studi di Bari Aldo Moro (UNIBA), Istituto di Genetica Medica, Centro Sclerosi Multipla, Ospedale Binaghi, Via Is Guadazzonis 2, Cagliari, Italy, University of Novara, IRCCS-Istituti Clinici Scientifici Maugeri, University of Milan, Milan, Italy, Department of Biomedical and Specialty Surgical Sciences, Università degli Studi di Ferrara (UniFE), S. Anna Hospital, Department of Neuroscience, Catholic University, Roma, Alma Mater Studiorum Università di Bologna [Bologna] (UNIBO), Institute of Medical Genetics, Catholic University, Rome, Italy, Department of Clinical Genetics, Department of Pathology University of Pittsburgh School of Medicine, Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière (CRICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Princeton University, University of Illinois at Urbana-Champaign [Urbana], University of Illinois System, Centre référent Sclérose Latérale Amyotrophique [CHRU Montpellier] (SLA CHRU Montpellier), Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Università degli Studi di Milano [Milano] (UNIMI), Laboratory of Neurogenetics, National Institute of Aging, Tel Aviv Sourasky Medical Center [Te Aviv], University of New Haven [Connecticut], Emory University [Atlanta, GA], UCL Institute of neurology, UCL Institute of Neurology, Cardiovascular, Renal and Metabolism, IMED Biotech Unit, AstraZeneca, Genomic Research Laboratory, Service of Infectious Disease, Hôpitaux Universitaires de Genève (HUG), Boston University [Boston] (BU), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Laboratoire de Biochimie [CHRU Nîmes], Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Department of Neurology and Center for Neuroscience, University of California at Davis, Sacramento, University of California [Davis] (UC Davis), University of California-University of California, Tanz Center Research in Neurodegenerative Diseases [Toronto], University of Toronto, Johns Hopkins University, School of Medicine, Department of Medicine, Surgery, and Dentistry, University of Milano, Institute for Clinical Neurobiology, Julius-Maximilians-Universität Würzburg [Wurtzbourg, Allemagne] (JMU), Penn State Hershey Medical Center, Penn State Health Milton S. Hershey Medical Center, Pennsylvania Commonwealth System of Higher Education (PCSHE)-Penn State System-Pennsylvania Commonwealth System of Higher Education (PCSHE)-Penn State System, Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Perelman School of Medicine, University of Pennsylvania [Philadelphia], Metacohorts Consortium, Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), University of Helsinki, Merck Research Laboratories, National Institutes of Health [Bethesda] (NIH), Center for Neuroscience and Regenerative Medicine [Bethesda] (CNRM), and Henry M. Jackson Foundation for the Advancement of Military Medicine (HJM)

Subjects
0301 basic medicine, Linkage disequilibrium, Multifactorial Inheritance, Multivariate analysis, LD SCORE REGRESSION, DYSLIPIDEMIA, Genome-wide association study, 3124 Neurology and psychiatry, 0302 clinical medicine, PROTECTIVE FACTOR, Mendelian Randomization Analysis, 3. Good health, ALZHEIMERS-DISEASE, Settore MED/26 - NEUROLOGIA, risk factor, BIAS, Neurology, CARDIOVASCULAR-DISEASE, MENDELIAN RANDOMIZATION, Amyotrophic lateral Sclerosis, LD score regression, Mendelian randomization, amyotrophic lateral sclerosis, public resource, Life Sciences & Biomedicine, Clinical psychology, Human, Clinical Neurology, Biology, NO, 03 medical and health sciences, Humans, Genetic Predisposition to Disease, Mendelian Randomization Analysi, MESH: Amyotrophic Lateral Sclerosis, Genetic Predisposition to Disease / genetics, Genome-Wide Association Study / methods, Mendolian Randomization Analysis / methods, Exercise, Genetic association, Science & Technology, [SCCO.NEUR]Cognitive science/Neuroscience, Amyotrophic Lateral Sclerosis, 3112 Neurosciences, Neurosciences, 030104 developmental biology, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, CHOLESTEROL HOMEOSTASIS, Causal inference, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Neurosciences & Neurology, Neurology (clinical), Genome-Wide Association Study, ALS, 030217 neurology & neurosurgery, Amyotrophic Lateral Sclerosi
Abstract

OBJECTIVE: To identify shared polygenic risk and causal associations in amyotrophic lateral sclerosis (ALS). METHODS: Linkage disequilibrium score regression and Mendelian randomization were applied in a large-scale, data-driven manner to explore genetic correlations and causal relationships between >700 phenotypic traits and ALS. Exposures consisted of publicly available genome-wide association studies (GWASes) summary statistics from MR Base and LD-hub. The outcome data came from the recently published ALS GWAS involving 20,806 cases and 59,804 controls. Multivariate analyses, genetic risk profiling, and Bayesian colocalization analyses were also performed. RESULTS: We have shown, by linkage disequilibrium score regression, that ALS shares polygenic risk genetic factors with a number of traits and conditions, including positive correlations with smoking status and moderate levels of physical activity, and negative correlations with higher cognitive performance, higher educational attainment, and light levels of physical activity. Using Mendelian randomization, we found evidence that hyperlipidemia is a causal risk factor for ALS and localized putative functional signals within loci of interest. INTERPRETATION: Here, we have developed a public resource (https://lng-nia.shinyapps.io/mrshiny) which we hope will become a valuable tool for the ALS community, and that will be expanded and updated as new data become available. Shared polygenic risk exists between ALS and educational attainment, physical activity, smoking, and tenseness/restlessness. We also found evidence that elevated low-desnity lipoprotein cholesterol is a causal risk factor for ALS. Future randomized controlled trials should be considered as a proof of causality. Ann Neurol 2019;85:470-481. ispartof: ANNALS OF NEUROLOGY vol:85 issue:4 pages:470-481 ispartof: location:United States status: published

Published
2019

6. Liquid chromatography–tandem mass spectrometric assay for the quantification of CDK4/6 inhibitors in human plasma in a clinical context of drug-drug interaction

Author

Alexandre Evrard, Fanny Leenhardt, Marie Alexandre, Nelly Firmin, William Jacot, Bénédicte Marion, Céline Gongora, S Pouderoux, Celine Roques, Catherine Perrin, Claudia Muracciole-Bich, Matthieu Gracia, Litaty Mbatchi, Unité de Nutrition Humaine (UNH), Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Institut des Biomolécules Max Mousseron [Pôle Chimie Balard] (IBMM), Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)-Institut de Chimie du CNRS (INC)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Génome et Transcriptome - Plateforme Génomique ( GeT-PlaGe), Plateforme Génome & Transcriptome (GET), Génopole Toulouse Midi-Pyrénées [Auzeville] (GENOTOUL), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Génopole Toulouse Midi-Pyrénées [Auzeville] (GENOTOUL), Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Institut du Cancer de Montpellier (ICM), Département d'oncologie Médicale, CRLCC Val d'Aurelle - Paul Lamarque, Laboratoire de Biochimie [CHRU Nîmes], Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Génopole Toulouse Midi-Pyrénées [Auzeville] (GENOTOUL), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Toulouse III - Paul Sabatier (UT3), and Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Université de Montpellier (UM)-Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)

Subjects
[SDV]Life Sciences [q-bio], Clinical Biochemistry, Pharmaceutical Science, Breast Neoplasms, Context (language use), Therapeutic drug monitoring, Palbociclib, 01 natural sciences, CDK4/6 inhibitor, Analytical Chemistry, Pharmacokinetics, Tandem Mass Spectrometry, Drug Discovery, medicine, Humans, Drug-drug interactions, Drug Interactions, Trough Concentration, Protein Kinase Inhibitors, ComputingMilieux_MISCELLANEOUS, Spectroscopy, Chromatography, medicine.diagnostic_test, HPLC-MS/MS, 010405 organic chemistry, Chemistry, 010401 analytical chemistry, Cyclin-Dependent Kinase 4, Cyclin-Dependent Kinase 6, Metastatic breast cancer, medicine.disease, Mass spectrometric, 0104 chemical sciences, 3. Good health, Pharmaceutical Preparations, Hormonal therapy, Benzimidazoles, Female, Chromatography, Liquid
Abstract

The CDK4/6 inhibitors palbociclib and ribociclib are kinase inhibitors used in association with hormonal therapy for the management of patients with metastatic breast cancer. Like most kinase inhibitors, therapeutic drug monitoring may be used for personalize their dosage. To this aim, we developed and validated a sensitive and specific HPLC-MS/MS method for palbociclib and ribociclib quantification in blood samples. We then quantified exposure to palbociclib (plasma trough concentration; Ctrough) in a real-life cohort of patients with locally invasive or metastatic breast cancer (n = 18) at day 15 of the first cycle of palbociclib treatment to characterize palbociclib concentration at steady state (Clinicaltrials.gov identifier NCT04025541, IdRCB n° 2018-A00064-51, 03/07/2018). The geometric mean (± standard deviation [min-max]) of palbociclib plasma Ctrough was 88.58 ng/mL (± 26.4 [46.5 ng/mL - 133 ng/mL]) at day 15. Some covariates, such as drug-drug interactions, could explain the concentration variations observed in our Caucasian cohort. These first results in real-life settings obtained with our HPLC-MS/MS method give important information on palbociclib monitoring and pharmacokinetic variability.

Published
2020

7. Relevance of total PSA and free PSA prescriptions

Author

Sylvain Loric, Laurent Bermont, Jean-Paul Brouillet, Pierre-Jean Lamy, Guy Fouillet, Clinique Médicale Beausoleil, Laboratoire de Biochimie [CHRU Nîmes], Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Institut de Recherche en Cancérologie de Montpellier (IRCM - U1194 Inserm - UM), CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Service de biochimie médicale [CHRU Besançon, hôpital Minjoz], Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Service de Biochimie [Mondor], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)

Subjects
Male, MESH: Prescriptions, medicine.medical_specialty, [SDV.CAN]Life Sciences [q-bio]/Cancer, 03 medical and health sciences, Prostate cancer, PSA, 0302 clinical medicine, Prostate, medicine, Humans, Mass Screening, Relevance (law), cancer, MESH: Early Detection of Cancer, 030212 general & internal medicine, MESH: Mass Screening, Practice Patterns, Physicians', Medical prescription, early detection, Early Detection of Cancer, prostate, MESH: Humans, business.industry, 030503 health policy & services, Free psa, Prostatic Neoplasms, Cancer, General Medicine, Prostate-Specific Antigen, medicine.disease, MESH: Male, 3. Good health, MESH: Prostate-Specific Antigen, Prescriptions, Prostate cancer screening, medicine.anatomical_structure, tumor markers, Family medicine, MESH: Prostatic Neoplasms, MESH: Practice Patterns, Physicians', 0305 other medical science, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Total psa
Abstract

International audience; The total PSA testing has been frequently criticized for its effectiveness in the early detection of prostate cancer. These widely resumed in and out of the medical community have led to a decrease in prescriptions. Recommendations against the use of PSA for screening have been issued in France and in most countries. In the US, the significant decline in total PSA use since 2004 has led to an increase in advanced cancer diagnosis, which has led the authorities to back down. The US preventive services task force (USPSTF) now recommends that men between the ages of 55 and 69 make an individual decision about prostate cancer screening with their clinician. The purpose of this work is to summarize the good practices for the use of the total and free PSA with the views of these last data.

Published
2018

8. Suivi thérapeutique pharmacologique du 5-fluorouracile : mise au point et recommandations du groupe STP-PT de la SFPT et du GPCO-Unicancer

Author

Alexandre Evrard, Etienne Chatelut, Joseph Ciccolini, Marie-Noëlle Paludetto, Françoise Goirand, Manon Launay, Antonin Schmitt, Florian Lemaitre, Jean-Christophe Boyer, Romain Guilhaumou, CHU Pontchaillou [Rennes], Centre d'Investigation Clinique [Rennes] (CIC), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Institut Claudius-Regaud [IUCT-O, Toulouse], Institut Universitaire du Cancer Toulouse - Oncopôle (IUCT), Institut de Recherche en Cancérologie de Montpellier (IRCM - U1194 Inserm - UM), CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Laboratoire de Biochimie [CHRU Nîmes], Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Institut Claudius Regaud, Institut Universitaire du Cancer de Toulouse - Oncopole (IUCT Oncopole - UMR 1037), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Marseille, Centre de Recherche en Cancérologie de Marseille (CRCM), Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER, Université de Rennes (UR)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Neurosciences des Systèmes (INS), and Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
Cancer Research, medicine.medical_specialty, medicine.medical_treatment, 5-fluorouracile, [SDV.CAN]Life Sciences [q-bio]/Cancer, Therapeutic drug monitoring, 030226 pharmacology & pharmacy, 03 medical and health sciences, Suivi thérapeutique pharmacologique, 0302 clinical medicine, Pharmacokinetics, Toxicité, Dihydropyrimidine dehydrogenase, Medicine, Radiology, Nuclear Medicine and imaging, Digestive cancer, Gynecology, Recommandation, medicine.diagnostic_test, Toxicity, business.industry, Pharmacocinétique, Hematology, General Medicine, 3. Good health, Regimen, Oncology, 030220 oncology & carcinogenesis, Dose reduction, business, Adjuvant, Fluoropyrimidine
Abstract

International audience; Despite being 60-years old now, 5-FU remains the backbone of numerous regimen to treat a variety of solid tumors such as breast, head-and-neck and digestive cancers either in neo-adjuvant, adjuvant or metastatic settings. Standard 5-FU usually claims 15-40% of severe toxicities and up to 1% of toxic-death. Numerous studies show a stiff relationship between 5-FU exposure and toxicity or efficacy. In addition, 5-FU pharmacokinetics is highly variable between patients. Indeed, 80% of the 5-FU dose is catabolized in the liver by dihydropyrimidine dehydrogenase (DPD) into inactive compounds. It is now well established that DPD deficiency could lead to severe toxicities and, thus, require dose reduction in deficient patients. However, despite dosage adaptation based on DPD status, some patients may still experience under- or over-exposure, leading to inefficacy or major toxicity. The "Suivi thérapeutique pharmacologique et personnalisation des traitements" (STP-PT) group of the "Société française de pharmacologie et de thérapeutique" (SFPT) and the "Groupe de pharmacologie clinique oncologique" (GPCO)-Unicancer, based on the latest and most up-to-date literature data, recommend the implementation of 5-FU Therapeutic Drug Monitoring in order to ensure an adequate 5-FU exposure.

Published
2018

9. Dépistage du déficit en dihydropyrimidine déshydrogénase (DPD) et sécurisation des chimiothérapies à base de fluoropyrimidines:mise au point et recommandations nationales du GPCO-Unicancer et du RNPGx

Author

Xavier Fonrose, Bernard Royer, Sylvie Quaranta, Anne-Sophie Wozny, Nicolas Picard, Vianney Poinsignon, Fadil Masskouri, Antonin Schmitt, Jean-Christophe Boyer, Franck Broly, Fabienne Thomas, Gérard Milano, Céline Narjoz, Claire Lafay-Chebassier, Joseph Ciccolini, Céline Verstuyft, Angelo Paci, Christine Bobin-Dubigeon, Alexandre Harlé, Marie-Christine Etienne-Grimaldi, Alexandre Evrard, Benjamin Hennart, Laurent Becquemont, Marie-Anne Loriot, Chantal Barin-Le-Guellec, CHU Lille, Institut Pasteur de Lille, Université de Lille, Toxicologie et Génopathies [CHRU Lille], Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Simulation & Modelling : Adaptive Response for Therapeutics in Cancer (SMARTc unit), Centre de Recherches en Oncologie biologique et Oncopharmacologie (CRO2), Institut National de la Santé et de la Recherche Médicale (INSERM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Aix Marseille Université (AMU), Institut Claudius Regaud, Interactions hôte-greffon-tumeur, ingénierie cellulaire et génique - UFC (UMR INSERM 1098) (RIGHT), Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté])-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), Département de pharmacogénomique, Centre de Lutte contre le Cancer Antoine Lacassagne [Nice] (UNICANCER/CAL), UNICANCER-Université Côte d'Azur (UCA)-UNICANCER-Université Côte d'Azur (UCA), Département Micro-Ondes (MO), Université européenne de Bretagne - European University of Brittany (UEB)-Télécom Bretagne-Institut Mines-Télécom [Paris] (IMT), Service de génétique moléculaire, pharmacogénétique et hormonologie, Hôpital Bicêtre-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Bases moléculaires de la réponse aux xénobiotiques (U775 (IFR95)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre d'épidémiologie des populations (CEP), Université de Bourgogne (UB)-Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER-UNICANCER, Institut de Cancérologie de l'Ouest [Angers/Nantes] (UNICANCER/ICO), UNICANCER, Centre de Recherche en Automatique de Nancy (CRAN), Centre National de la Recherche Scientifique (CNRS)-Université de Lorraine (UL), Pharmacologie, Département de biologie et pathologie médicales [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Laboratoire de Biochimie [CHRU Nîmes], Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Institut de Recherche en Cancérologie de Montpellier (IRCM - U1194 Inserm - UM), CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Laboratoire de Toxicologie, Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Ciblage thérapeutique en Oncologie (EA3738), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon, UNICANCER-Université Côte d'Azur (UCA), Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Aix Marseille Université (AMU)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM), Individualisation des traitements des cancers ovariens (ITCO), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut Universitaire du Cancer Toulouse - Oncopôle (IUCT), Interactions hôte-greffon-tumeur, ingénierie cellulaire et génique - UFC (UMR INSERM 1098) (HOTE GREFFON), Université de Franche-Comté (UFC)-Etablissement français du sang [Bourgogne-France-Comté] (EFS [Bourgogne-France-Comté])-Institut National de la Santé et de la Recherche Médicale (INSERM), CRLCC Antoine Lacassagne, Institut Mines-Télécom [Paris] (IMT)-Télécom Bretagne-Université européenne de Bretagne - European University of Brittany (UEB), Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Bicêtre, Université de Bourgogne (UB)-Centre Régional de Lutte contre le cancer - Centre Georges-François Leclerc (CRLCC - CGFL), Institut de cancérologie de l'Ouest - Nantes (ICO Nantes), CRLCC Paul Papin-CRLCC René Gauducheau, Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Régional Universitaire de Nîmes (CHRU Nîmes), Centre Antoine Lacassagne, Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS BFC)-Université de Franche-Comté (UFC), and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Bicêtre

Subjects
03 medical and health sciences, Cancer Research, 0302 clinical medicine, Oncology, 030220 oncology & carcinogenesis, Radiology, Nuclear Medicine and imaging, [SDV.CAN]Life Sciences [q-bio]/Cancer, Hematology, General Medicine, Fluoropyrimidine, 5-Fluorouracile, Capécitabine, Dihydropyrimidine déshydrogénase, DPYD, Dépistage, Toxicité, Recommandation, Pharmacogénétique, 030226 pharmacology & pharmacy, 5Fluorouracil, Capecitabine, Dihydropyrimidine dehydrogenase, Screening, Toxicity, Recommendation, Pharmacogenetics, 3. Good health
Abstract

Les fluoropyrimidines restent les molécules anticancéreuses les plus prescrites dans le traitement des tumeurs solides. Elles induisent des toxicités sévères chez 10–40 % des patients et des toxicités létales chez 0,2–0,8 % des patients. Une abondante littérature a établi le lien entre un déficit enzymatique en dihydropyrimidine déshydrogénase (DPD, enzyme qui dégrade le 5-FU) et la survenue d’une toxicité sévère sous fluoropyrimidine. Si les déficits complets en DPD sont rares (0,1–0,5 %), les déficits partiels sont retrouvés chez 3–15 % des patients. La recherche du déficit en DPD peut être réalisée par phénotypage (mesure directe ou indirecte de l’activité enzymatique) ou par génotypage (recherche des principaux polymorphismes fonctionnels du gène DPYD). Actuellement, il n’existe pas d’obligation réglementaire pour le dépistage du déficit en DPD avant l’administration de fluoropyrimidines. Sur la base des niveaux de preuve issus de la littérature, et des pratiques actuelles, le Groupe de Pharmacologie Clinique Oncologique (GPCO)-UNICANCER et le Réseau National de Pharmacogénétique hospitalière (RNPGx) recommandent : (1) de rechercher un déficit en DPD avant la mise en route de tout traitement à base de 5-FU ou capécitabine ; (2) de réaliser ce dépistage par phénotypage en dosant en première intention l’uracile plasmatique (U) (éventuellement complété par le rapport dihydrouracil/U) et en y associant le génotypage des variants *2A, *13, p.D949V et HapB3 ; (3) de réduire si nécessaire la posologie en fonction du statut DPD dès la première cure et d’envisager une augmentation de dose aux cures suivantes en fonction de la tolérance. Actuellement en France, 17 laboratoires hospitaliers réalisent en routine la recherche du déficit en DPD. Fluoropyrimidines (FU) are still the most prescribed anticancer drugs for the treatment of solid cancers. However, fluoropyrimidines cause severe toxicities in 10 to 40% of patients and toxic deaths in 0.2 to 0.8% of patients, resulting in a real public health problem. The main origin of FU-related toxicities is a deficiency of dihydropyrimidine dehydrogenase (DPD), the rate-limiting enzyme of 5-FU catabolism. DPD deficiency may be identified through pharmacogenetics testing including phenotyping (direct or indirect measurement of enzyme activity) or genotyping (detection of inactivating polymorphisms on the DPYD gene). Approximately 3 to 15% of patients exhibit a partial deficiency and 0.1 to 0.5% a complete DPD deficiency. Currently, there is no regulatory obligation for DPD deficiency screening in patients scheduled to receive a fluoropyrimidine-based chemotherapy. Based on the levels of evidence from the literature data and considering current French practices, the Group of Clinical Pharmacology in Oncology (GPCO)-UNICANCER and the French Network of Pharmacogenetics (RNPGx) recommend the following: (1) to screen DPD deficiency before initiating any chemotherapy containing 5-FU or capecitabine; (2) to perform DPD phenotyping by measuring plasma uracil (U) concentrations (possibly associated with dihydrouracil/U ratio), and DPYD genotyping (variants *2A, *13, p.D949V, HapB3); (3) to reduce the initial FU dose (first cycle) according to DPD status, if needed, and further, to consider increasing the dose at subsequent cycles according to treatment tolerance. In France, 17 public laboratories currently undertake routine screening of DPD deficiency. 105;4

Published
2018

10. Genetic variations of the xenoreceptors NR1I2 and NR1I3 and their effect on drug disposition and response variability

Author

Alexandre Evrard, Litaty Mbatchi, Jean-Paul Brouillet, Laboratoire de Biochimie [CHRU Nîmes], Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Institut de Recherche en Cancérologie de Montpellier (IRCM - U1194 Inserm - UM), and CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)

Subjects
MESH: Xenobiotics, Receptors, Steroid, Receptors, Cytoplasmic and Nuclear, MESH: Pregnane X Receptor, Pharmacology, Biology, MESH: Receptors, Cytoplasmic and Nuclear, 030226 pharmacology & pharmacy, Xenobiotics, xenoreceptors, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Pharmacokinetics, Genetic variation, MESH: Polymorphism, Genetic, Genetics, medicine, Humans, Constitutive Androstane Receptor, pharmacogenetics, Pregnane X receptor, Polymorphism, Genetic, MESH: Humans, Pregnane X Receptor, Tacrolimus, 3. Good health, Atazanavir, Nuclear receptor, chemistry, 030220 oncology & carcinogenesis, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, Molecular Medicine, Xenobiotic, pharmacokinetics, Pharmacogenetics, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, medicine.drug, MESH: Receptors, Steroid
Abstract

International audience; NR1I2 (PXR) and NR1I3 (CAR) are nuclear receptors that are classified as xenoreceptors. Upon activation by various xenobiotics, including marketed drugs, they regulate the transcription level of major drug-metabolizing enzymes and transporters and facilitate the elimination of xenobiotics from the body. The modulation of the activity of these two xenoreceptors by various ligands is a major source of pharmacokinetic variability of environmental origin. NR1I2 and NR1I3 genetic polymorphisms can affect the pharmacokinetics and therapeutic response to many drugs, such as irinotecan, tacrolimus and atazanavir. This review provides an overview of NR1I2 and NR1I3 pharmacogenetic studies in various therapeutic fields (oncology, immunomodulation and infectiology) and discusses the implementation of NR1I2 and NR1I3 genetic polymorphism testing in the clinical routine.

Published
2018

11. Circulating tumour cells from patients with colorectal cancer have cancer stem cell hallmarks in ex vivo culture

Author

Elsa Bayet, Sophie Bravo, Jean-François Bourgaux, Lucile Canterel-Thouennon, Arthur Hsu, Kym Pham, Ebba Louise Lagerqvist, Michel Prudhomme, Claire Philippe, Nathalie Rolland, Frédéric Hollande, Graham R. Taylor, Jean Christophe Boyer, Emmanuelle Charafe-Jauffret, Christina Mølck, Luke Zappia, Fanny Grillet, Jean-Marc Pascussi, Julie Pannequin, Olivia Villeronce, Sebastian Lunke, Institut de Génomique Fonctionnelle (IGF), Université de Montpellier (UM)-Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 2 - Sciences et Techniques (UM2)-Centre National de la Recherche Scientifique (CNRS), University of Melbourne, Centre de Recherche en Cancérologie de Marseille (CRCM), Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Laboratoire de Biochimie [CHRU Nîmes], Institut de Recherche en Cancérologie de Montpellier (IRCM - U1194 Inserm - UM), CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Aix Marseille Université (AMU), Centre Hospitalier Régional Universitaire de Nîmes (CHRU Nîmes), Biochimie et Physiologie Moléculaire des Plantes (BPMP), Université de Montpellier (UM)-Centre international d'études supérieures en sciences agronomiques (Montpellier SupAgro)-Institut national d’études supérieures agronomiques de Montpellier (Montpellier SupAgro)-Institut National de la Recherche Agronomique (INRA)-Centre National de la Recherche Scientifique (CNRS), Herrada, Anthony, and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
0301 basic medicine, Pathology, medicine.medical_specialty, Colorectal cancer, Cellular differentiation, Biology, Metastasis, LIVER METASTASES, 03 medical and health sciences, 0302 clinical medicine, Cancer stem cell, medicine, Cytotoxic T cell, neoplasms, COLORECTAL CANCER, DRUG TOXICITY, Gastroenterology, Cancer, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, medicine.disease, [SDV.MHEP.HEG] Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, digestive system diseases, 3. Good health, 030104 developmental biology, Cell culture, 030220 oncology & carcinogenesis, Cancer research, Ex vivo
Abstract

International audience; OBJECTIVE:Although counting of circulating tumour cells (CTC) has attracted a broad interest as potential markers of tumour progression and treatment response, the lack of functional characterisation of these cells had become a bottleneck in taking these observations to the clinic. Our objective was to culture these cells in order to understand them and exploit their therapeutic potential to the full.DESIGN:Here, hypothesising that some CTC potentially have cancer stem cell (CSC) phenotype, we generated several CTC lines from the blood of patients with advanced metastatic colorectal cancer (CRC) based on their self-renewal abilities. Multiple standard tests were then employed to characterise these cells.RESULTS:Our CTC lines self-renew, express CSC markers and have multilineage differentiation ability, both in vitro and in vivo. Patient-derived CTC lines are tumorigenic in subcutaneous xenografts and are also able to colonise the liver after intrasplenic injection. RNA sequencing analyses strikingly demonstrate that drug metabolising pathways represent the most upregulated feature among CTC lines in comparison with primary CRC cells grown under similar conditions. This result is corroborated by the high resistance of the CTC lines to conventional cytotoxic compounds.CONCLUSIONS:Taken together, our results directly demonstrate the existence of patient-derived colorectal CTCs that bear all the functional attributes of CSCs. The CTC culture model described here is simple and takes

Published
2017

12. Cancer genomics guide clinical practice in personalized medicine

Author

Jacqueline Lehmann-Che, Alexandre Evrard, Jean-Christophe Boyer, Brigitte Poirot, Hôpital Saint-Louis, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), Pathologie cellulaire : aspects moléculaires et viraux / Pathologie et Virologie Moléculaire, Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7)-Université Paris Diderot - Paris 7 (UPD7)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de Biochimie [CHRU Nîmes], Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Aide à la Décision pour une Médecine Personnalisé - Laboratoire de Biostatistique, Epidémiologie et Recherche Clinique - EA 2415 (AIDMP), Université Montpellier 1 (UM1)-Université de Montpellier (UM), Institut de Recherche en Cancérologie de Montpellier (IRCM - U1194 Inserm - UM), CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Université Paris Diderot - Paris 7 (UPD7)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS), Université Paris Diderot - Paris 7 (UPD7)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Régional Universitaire de Nîmes (CHRU Nîmes), and Université de Montpellier (UM)-Université Montpellier 1 (UM1)

Subjects
0301 basic medicine, medicine.medical_specialty, medicine.medical_treatment, Genomics, Bioinformatics, Targeted therapy, 03 medical and health sciences, Therapeutic approach, 0302 clinical medicine, Neoplasms, medicine, Humans, Pharmacology (medical), Medical physics, Molecular Targeted Therapy, Precision Medicine, Theranostic biomarkers, business.industry, Cancer, Treatment options, High-Throughput Nucleotide Sequencing, Precision medicine, medicine.disease, Personalized medicine, 3. Good health, Clinical Practice, 030104 developmental biology, Pharmacogenetics, 030220 oncology & carcinogenesis, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, business
Abstract

International audience; Targeted therapies have revolutionized the treatment of many cancers. Widely developed over the last decade, this new concept of precision medicine relies on the use of genomic technologies to analyze tumor samples in order to identify actionable targets and biomarkers of resistance. The goal is to optimize treatment by identifying which therapeutic approach is best for each patient, i.e. the treatment that is effective, has minimal adverse effects, and avoids unnecessary intervention and cost. The purpose of this review is to highlight, using a few seminal examples of therapeutic targets, the important contribution of appropriate analysis of key oncogenes or driver genes in making clinical decisions. Cancer genomics is now an indispensable part of clinical management. Furthermore, the development of next generation sequencing (NGS) will enable exploration of more and more genes of interest, leading to new treatment options for personalized medicine.

Published
2017

13. Association of NR1I2, CYP3A5 and ABCB1 genetic polymorphisms with variability of temsirolimus pharmacokinetics and toxicity in patients with metastatic bladder cancer

Author

Matthieu Gassiot, Philippe Pourquier, Nadine Houédé, Alejando Goberna, Litaty Mbatchi, Hakim Mahammedi, Loic Mourey, Serge Lumbroso, Alexandre Evrard, Florence Joly, Laboratoire de Biochimie [CHRU Nîmes], Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Institut de Recherche en Cancérologie de Montpellier (IRCM - U1194 Inserm - UM), CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Institut Bergonié [Bordeaux], UNICANCER, Centre Jean Perrin [Clermont-Ferrand] (UNICANCER/CJP), Institut Universitaire du Cancer de Toulouse - Oncopole (IUCT Oncopole - UMR 1037), CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU), Institut des Neurosciences de Montpellier - Déficits sensoriels et moteurs (INM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM), Signalisation et Mecanismes Moleculaires de l'Apoptose, Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale (INSERM), Medical oncology department [Toulouse], Institut Claudius Regaud, Cancers et préventions, Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Herrada, Anthony, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM), Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN), and Institut des Neurosciences de Montpellier (INM)

Subjects
Male, 0301 basic medicine, Cancer Research, Temsirolimus, CYP3A5, Genotype, [SDV]Life Sciences [q-bio], Antineoplastic Agents, Single-nucleotide polymorphism, [SDV.CAN]Life Sciences [q-bio]/Cancer, Pharmacology, Toxicology, Polymorphism, Single Nucleotide, 03 medical and health sciences, 0302 clinical medicine, NR1I2, [SDV.CAN] Life Sciences [q-bio]/Cancer, Pharmacokinetics, Cytochrome P-450 CYP3A, Humans, Medicine, Pharmacology (medical), ComputingMilieux_MISCELLANEOUS, Aged, Sirolimus, Polymorphism, Genetic, Bladder cancer, business.industry, ABCB1, Middle Aged, medicine.disease, 3. Good health, 030104 developmental biology, Urinary Bladder Neoplasms, Oncology, Pharmacogenetics, [SDV.SP.PHARMA] Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, 030220 oncology & carcinogenesis, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, Female, Mantle cell lymphoma, business, medicine.drug
Abstract

International audience; PURPOSE:Temsirolimus is a mammalian target of rapamycin (mTOR) inhibitor that exhibits antitumor activity in renal cell carcinoma and mantle cell lymphoma. The metabolism of temsirolimus and its active metabolite sirolimus mainly depends on cytochrome P450 3A4/5 (CYP3A4/A5) and the ABCB1 transporter. Differently from sirolimus, no pharmacogenetic study on temsirolimus has been conducted. Therefore, the aim of this pilot study was to identify genetic determinants of the inter-individual variability in temsirolimus pharmacokinetics and toxicity.METHODS:Pharmacokinetic profiles were obtained for 16 patients with bladder cancer after intravenous infusion of 25 mg temsirolimus. Non-compartmental analysis was performed to calculate the pharmacokinetic parameters of temsirolimus and sirolimus, its main metabolite. The presence of single nucleotide polymorphisms (SNPs) in CYP3A5, ABCB1 and in their transcriptional regulator NR1I2 (PXR) was assessed by genotyping. Non-parametric statistical tests were used to assess associations between candidate SNPs and temsirolimus pharmacokinetics and toxicity.RESULTS:The ratio between sirolimus AUC and temsirolimus AUC was 1.6-fold higher in patients who experienced serious toxic events (p = 0.034). The frequency of adverse events was significantly higher in patients homozygous for the NR1I2-rs6785049 A allele (OR = 0.065, p = 0.04) or NR1I2-rs3814055 C allele (OR = 0.032, p = 0.006). These NR1I2 SNPs were also predictive of temsirolimus half-life and global exposure to temsirolimus and sirolimus. Finally, the effect of the ABCB1-rs1128503, ABCB1-rs2032582 and CYP3A5*3 SNPs on sirolimus pharmacokinetics was confirmed.CONCLUSIONS:Our findings suggest that SNPs of NR1I2 and its target genes CYP3A5 and ABCB1 are genetic determinants of temsirolimus pharmacokinetics and toxicity in patients with bladder cancer.

Published
2017

14. Prevention of 5-fluorouracil–induced early severe toxicity by pre-therapeutic dihydropyrimidine dehydrogenase deficiency screening: The multiparametric approach is not convincing

Author

Jean-Christophe Boyer, Alexandre Evrard, Bernard Royer, Marie-Christine Etienne-Grimaldi, Chantal Le Guellec, Fabienne Thomas, Angelo Paci, Joseph Ciccolini, Etienne Chatelut, Marie-Anne Loriot, Centre de Lutte contre le Cancer Antoine Lacassagne [Nice] (UNICANCER/CAL), UNICANCER-Université Côte d'Azur (UCA), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Laboratoire de Biochimie [CHRU Nîmes], Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Institut Claudius Regaud, Institut de Recherche en Cancérologie de Montpellier (IRCM - U1194 Inserm - UM), CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Département de pharmacie clinique [Gustave Roussy], Institut Gustave Roussy (IGR), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Simulation and Modeling of Adaptive Response for Therapeutics in Cancer (SMARTc), Centre de Recherche en Cancérologie de Marseille (CRCM), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Aix Marseille Université (AMU), Pharmacocinétique Toxicocinétique - [Hôpital de la Timone - APHM], Hôpital de la Timone [CHU - APHM] (TIMONE)-Assistance Publique - Hôpitaux de Marseille (APHM), CRLCC Antoine Lacassagne, Centre Hospitalier Régional Universitaire de Tours (CHRU TOURS), Centre Hospitalier Régional Universitaire de Nîmes (CHRU Nîmes), Biochimie et Physiologie Moléculaire des Plantes (BPMP), Université de Montpellier (UM)-Centre international d'études supérieures en sciences agronomiques (Montpellier SupAgro)-Institut national d’études supérieures agronomiques de Montpellier (Montpellier SupAgro)-Institut National de la Recherche Agronomique (INRA)-Centre National de la Recherche Scientifique (CNRS), CRLCC Institut Claudius Regaud, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Hôpital Jean Minjoz, Centre Hospitalier Régional Universitaire [Besançon] (CHRU Besançon), Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), CRLCC Val d'Aurelle - Paul Lamarque-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU)-Institut Paoli-Calmettes, and Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
0301 basic medicine, Dihydropyrimidine Dehydrogenase Deficiency, Drug-Related Side Effects and Adverse Reactions, business.industry, [SDV.CAN]Life Sciences [q-bio]/Cancer, Hematology, medicine.disease, 3. Good health, 03 medical and health sciences, Dihydropyrimidine dehydrogenase deficiency, 030104 developmental biology, 0302 clinical medicine, Oncology, Fluorouracil, 030220 oncology & carcinogenesis, Cancer research, medicine, Humans, business, Severe toxicity, Dihydrouracil Dehydrogenase (NADP), ComputingMilieux_MISCELLANEOUS, medicine.drug
Abstract

International audience

Published
2017

15. Effect of Single Nucleotide Polymorphisms in the Xenobiotic-sensing Receptors NR1I2 and NR1I3 on the Pharmacokinetics and Toxicity of Irinotecan in Colorectal Cancer Patients

Author

Fabienne Thomas, Jacques Robert, Matthieu Gassiot, Litaty Mbatchi, Alexandre Evrard, Nicole Tubiana, Marc Ychou, Maguy Del Rio, Jean-Christophe Boyer, Laboratoire de Biochimie [CHRU Nîmes], Centre Hospitalier Régional Universitaire de Nîmes (CHRU Nîmes), Institut de Recherche en Cancérologie de Montpellier (IRCM - U1194 Inserm - UM), CRLCC Val d'Aurelle - Paul Lamarque-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Validation et identification de nouvelles cibles en oncologie (VINCO), Université Bordeaux Segalen - Bordeaux 2-Institut Bergonié - CRLCC Bordeaux-Institut National de la Santé et de la Recherche Médicale (INSERM), UNICANCER - Institut régional du Cancer [Montpellier] (ICM), CRLCC Val d'Aurelle - Paul Lamarque, Biochimie et Physiologie Moléculaire des Plantes (BPMP), Université de Montpellier (UM)-Centre international d'études supérieures en sciences agronomiques (Montpellier SupAgro)-Institut national d’études supérieures agronomiques de Montpellier (Montpellier SupAgro)-Institut National de la Recherche Agronomique (INRA)-Centre National de la Recherche Scientifique (CNRS), Individualisation des traitements des cancers ovariens (ITCO), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut Universitaire du Cancer Toulouse - Oncopôle (IUCT), CRLCC Institut Claudius Regaud, CHU Limoges, Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Institut Bergonié [Bordeaux], UNICANCER-UNICANCER-Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale (INSERM), UNICANCER - Institut régional du Cancer Montpellier Val d'Aurelle (ICM), and Institut Claudius Regaud

Subjects
0301 basic medicine, Adult, Genetic Markers, Male, Receptors, Steroid, Colorectal cancer, Receptors, Cytoplasmic and Nuclear, Single-nucleotide polymorphism, Pharmacology, Irinotecan, Polymorphism, Single Nucleotide, Xenobiotics, Cohort Studies, 03 medical and health sciences, 0302 clinical medicine, Pharmacokinetics, Predictive Value of Tests, Constitutive androstane receptor, medicine, Humans, Pharmacology (medical), Drug Interactions, Neoplasm Metastasis, Constitutive Androstane Receptor, Aged, Aged, 80 and over, Pregnane X receptor, business.industry, Pregnane X Receptor, Middle Aged, medicine.disease, Antineoplastic Agents, Phytogenic, digestive system diseases, 3. Good health, 030104 developmental biology, Pharmacogenetics, 030220 oncology & carcinogenesis, Toxicity, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, Camptothecin, Female, France, business, Colorectal Neoplasms, medicine.drug
Abstract

International audience; BACKGROUND AND OBJECTIVES:Nuclear receptors PXR (pregnane X receptor, NR1I2) and CAR (constitutive androstane receptor, NR1I3) are key regulators of irinotecan metabolism, and ligand-dependent modulation of their activity leads to significant drug-drug interactions. Because genetic polymorphisms can also affect the activity of these xenobiotic-sensing receptors, we hypothesized that they could contribute to the interpatient variability of irinotecan pharmacokinetics and to the toxicity of irinotecan-based regimens.PATIENTS AND METHODS:In a cohort of 109 metastatic colorectal cancer patients treated with irinotecan (180 mg/m(2)) in combination with other drugs, associations were assessed between 21 selected single nucleotide polymorphisms of NR1I2 or NR1I3 and pharmacokinetic parameters or toxicity of irinotecan and its metabolites.RESULTS:After adjustment of the tests by the UGT1A1*28 genotype and correction for multiple testing, the A allele of NR1I2-rs10934498 was associated with a decreased exposition and an increased degradation of SN-38, the active metabolite (p = 0.009 and p = 0.017, respectively). The risk of hematological toxicity was associated with NR1I2-rs10934498 and NR1I2-rs2472677 (p = 0.009 and p = 0.003, respectively).CONCLUSION:Our results reveal for the first time the involvement of NR1I2 in the pharmacogenetics of irinotecan and suggest that it may help to predict the toxicity of low-dose irinotecan.

Published
2016

16. Impact of 30 mg/kg amikacin and 8 mg/kg gentamicin on serum concentrations in critically ill patients with severe sepsis

Author

Bastian Nucci, Laurent Muller, Haroun Knani, Jason A. Roberts, Arnaud Friggeri, Jean-Philippe Lavigne, Bernard Allaouchiche, Jean-Yves Lefrant, Alexandre Evrard, Claire Roger, Benjamin Louart, Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Caractéristiques féminines des dysfonctions des interfaces cardio-vasculaires (EA 2992), Université Montpellier 1 (UM1)-Université de Montpellier (UM), Service d'anesthésie-réanimation [Centre Hospitalier Lyon Sud - HCL], Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Laboratoire de Biochimie [CHRU Nîmes], Institut de Recherche en Cancérologie de Montpellier (IRCM - U1194 Inserm - UM), CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Virulence bactérienne et maladies infectieuses (VBMI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), and University of Queensland [Brisbane]

Subjects
0301 basic medicine, Microbiology (medical), Adult, Male, Serum, Icu patients, Critical Illness, 030106 microbiology, Cmax, Microbial Sensitivity Tests, Sepsis, 03 medical and health sciences, Young Adult, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, medicine, Humans, Pharmacology (medical), Amikacin, Severe sepsis, Aged, Pharmacology, Aged, 80 and over, Critically ill, business.industry, Serum concentration, Middle Aged, medicine.disease, 3. Good health, Anti-Bacterial Agents, Infectious Diseases, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, Anesthesia, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, Gentamicin, Administration, Intravenous, Female, France, Gentamicins, business, medicine.drug
Abstract

International audience; OBJECTIVES:Low first-dose peak serum concentrations of amikacin and gentamicin are commonly reported in ICU patients. The present study aimed to assess whether 30 mg/kg amikacin or 8 mg/kg gentamicin achieved target concentrations in ICU patients with severe sepsis.PATIENTS AND METHODS:Sixty-three ICU patients (Simplified Acute Physiology Score II = 43 ± 16) with severe sepsis and an indication for intravenous amikacin (n = 47) or gentamicin (n = 16) were included. The first (30 mg/kg amikacin; 8 mg/kg gentamicin) and subsequent doses and corresponding peak concentrations (30 min after the completion of an infusion) were recorded. French guideline target concentrations were ≥60 and ≥30 mg/L for amikacin and gentamicin, respectively. A target pharmacokinetic/pharmacodynamic ratio of 10 × MIC was also measured.RESULTS:Pulmonary, abdominal and urinary tract infections were diagnosed in 56 patients. Infection was confirmed in 37 patients (59%). The targeted first-dose peak concentration was achieved in 37/63 patients (59%) [amikacin 36/47 (77%) and gentamicin 1/16 (6%)], and 59/63 patients (94%) achieved the pharmacokinetic/pharmacodynamic ratio using the MIC data that were available from 21 patients. However, the second dose of aminoglycoside was withheld because of high trough concentrations in nearly half of patients who did not have renal dysfunction.CONCLUSIONS:In this study, 30 mg/kg amikacin and 8 mg/kg gentamicin led to target peak serum concentrations in 59% of patients.

Published
2016

17. Standard dosing of amikacin and gentamicin in critically ill patients results in variable and subtherapeutic concentrations

Author

Sophie Lloret, G. Saissi, Gael Pradel, Anne Polge, Nicolas Molinari, Jason A. Roberts, Bastian Nucci, Jean-Yves Lefrant, Loubna Elotmani, Laurent Muller, Saber Barbar, Sophie Bastide, Clément Aubert, Claire Roger, Centre Hospitalier Régional Universitaire de Nîmes (CHRU Nîmes), Caractéristiques féminines des dysfonctions des interfaces cardio-vasculaires (EA 2992), Université de Montpellier (UM)-Université Montpellier 1 (UM1), Mathématiques, Informatique et STatistique pour l'Environnement et l'Agronomie (MISTEA), Institut National de la Recherche Agronomique (INRA)-Institut national d’études supérieures agronomiques de Montpellier (Montpellier SupAgro), BESPIM, CH Avignon, Laboratoire de Biochimie [CHRU Nîmes], University of Queensland [Brisbane], Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Université Montpellier 1 (UM1)-Université de Montpellier (UM), Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro), Centre Hospitalier Henri Duffaut (Avignon), and Australian National Health and Medical Research Council Fellowship : APP1048652

Subjects
Male, law.invention, Cohort Studies, Plasma, 0302 clinical medicine, law, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, polycyclic compounds, Pharmacology (medical), 030212 general & internal medicine, Aged, 80 and over, 0303 health sciences, Aminoglycoside, digestive, oral, and skin physiology, General Medicine, Bacterial Infections, Middle Aged, Intensive care unit, 3. Good health, Anti-Bacterial Agents, Infectious Diseases, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, Amikacin, SAPS II, Anesthesia, Urinary Tract Infections, Gentamicin, Female, medicine.drug, Microbiology (medical), Adult, medicine.medical_specialty, Urinary system, Critical Illness, Cmax, 03 medical and health sciences, medicine, Pneumonia, Bacterial, Humans, Dosing, Aged, 030306 microbiology, business.industry, Peak plasma concentration, Surgery, ICU, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, Intraabdominal Infections, Gentamicins, business
Abstract

International audience; Low peak plasma concentrations (Cmax) of amikacin and gentamicin are reported in intensive care unit (ICU) patients after administration of the first dose. The present study aimed to describe the proportion of ICU patients in whom an adequate Cmax was achieved throughout the course of therapy. Septic ICU patients with an indication for intravenous amikacin or gentamicin were eligible for inclusion in this single-centre observational study. The first and subsequent doses and the corresponding Cmax values were recorded. The target Cmax was ≥60mg/L for amikacin and ≥30mg/L for gentamicin. Amikacin and gentamicin plasma concentrations were available in 66 and 24 patients, respectively (59±17 years; 79±19kg; height 169±12cm; SAPS II score 46±19). Pulmonary, abdominal and urinary tract infections were diagnosed in 64 patients. Culture-positive infection was confirmed in 65 patients (72%). A target first Cmax was achieved in 17/90 patients (19%). For amikacin, the target Cmax was achieved in 16/66 patients (24%) after the initial dose. In the 50 remaining patients, a change in dosing was performed in 14 patients, leading adequate peak plasma level in 2 patients. For gentamicin, the targeted Cmax was achieved in only 1/24 patient (4%) after the initial dose and was never achieved after the third dose. In conclusion, standard dosing of amikacin or gentamicin led to adequate Cmax in only 19% of patients. Subtherapeutic Cmax were not significantly corrected after subsequent doses.

Published
2015

18. Polymorphisms in SLCO1B3 and NR1I2 as genetic determinants of hematotoxicity of carboplatin and paclitaxel combination

Author

Philippe Pourquier, Litaty Mbatchi, Fabienne Thomas, Alexandre Evrard, Yoann Cazaubon, Jacques Robert, Etienne Chatelut, Serge Lumbroso, Jean-Paul Brouillet, Antonin Schmitt, Jean-Christophe Boyer, Herrada, Anthony, Laboratoire de Biochimie [CHRU Nîmes], Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Institut de Recherche en Cancérologie de Montpellier (IRCM - U1194 Inserm - UM), CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Individualisation des traitements des cancers ovariens (ITCO), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut Universitaire du Cancer Toulouse - Oncopôle (IUCT), Université de Montpellier (UM), Validation et identification de nouvelles cibles en oncologie (VINCO), Institut Bergonié [Bordeaux], UNICANCER-UNICANCER-Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut des Neurosciences de Montpellier (INM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Signalisation et Mecanismes Moleculaires de l'Apoptose, Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Bergonié [Bordeaux], UNICANCER-UNICANCER-Université Bordeaux Segalen - Bordeaux 2, Institut des Neurosciences de Montpellier - Déficits sensoriels et moteurs (INM), Centre Hospitalier Régional Universitaire de Nîmes (CHRU Nîmes), Centre d'épidémiologie des populations (CEP), Université de Bourgogne (UB)-Centre Régional de Lutte contre le cancer - Centre Georges-François Leclerc (CRLCC - CGFL), Evaluation et modélisation des effets thérapeutiques, Département biostatistiques et modélisation pour la santé et l'environnement [LBBE], Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS), Laboratoire Aimé Cotton (LAC), École normale supérieure - Cachan (ENS Cachan)-Université Paris-Sud - Paris 11 (UP11)-Centre National de la Recherche Scientifique (CNRS), Institut de Génomique Fonctionnelle (IGF), Université de Montpellier (UM)-Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 2 - Sciences et Techniques (UM2)-Centre National de la Recherche Scientifique (CNRS), EA3035, Institut Claudius Regaud, Biochimie et Physiologie Moléculaire des Plantes (BPMP), Université de Montpellier (UM)-Centre international d'études supérieures en sciences agronomiques (Montpellier SupAgro)-Institut national d’études supérieures agronomiques de Montpellier (Montpellier SupAgro)-Institut National de la Recherche Agronomique (INRA)-Centre National de la Recherche Scientifique (CNRS), CRLCC Val d'Aurelle - Paul Lamarque-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Université Bordeaux Segalen - Bordeaux 2-Institut Bergonié - CRLCC Bordeaux-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
Male, Oncology, Receptors, Steroid, [SDV]Life Sciences [q-bio], Organic Anion Transporters, Sodium-Independent, Pharmacology, 030226 pharmacology & pharmacy, Linkage Disequilibrium, Cohort Studies, chemistry.chemical_compound, paclitaxel, pregnane X receptor, 0302 clinical medicine, Gene Frequency, hemic and lymphatic diseases, ComputingMilieux_MISCELLANEOUS, Aged, 80 and over, Middle Aged, 3. Good health, Paclitaxel, 030220 oncology & carcinogenesis, [SDV.SP.PHARMA] Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, carboplatin, Molecular Medicine, Female, Adult, medicine.medical_specialty, PXR, SNP, Antineoplastic Agents, Single-nucleotide polymorphism, Neutropenia, Polymorphism, Single Nucleotide, Solute Carrier Organic Anion Transporter Family Member 1B3, Young Adult, 03 medical and health sciences, Internal medicine, Genetics, medicine, Humans, Allele, Alleles, Genetic Association Studies, Aged, hematotoxicity, business.industry, Haplotype, SLCO1B3, medicine.disease, Antineoplastic Agents, Phytogenic, Thrombocytopenia, Carboplatin, drug metabolism, Haplotypes, chemistry, Pharmacodynamics, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, business
Abstract

Aim: The goal of our study was to assess the impact of patients’ genetic background on their sensitivity to carboplatin/paclitaxel hematotoxicity. Patients & methods: Parameters describing sensitivity to neutropenia and to thrombocytopenia of 201 patients were extracted from a previous pharmacokinetic/pharmacodynamics analysis, in order to assess their association with 52 candidates SNPs in 18 genes. Results: Carriers of a T allele of SLCO1B3-rs4149117 were 19% less sensitive to thrombocytopenia than the homozygotes for the G allele (p = 0.00279). Carriers of two copies of the ATG haplotypes of NR1I2-rs1523130, rs3814055 and rs1523127 were 19% less sensitive to thrombocytopenia than those harboring other haplotypes (p = 0.025). Conclusion: Our results revealed the importance of SLCO1B3 and NR1I2 in the sensitivity to carboplatin/paclitaxel thrombocytopenia.

Published
2015

19. Performance and cost efficiency of KRAS mutation testing for metastatic colorectal cancer in routine diagnosis: the MOKAECM study, a nationwide experience

Author

Pierre Laurent-Puig, Jean-François Emile, Marie-Claude Gorisse, Pascaline Aucouturier, Jean-Philippe Merlio, Florence de Fraipont, Jean-Louis Merlin, Isabelle Durand-Zaleski, Frédérique Nowak, Karen Leroy, Thierry Frebourg, Alain Morel, Hélène Blons, Delphine Le Corre, Gilles Chatellier, Jean-François Côté, Jean-Christophe Sabourin, L'Houcine Ouafik, Etienne Rouleau, Jean-Christophe Boyer, Nathanaël Charrier, Jean-Christophe Pages, Gérard Milano, Patricia de Cremoux, Bases moléculaires de la réponse aux xénobiotiques (U775 (IFR95)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire d'Oncogénétique, CRLCC René Huguenin, Service de Santé Publique, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Hôpital Albert Chenevier, Centre d'Investigation Clinique - Epidemiologie Clinique/essais Cliniques [CHU HEGP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Recherches Cliniques de Montréal (IRCM), Université de Montréal (UdeM), Virus, pseudo-virus: Morphogénèse et Antigénicité, Université de Tours (UT)-EA3856, Hôpital Bretonneau, Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Institut d'oncologie/développement Albert Bonniot de Grenoble (INSERM U823), Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de Biochimie [CHRU Nîmes], Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), CHU Bordeaux [Bordeaux], Oppelia, Institut Jean Godinot [Reims], UNICANCER, Hôpital Saint Louis, Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Département de pathologie [Mondor], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Département de pharmacogénomique, Centre de Lutte contre le Cancer Antoine Lacassagne [Nice] (UNICANCER/CAL), UNICANCER-Université Côte d'Azur (UCA)-UNICANCER-Université Côte d'Azur (UCA), Centre de Recherches en Oncologie biologique et Oncopharmacologie (CRO2), Aix Marseille Université (AMU)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche en Automatique de Nancy (CRAN), Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS), Centre Alexis Vautrin (CAV), CHU Rouen, Normandie Université (NU), Institut national du cancer [Boulogne] (INCA), Génétique du cancer et des maladies neuropsychiatriques (GMFC), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Biomarqueurs et essais cliniques en Cancérologie et Onco-Hématologie (BECCOH), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Saclay, Service d'anatomie pathologique [CHU Ambroise-Paré], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Ambroise Paré [AP-HP], Département de la recherche clinique et du développement, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôtel-Dieu-Unité de Recherche Clinique en Economie de la santé d'Ile de France (URC Eco), Médecine Personnalisée, Pharmacogénomique, Optimisation Thérapeutique (MEPPOT - U1147), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Tours-EA3856, Institut National de la Santé et de la Recherche Médicale (INSERM)-EFS-CHU Grenoble-Université Joseph Fourier - Grenoble 1 (UJF), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Henri Mondor-Hôpital Albert Chenevier, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Recherches Cliniques de Montréal, Université de Montréal, Université de Montréal [Montréal], Biochimie et Physiologie Moléculaire des Plantes (BPMP), Université de Montpellier (UM)-Centre international d'études supérieures en sciences agronomiques (Montpellier SupAgro)-Institut national d’études supérieures agronomiques de Montpellier (Montpellier SupAgro)-Institut National de la Recherche Agronomique (INRA)-Centre National de la Recherche Scientifique (CNRS), Institut Jean Godinot, CRLCC Jean Godinot, CHU Saint Louis [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), CRLCC Antoine Lacassagne, Laboratoire épidémiologie et oncogénèse des tumeurs digestives, Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Service d'anatomie pathologique, Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Ambroise Paré, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Cochin [AP-HP]-Hôtel-Dieu-Unité de Recherche Clinique en Economie de la santé d'Ile de France (URC Eco), Centre National de la Recherche Scientifique (CNRS)-Université de Lorraine (UL), Bases moléculaires de la réponse aux xénobiotiques ( U775 (IFR95) ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Henri Mondor-Hôpital Albert Chenevier, Centre d'Investigation Clinique - Epidemiologie Clinique/essais Cliniques de l'Hopital Europeen Georges Pompidou, Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Européen Georges Pompidou [APHP] ( HEGP ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université de Montréal, CHRU Tours, Institut d'oncologie/développement Albert Bonniot de Grenoble ( INSERM U823 ), Université Joseph Fourier - Grenoble 1 ( UJF ) -CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Biochimie et Physiologie Moléculaire des Plantes ( BPMP ), Centre National de la Recherche Scientifique ( CNRS ) -Université de Montpellier ( UM ) -Centre international d'études supérieures en sciences agronomiques ( Montpellier SupAgro ) -Institut national d’études supérieures agronomiques de Montpellier ( Montpellier SupAgro ) -Institut national de la recherche agronomique [Montpellier] ( INRA Montpellier ), Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 ( UPEC UP12 ), Centre de Recherches en Oncologie biologique et Oncopharmacologie ( CRO2 ), Aix Marseille Université ( AMU ) - Hôpital de la Timone [CHU - APHM] ( TIMONE ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Centre de Recherche en Automatique de Nancy ( CRAN ), Université de Lorraine ( UL ) -Centre National de la Recherche Scientifique ( CNRS ), Centre Alexis Vautrin ( CAV ), Institut national du cancer [Boulogne] ( INCA ), Génétique du cancer et des maladies neuropsychiatriques ( GMFC ), Université de Rouen Normandie ( UNIROUEN ), Normandie Université ( NU ) -Normandie Université ( NU ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université de Versailles Saint-Quentin-en-Yvelines ( UVSQ ), Université de Versailles Saint-Quentin-en-Yvelines ( UVSQ ) -Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Ambroise Paré, Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Cochin [AP-HP]-Hôtel-Dieu-Unité de Recherche Clinique en Economie de la santé d'Ile de France (URC Eco), Médecine Personnalisée, Pharmacogénomique, Optimisation Thérapeutique ( MEPPOT - U1147 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), and Merlin, Jean-Louis

Subjects
Oncology, Colorectal cancer, Epidemiology, Molecular oncology, MESH: Antibodies, Monoclonal, 0302 clinical medicine, MESH : Fixatives, MESH: Fixatives, Neoplasm Metastasis, lcsh:Science, MESH: Tissue Embedding, 0303 health sciences, MESH: Genetic Testing, Antibodies, Monoclonal, 3. Good health, MESH: Reproducibility of Results, ErbB Receptors, [ SDV.BBM.GTP ] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], 030220 oncology & carcinogenesis, MESH : Neoplasm Metastasis, MESH : Proto-Oncogene Proteins, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Medicine, MESH : Colorectal Neoplasms, MESH : Sensitivity and Specificity, MESH: ras Proteins, medicine.medical_specialty, MESH: Receptor, Epidermal Growth Factor, Gastroenterology and Hepatology, Sensitivity and Specificity, Proto-Oncogene Proteins p21(ras), 03 medical and health sciences, Fixatives, MESH : Genetic Testing, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], External quality assessment, Gastrointestinal Tumors, Cancer Detection and Diagnosis, Humans, Genetic Testing, Genotyping, Biology, MESH: Humans, Tissue Embedding, MESH : Reproducibility of Results, MESH : Humans, lcsh:R, medicine.disease, MESH: Neoplasm Metastasis, MESH: Sensitivity and Specificity, MESH : Biopsy, ras Proteins, lcsh:Q, MESH : Sequence Analysis, DNA, MESH: Sequence Analysis, DNA, Biopsy, Cancer Treatment, lcsh:Medicine, Bioinformatics, medicine.disease_cause, MESH : Tissue Embedding, MESH: Biopsy, MESH : Receptor, Epidermal Growth Factor, Gastrointestinal Cancers, Sanger sequencing, Multidisciplinary, Drug development, MESH : Antibodies, Monoclonal, symbols, KRAS, France, Colorectal Neoplasms, Research Article, MESH: Cell Line, Tumor, Clinical Research Design, Rectal Cancer, symbols.namesake, Antibody Therapy, Diagnostic Medicine, Molecular genetics, Internal medicine, Cell Line, Tumor, Proto-Oncogene Proteins, medicine, MESH : France, 030304 developmental biology, Population Biology, MESH : Cell Line, Tumor, business.industry, Reproducibility of Results, Cancers and Neoplasms, Sequence Analysis, DNA, MESH: France, MESH: Proto-Oncogene Proteins, Gastric Cancer, MESH : ras Proteins, business, MESH: Colorectal Neoplasms
Abstract

International audience; PURPOSE: Rapid advances in the understanding of cancer biology have transformed drug development thus leading to the approval of targeted therapies and to the development of molecular tests to select patients that will respond to treatments. KRAS status has emerged as a negative predictor of clinical benefit from anti-EGFR antibodies in colorectal cancer, and anti-EGFR antibodies use was limited to KRAS wild type tumors. In order to ensure wide access to tumor molecular profiling, the French National Cancer Institute (INCa) has set up a national network of 28 regional molecular genetics centers. Concurrently, a nationwide external quality assessment for KRAS testing (MOKAECM) was granted to analyze reproducibility and costs. METHODS: 96 cell-line DNAs and 24 DNA samples from paraffin embedded tumor tissues were sent to 40 French laboratories. A total of 5448 KRAS results were collected and analyzed and a micro-costing study was performed on sites for 5 common methods by an independent team of health economists. RESULTS: This work provided a baseline picture of the accuracy and reliability of KRAS analysis in routine testing conditions at a nationwide level. Inter-laboratory Kappa values were >0.8 for KRAS results despite differences detection methods and the use of in-house technologies. Specificity was excellent with only one false positive in 1128 FFPE data, and sensitivity was higher for targeted techniques as compared to Sanger sequencing based methods that were dependent upon local expertise. Estimated reagent costs per patient ranged from €5.5 to €19.0. CONCLUSION: The INCa has set-up a network of public laboratories dedicated to molecular oncology tests. Our results showed almost perfect agreements in KRAS testing at a nationwide level despite different testing methods ensuring a cost-effective equal access to personalized colorectal cancer treatment.

Published
2013

20. Cross-Validation Study for Epidermal Growth Factor Receptor and KRAS Mutation Detection in 74 Blinded Non-small Cell Lung Carcinoma Samples: A Total of 5550 Exons Sequenced by 15 Molecular French Laboratories (Evaluation of the EGFR Mutation Status for the Administration of EGFR-TKIs in Non-Small Lung Carcinoma [ERMETIC] Project-Part 1)

Author

Véronique Barbu, Jean-Luc Prétet, Sylviane Olschwang, Nicolas Richard, Ivan Bièche, Patrick Saulnier, A. Degeorges, Gérard Zalcman, Stefan Michiels, Sarab Lizard, M. Mounawar, Michèle Beau-Faller, Christos Chouaid, Florence Coulet, Jean-Christophe Boyer, Florence de Fraipont, Marie-Pierre Buisine, Jacques Cadranel, Audrey Mauguen, Claire Danel, Elisabeth Brambilla, Martine Antoine, Estelle Rolland, Hélène Blons, Delphine Prunier-Mirebeau, Virginie Poulot, Pierre Hainaut, Laboratoire de Biochimie et de Biologie Moléculaire, CHU Strasbourg-Hôpital de Hautepierre [Strasbourg], Unité de pharmacologie, Institut Curie [Paris], Institut Gustave Roussy (IGR), Unit of Environment Cancer Epidemiology, IARC, CHU Tenon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), CHU Saint-Antoine [AP-HP], Laboratoire de Neurobiologie et Pharmacologie Cardiovasculaire [UNIV Strasbourg] (PMT EA 4438), Université de Strasbourg (UNISTRA), Carcinogénèse épithéliale : facteurs prédictifs et pronostiques - UFC (UR 3181) (CEF2P / CARCINO), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), Laboratoire de biologie cellulaire et moléculaire (CHRU Besançon), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Genetique Moleculaire des Cancers d'Origine Epitheliale, Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Bases moléculaires de la réponse aux xénobiotiques (U775 (IFR95)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Biochimie [CHRU Nîmes], Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Laboratoire de Biochimie et Biologie Moléculaire [CHRU Lille] (Pôle de Biologie Pathologie Génétique), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), INSERM U823, équipe 5 (cibles diagnostiques ou thérapeutiques et vectorisation de drogues dans le cancer du poumon), Institut d'oncologie/développement Albert Bonniot de Grenoble (INSERM U823), Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM)-Unité de Cancérologie Biologique et biothérapies, CHU Grenoble, Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER, Centre de Recherche en Cancérologie de Marseille (CRCM / U891 Inserm), Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Ingénierie de la vectorisation particulaire, Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Génétique [CHU Caen], Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), Service d'anatomo-pathologie [CHU HEGP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Département d'anatomie et cythologie pathologique, CHU Grenoble-Hôpital Michallon, Epidémiologie des maladies infectieuses et modélisation (ESIM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Pneumologie, Hôpital Côte de Nacre [CHU Caen], CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN), International Agency for Cancer Research (IACR), Service de biostatistique et d'épidémiologie (SBE), Direction de la recherche clinique [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Institut Curie, Carcinogénèse épithéliale : facteurs prédictifs et pronostiques - UFC (EA 3181) (CEF2P / CARCINO), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Centre Hospitalier Régional Universitaire [Besançon] (CHRU Besançon)-Université de Franche-Comté (UFC), Institut Curie-Institut National de la Santé et de la Recherche Médicale (INSERM), Biochimie et Physiologie Moléculaire des Plantes (BPMP), Université de Montpellier (UM)-Centre international d'études supérieures en sciences agronomiques (Montpellier SupAgro)-Institut national d’études supérieures agronomiques de Montpellier (Montpellier SupAgro)-Institut National de la Recherche Agronomique (INRA)-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche en Cancérologie de Marseille (CRCM), Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), CHU Saint-Antoine [APHP], INSTITUT CURIE, Carcinogénèse épithéliale : facteurs prédictifs et pronostiques - UFC (EA 3181) ( CEF2P / CARCINO ), Centre Hospitalier Régional Universitaire [Besançon] ( CHRU Besançon ) -Université Bourgogne Franche-Comté [COMUE] ( UBFC ) -Université de Franche-Comté ( UFC ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -INSTITUT CURIE, Bases moléculaires de la réponse aux xénobiotiques ( U775 (IFR95) ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Biochimie et Physiologie Moléculaire des Plantes ( BPMP ), Centre National de la Recherche Scientifique ( CNRS ) -Université de Montpellier ( UM ) -Centre international d'études supérieures en sciences agronomiques ( Montpellier SupAgro ) -Institut national d’études supérieures agronomiques de Montpellier ( Montpellier SupAgro ) -Institut national de la recherche agronomique [Montpellier] ( INRA Montpellier ), Institut d'oncologie/développement Albert Bonniot de Grenoble ( INSERM U823 ), Université Joseph Fourier - Grenoble 1 ( UJF ) -CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Joseph Fourier - Grenoble 1 ( UJF ) -CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Unité de Cancérologie Biologique et biothérapies, Centre de Recherche en Cancérologie de Marseille ( CRCM ), Aix Marseille Université ( AMU ) -Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Université d'Angers ( UA ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Service de génétique, CHU Caen-Hôpital Clémenceau, Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Européen Georges Pompidou [APHP] ( HEGP ), Epidémiologie des maladies infectieuses et modélisation ( ESIM ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Saint-Antoine [APHP], CHU Côte de Nacre, International Agency for Cancer Research ( IACR ), International Agency for Cancer Research, Service de biostatistique et d'épidémiologie ( SBE ), Institut Gustave Roussy ( IGR ) -Institut Gustave Roussy ( IGR ), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Aix Marseille Université (AMU), Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Centre Hospitalier Régional Universitaire [Besançon] (CHRU Besançon)-Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université de Franche-Comté (UFC), Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Université de Caen Normandie (UNICAEN), Normandie Université (NU), Service d'anatomie pathologique [CHU Tenon], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Tenon [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Laboratoire commun de biologie et génétique moléculaires [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), Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC)-Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Curie [Paris], Sorbonne Université-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université-Sorbonne Université, Centre Hospitalier Régional Universitaire [Besançon] (CHRU Besançon)-Université de Franche-Comté (UFC), Centre Hospitalier Régional Universitaire [Besançon] (CHRU Besançon), Institut National de la Santé et de la Recherche Médicale (INSERM)-EFS-CHU Grenoble-Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM)-EFS-CHU Grenoble-Université Joseph Fourier - Grenoble 1 (UJF)-Unité de Cancérologie Biologique et biothérapies, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université

Subjects
Male, Pathology, Lung Neoplasms, DNA Mutational Analysis, Cell, medicine.disease_cause, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, Exon, 0302 clinical medicine, Non-small cell lung cancer, Carcinoma, Non-Small-Cell Lung, Medicine, Single-Blind Method, Epidermal growth factor receptor, Aged, 80 and over, 0303 health sciences, Mutation, Paraffin Embedding, biology, Exons, Middle Aged, 3. Good health, ErbB Receptors, medicine.anatomical_structure, Oncology, 030220 oncology & carcinogenesis, Female, France, KRAS, Adult, Pulmonary and Respiratory Medicine, KRAS mutations, medicine.medical_specialty, Antineoplastic Agents, [SDV.CAN]Life Sciences [q-bio]/Cancer, Proto-Oncogene Proteins p21(ras), 03 medical and health sciences, Proto-Oncogene Proteins, Carcinoma, Humans, Protein Kinase Inhibitors, Aged, 030304 developmental biology, Lung, business.industry, Reproducibility of Results, Gold standard (test), medicine.disease, EGFR mutations, ras Proteins, Cancer research, biology.protein, Laboratories, business
Abstract

International audience; INTRODUCTION:: The Evaluation of the epidermal growth factor receptor (EGFR) Mutation status for the administration of EGFR-Tyrosine Kinase Inhibitors in non-small cell lung Carcinoma (NSCLC) (ERMETIC) project part 1 assessed the accuracy of EGFR and KRAS mutations detection in NSCLC among 15 French centers. METHODS:: The 15 ERMETIC centers selected 74 NSCLC surgical specimens from previously untreated patients. Paraffin and paired frozen DNA were sequenced for EGFR exons 18 to 21 and KRAS exon 2 by an external molecular laboratory, yielding a gold standard. The 74 blinded paraffin DNAs were redistributed to the 15 ERMETIC laboratories for sequencing of a total of 5550 exons. Results were compared with the gold standard and between centers by discordance rates and kappa statistics. RESULTS:: The gold standard included 39 mutated samples with 22 EGFR and 17 KRAS mutated samples. Kappa statistics showed that 10, 6, and 6 of the 15 ERMETIC centers had a moderate to good kappa score, when compared with external laboratory for EGFR exon 19, EGFR exon 21, and KRAS exon 2, respectively. Kappa statistics showed moderate score between centers which increased to good for EGFR exon 19 mutation when removing 16 poor-quality samples with high nonamplificable rates. CONCLUSIONS:: Paraffin-embedded specimens may represent a suitable source of DNA for sequencing analyses in ERMETIC centers. EGFR exon 19 deletions were most accurately detected by ERMETIC centers. Ease and accuracy of results, depended more on the quality of sample than on the difference in molecular sequencing procedures between centers, emphasize the need of preanalytical quality control programs.

Published
2011

21. MiniSOX9, a dominant-negative variant in colon cancer cells

Author

Francis Poulat, C. Rammah, J. Giraud, Rana Abdel-Samad, Corinne Quittau-Prévostel, C Bonnans, Philippe Blache, H. Zalzali, C. Naudin, Sébastien Dupasquier, S Lumbroso, Pierre Raynaud, C Pignodel, Philippe Fort, Brigitte Boizet-Bonhoure, K Mouzat, Institut de Génomique Fonctionnelle (IGF), Université de Montpellier (UM)-Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 2 - Sciences et Techniques (UM2)-Centre National de la Recherche Scientifique (CNRS), Institut de génétique humaine (IGH), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Biochimie [CHRU Nîmes], Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Centre de recherches de biochimie macromoléculaire (CRBM), and Université Montpellier 1 (UM1)-Université Montpellier 2 - Sciences et Techniques (UM2)-IFR122-Centre National de la Recherche Scientifique (CNRS)

Subjects
Cancer Research, medicine.medical_specialty, Cell signaling, Protein Kinase C-alpha, Colorectal cancer, Molecular Sequence Data, [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], Biology, Adenocarcinoma, medicine.disease_cause, [SDV.BID.SPT]Life Sciences [q-bio]/Biodiversity/Systematics, Phylogenetics and taxonomy, Malignant transformation, 03 medical and health sciences, Transactivation, Mice, 0302 clinical medicine, Internal medicine, Cell Line, Tumor, Genetics, medicine, Animals, Humans, Promoter Regions, Genetic, Molecular Biology, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, Genes, Dominant, 0303 health sciences, [SDV.GEN]Life Sciences [q-bio]/Genetics, Base Sequence, Wnt signaling pathway, Cancer, SOX9 Transcription Factor, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, medicine.disease, Introns, Mice, Mutant Strains, 3. Good health, Wnt Proteins, Alternative Splicing, Endocrinology, [SDV.BDD.EO]Life Sciences [q-bio]/Development Biology/Embryology and Organogenesis, 030220 oncology & carcinogenesis, Colonic Neoplasms, Mutation, Cancer research, Carcinogenesis
Abstract

Inherited and acquired changes in pre-mRNA processing have significant roles in human diseases, especially cancer. Characterization of aberrantly spliced mRNAs may thus contribute to understand malignant transformation. We recently reported an anti-oncogenic potential for the SOX9 transcription factor in the colon. For instance, the Sox9 gene knock out in the mouse intestine results in an excess of proliferation with appearance of hyperplasia. SOX9 is expressed in colon cancer cells but its endogenous activity is weak. We looked for SOX9 variants that may impair SOX9 activity in colon cancer cells and we discovered MiniSOX9, a truncated version of SOX9 devoid of transactivation domain as a result of retention of the second intron. A significant overexpression of MiniSOX9 mRNA in human tumor samples compared with their matched normal tissues was observed by real-time reverse transcriptase-PCR. Immunohistochemistry revealed that MiniSOX9 is expressed at high levels in human colon cancer samples whereas it is undetectable in the surrounding healthy tissues. Finally, we discovered that MiniSOX9 behaves as a SOX9 inhibitor, inhibits protein kinase Cα promoter activity and stimulates the canonical Wnt pathway. This potential oncogenic activity of the SOX9 locus gives new insights on its role in colon cancer.

Published
2011

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