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1. EGR2 mutations define a new clinically aggressive subgroup of chronic lymphocytic leukemia

Author: Young, E, Noerenberg, D, Mansouri, L, Ljungström, V, Frick, M, Sutton, L-A, Blakemore, SJ, Galan-Sousa, J, Plevova, K, Baliakas, P, Rossi, D, Clifford, R, Roos-Weil, D, Navrkalova, V, Dörken, B, Schmitt, CA, Smedby, KE, Juliusson, G, Giacopelli, B, Blachly, JS, Belessi, C, Panagiotidis, P, Chiorazzi, N, Davi, F, Langerak, AW, Oscier, D, Schuh, A, Gaidano, G, Ghia, P, Xu, W, Fan, L, Bernard, OA, Nguyen-Khac, F, Rassenti, L, Li, J, Kipps, TJ, Stamatopoulos, K, Pospisilova, S, Zenz, T, Oakes, CC, Strefford, JC, Rosenquist, R, and Damm, F
Subjects: Biomedical and Clinical Sciences, Cardiovascular Medicine and Haematology, Oncology and Carcinogenesis, Cancer, Hematology, Rare Diseases, Lymphoma, Clinical Research, Genetics, 4.1 Discovery and preclinical testing of markers and technologies, Detection, screening and diagnosis, Adult, Aged, Early Growth Response Protein 2, Female, Genes, p53, Humans, Leukemia, Lymphocytic, Chronic, B-Cell, Male, Middle Aged, Mutation, Proportional Hazards Models, Clinical Sciences, Immunology, Cardiovascular medicine and haematology, Clinical sciences, Oncology and carcinogenesis
Abstract: Recurrent mutations within EGR2 were recently reported in advanced-stage chronic lymphocytic leukemia (CLL) patients and associated with a worse outcome. To study their prognostic impact, 2403 CLL patients were examined for mutations in the EGR2 hotspot region including a screening (n=1283) and two validation cohorts (UK CLL4 trial patients, n=366; CLL Research Consortium (CRC) patients, n=490). Targeted deep-sequencing of 27 known/postulated CLL driver genes was also performed in 38 EGR2-mutated patients to assess concurrent mutations. EGR2 mutations were detected in 91/2403 (3.8%) investigated cases, and associated with younger age at diagnosis, advanced clinical stage, high CD38 expression and unmutated IGHV genes. EGR2-mutated patients frequently carried ATM lesions (42%), TP53 aberrations (18%) and NOTCH1/FBXW7 mutations (16%). EGR2 mutations independently predicted shorter time-to-first-treatment (TTFT) and overall survival (OS) in the screening cohort; they were confirmed associated with reduced TTFT and OS in the CRC cohort and independently predicted short OS from randomization in the UK CLL4 cohort. A particularly dismal outcome was observed among EGR2-mutated patients who also carried TP53 aberrations. In summary, EGR2 mutations were independently associated with an unfavorable prognosis, comparable to CLL patients carrying TP53 aberrations, suggesting that EGR2-mutated patients represent a new patient subgroup with very poor outcome.
Published: 2017

2. Reproducible diagnosis of chronic lymphocytic leukemia by flow cytometry:An European Research Initiative on CLL (ERIC) & European Society for Clinical Cell Analysis (ESCCA) Harmonisation project

Author: Rawstron, AC, Kreuzer, K-A, Soosapilla, A, Spacek, M, Stehlikova, O, Gambell, P, McIver-Brown, N, Villamor, N, Psarra, K, Arroz, M, Milani, R, de la Serna, J, Cedena, MT, Jaksic, O, Nomdedeu, J, Moreno, C, Rigolin, GM, Cuneo, A, Johansen, P, Johnsen, HE, Rosenquist, R, Niemann, CU, Kern, W, Westerman, D, Trneny, M, Mulligan, S, Doubek, M, Pospisilova, S, Hillmen, P, Oscier, D, Hallek, M, Ghia, P, Montserrat, E, Rawstron, Andy C., Kreuzer, Karl-Anton, Soosapilla, Asha, Spacek, Martin, Stehlikova, Olga, Gambell, Peter, McIver-Brown, Neil, Villamor, Neu, Psarra, Katherina, Arroz, Maria, Milani, Raffaella, de la Serna, Javier, Cedena, M. Teresa, Jaksic, Ozren, Nomdedeu, Josep, Moreno, Carol, Rigolin, Gian Matteo, Cuneo, Antonio, Johansen, Preben, Johnsen, Hans E., Rosenquist, Richard, Niemann, Carsten Utoft, Kern, Wolfgang, Westerman, David, Trneny, Marek, Mulligan, Stephen, Doubek, Michael, Pospisilova, Sarka, Hillmen, Peter, Oscier, David, Hallek, Michael, Ghia, Paolo, and Montserrat, Emili
Subjects: chronic lymphocytic leukemia, diagnosis, flow cytometry, 2734, Histology, Cell Biology, Clinical Laboratory Medicine, Reproducibility of Results, Pilot Projects, Original Articles, Leukemia, Lymphocytic, Chronic, B-Cell, NO, Immunophenotyping, diagnosi, Klinisk laboratoriemedicin, immune system diseases, hemic and lymphatic diseases, Biomarkers, Tumor, Humans, Original Article, Retrospective Studies
Abstract: The diagnostic criteria for CLL rely on morphology and immunophenotype. Current approaches have limitations affecting reproducibility and there is no consensus on the role of new markers. The aim of this project was to identify reproducible criteria and consensus on markers recommended for the diagnosis of CLL. ERIC/ESCCA members classified 14 of 35 potential markers as ârequiredâ or ârecommendedâ for CLL diagnosis, consensus being defined as >75% and >50% agreement, respectively. An approach to validate ârequiredâ markers using normal peripheral blood was developed. Responses were received from 150 participants with a diagnostic workload >20 CLL cases per week in 23/150 (15%), 5â20 in 82/150 (55%), and 97% concordance with current approaches. A pilot study to validate staining quality was completed in 11 centers. Markers considered as ârequiredâ for the diagnosis of CLL by the participants in this study (CD19, CD5, CD20, CD23, Kappa, and Lambda) are consistent with current diagnostic criteria and practice. Importantly, a reproducible approach to validate and apply these markers in individual laboratories has been identified. Finally, a consensus ârecommendedâ panel of markers to refine diagnosis in borderline cases (CD43, CD79b, CD81, CD200, CD10, and ROR1) has been defined and will be prospectively evaluated. Â© 2017 International Clinical Cytometry Society.
Published: 2018

3. Genomic disruption of the histone methyltransferase SETD2 in chronic lymphocytic leukaemia

Author: Parker, H, Rose Zerilli, M. J. J, Larrayoz, M, Clifford, R, Edelmann, J, Blakemore, S, Gibson, J, Wang, J, Ljungstr�m, V, Wojdacz, T. K, Chaplin, T, Roghanian, A, Davis, Z, Parker, A, Tausch, E, Ntoufa, S, Ramos, S, Robbe, P, Alsolami, R, Steele, A. J, Packham, G, Rodr�ez Vicente, A. E, Brown, L, Mcnicholl, F, Forconi, Francesco, Pettitt, A, Hillmen, P, Dyer, M, Cragg, M. S, Chelala, C, Oakes, C. C, Rosenquist, R, Stamatopoulos, K, Stilgenbauer, S, Knight, S, Schuh, A, Oscier, D. G, Strefford, J. C., Leukaemia & Lymphoma Research (UK), Royal Marsden NHS Foundation Trust, The Institute of Cancer Research (UK), Swedish Research Council, Swedish Cancer Society, Polysackaridforskning i Uppsala AB, German Research Foundation, Leukaemia Foundation, Wessex Medical Research, Kay Kendall Leukaemia Fund, and Cancer Research UK
Subjects: Male, Ataxia Telangiectasia Mutated Proteins, Disease-Free Survival, Humans, Genes, Tumor Suppressor, Hematologi, Chronic, Cancer och onkologi, Leukemia, B-Cell, Genomics, Histone-Lysine N-Methyltransferase, Hematology, Prognosis, Leukemia, Lymphocytic, Chronic, B-Cell, Lymphocytic, Survival Rate, Mutation, Tumor Suppressor Protein p53, Genes, Cancer and Oncology, Histone Methyltransferases, Female, Original Article, Tumor Suppressor
Abstract: Histone methyltransferases (HMTs) are important epigenetic regulators of gene transcription and are disrupted at the genomic level in a spectrum of human tumours including haematological malignancies. Using high-resolution single nucleotide polymorphism (SNP) arrays, we identified recurrent deletions of the SETD2 locus in 3% (8/261) of chronic lymphocytic leukaemia (CLL) patients. Further validation in two independent cohorts showed that SETD2 deletions were associated with loss of TP53, genomic complexity and chromothripsis. With next-generation sequencing we detected mutations of SETD2 in an additional 3.8% of patients (23/602). In most cases, SETD2 deletions or mutations were often observed as a clonal event and always as a mono-allelic lesion, leading to reduced mRNA expression in SETD2-disrupted cases. Patients with SETD2 abnormalities and wild-type TP53 and ATM from five clinical trials employing chemotherapy or chemo-immunotherapy had reduced progression-free and overall survival compared with cases wild type for all three genes. Consistent with its postulated role as a tumour suppressor, our data highlight SETD2 aberration as a recurrent, early loss-of-function event in CLL pathobiology linked to aggressive disease., This work was funded by Bloodwise (11052, 12036), the Kay Kendall Leukaemia Fund (873), Cancer Research UK (C34999/A18087, ECMC C24563/A15581), Wessex Medical Research and the Bournemouth Leukaemia Fund. SS is supported by the Else Kröner-FreseniusStiftung (2012_A146) and Deutsche Forschungsgemeinschaft (SFB 1074 projects B1, B2). The LRF CLL4 trial was funded by a core grant from Leukaemia and Lymphoma Research. DG and DC acknowledge the support by The Royal Marsden Hospital and The Institute of Cancer Research National Institute of Health Research Biomedical Research Center. RR is supported by the Swedish Cancer Society, the Swedish Research Council, Science for Life Laboratory, Uppsala University, Uppsala University Hospital, and the Lion’s Cancer Research Foundation, Uppsala.
Published: 2016

4. Common variation at 12q24.13 (OAS3) influences chronic lymphocytic leukemia risk

Author: Sava, G P, Speedy, H E, Di Bernardo, M C, Dyer, M J S, Holroyd, A, Sunter, N J, Marr, H, Mansouri, L, Deaglio, S, Karabon, L, Frydecka, I, Jamroziak, K, Woszczyk, D, Juliusson, G, Smedby, K E, Jayne, S, Majid, A, Wang, Y, Dearden, C, Hall, A G, Mainou-Fowler, T, Jackson, G H, Summerfield, G, Harris, R J, Pettitt, A R, Allsup, D J, Bailey, J R, Pratt, G, Pepper, C, Fegan, C, Rosenquist, R, Catovsky, D, Allan, J M, and Houlston, R S
Subjects: Risk, Chromosomes, Human, Pair 12, Chromosome Mapping, Leukemia, Lymphocytic, Chronic, B-Cell, Polymorphism, Single Nucleotide, R1, Introns, Gene Frequency, Genetic Loci, Case-Control Studies, 2',5'-Oligoadenylate Synthetase, Odds Ratio, Humans, Genetic Predisposition to Disease, Letter to the Editor, Alleles, Genome-Wide Association Study
Published: 2015

5. Genome-Wide Association Study in BRCA1 Mutation Carriers Identifies Novel Loci Associated with Breast and Ovarian Cancer Risk

Author: Couch, Fergus J., Xianshu, Wang, Lesley, Mcguffog, Andrew, Lee, Curtis, Olswold, Kuchenbaecker, Karoline B., Penny, Soucy, Zachary, Fredericksen, Daniel, Barrowdale, Joe, Dennis, Gaudet, Mia M., Dicks, Ed, Matthew, Kosel, Sue, Healey, Sinilnikova, Olga M., Adam, Lee, François, Bacot, Daniel, Vincent, Hogervorst, Frans B. L., Susan, Peock, Dominique Stoppa Lyonnet, Anna, Jakubowska, Paolo, Radice, Rita Katharina Schmutzler, Domchek, S. M., Piedmonte, M., Singer, C. F., Friedman, E., Thomassen, M., Hansen, T. V. O., Neuhausen, S. L., Szabo, C. I., Blanco, I., Greene, M. H., Karlan, B. Y., Garber, J., Phelan, C. M., Weitzel, J. N., Montagna, M., Olah, E., Andrulis, I. L., Godwin, A. K., Yannoukakos, D., Goldgar, D. E., Caldes, T., Nevanlinna, H., Osorio, A., Terry, M. B., Daly, M. B., Van Rensburg, E. J., Hamann, U., Ramus, S. J., Ewart Toland, A., Caligo, M. A., Olopade, O. I., Tung, N., Claes, K., Beattie, M. S., Southey, M. C., Imyanitov, E. N., Tischkowitz, M., Janavicius, R., John, E. M., Kwong, A., Diez, O., Balmana, J., Barkardottir, R. B., Arun, B. K., Rennert, G., Teo, S. H., Ganz, P. A., Campbell, I., Van Der Hout, A. H., Van Deurzen, C. H. M., Seynaeve, C., Gomez Garcia, E. B., Van Leeuwen, F. E., Meijers Heijboer, H. E. J., Gille, J. J. P., Ausems, M. G. E. M., Blok, M. J., Ligtenberg, M. J. L., Rookus, M. A., Devilee, P., Verhoef, S., Van Os, T. A. M., Wijnen, J. T., Frost, D., Ellis, S., Fineberg, E., Platte, R., Evans, D. G., Izatt, L., Eeles, R. A., Adlard, J., Eccles, D. M., Cook, J., Brewer, C., Douglas, F., Hodgson, S., Morrison, P. J., Side, L. E., Donaldson, A., Houghton, C., Rogers, M. T., Dorkins, H., Eason, J., Gregory, H., Mccann, E., Murray, A., Calender, A., Hardouin, A., Berthet, P., Delnatte, C., Nogues, C., Lasset, C., Houdayer, C., Leroux, D., Rouleau, E., Prieur, F., Damiola, F., Sobol, H., Coupier, I., Venat Bouvet, L., Castera, L., Gauthier Villars, M., Leone, M., Pujol, P., Mazoyer, S., Bignon, Y. J., Zlowocka Perlowska, E., Gronwald, J., Lubinski, J., Durda, K., Jaworska, K., Huzarski, T., Spurdle, A. B., Viel, A., Peissel, B., Bonanni, B., Melloni, G., Ottini, Laura, Papi, L., Varesco, L., Tibiletti, M. G., Peterlongo, P., Volorio, S., Manoukian, S., Pensotti, V., Arnold, N., Engel, C., Deissler, H., Gadzicki, D., Gehrig, A., Kast, K., Rhiem, K., Meindl, A., Niederacher, D., Ditsch, N., Plendl, H., Preisler Adams, S., Engert, S., Sutter, C., Varon Mateeva, R., Wappenschmidt, B., Weber, B. H. F., Arver, B., Stenmark Askmalm, M., Loman, N., Rosenquist, R., Einbeigi, Z., Nathanson, K. L., Rebbeck, T. R., Blank, S. V., Cohn, D. E., Rodriguez, G. C., Small, L., Friedlander, M., Bae Jump, V. L., Fink Retter, A., Rappaport, C., Gschwantler Kaulich, D., Pfeiler, G., Tea, M. K., Lindor, N. M., Kaufman, B., Shimon Paluch, S., Laitman, Y., Skytte, A. B., Gerdes, A. M., Pedersen, I. S., Moeller, S. T., Kruse, T. A., Jensen, U. B., Vijai, J., Sarrel, K., Robson, M., Kauff, N., Mulligan, A. M., Glendon, G., Ozcelik, H., Ejlertsen, B., Nielsen, F. C., Jonson, L., Andersen, M. K., Ding, Y. C., Steele, L., Foretova, L., Teule, A., Lazaro, C., Brunet, J., Pujana, M. A., Mai, P. L., Loud, J. T., Walsh, C., Lester, J., Orsulic, S., Narod, S. A., Herzog, J., Sand, S. R., Tognazzo, S., Agata, S., Vaszko, T., Weaver, J., Stavropoulou, A. V., Buys, S. S., Romero, A., De La Hoya, M., Aittomaki, K., Muranen, T. A., Duran, M., Chung, W. K., Lasa, A., Dorfling, C. M., Miron, A., Benitez, J., Senter, L., Huo, D., Chan, S. B., Sokolenko, A. P., Chiquette, J., Tihomirova, L., Friebel, T. M., Agnarsson, B. A., K. H., Lu, Lejbkowicz, F., James, P. A., Hall, P., Dunning, A. M., Tessier, D., Cunningham, J., Slager, S. L., Wang, C., Hart, S., Stevens, K., Simard, J., Pastinen, T., Pankratz, V. S., Offit, K., Easton, D. F., Chenevix Trench, G., Antoniou, A. C., Thorne, H., Niedermayr, E., Borg, A., Olsson, H., Jernstrom, H., Henriksson, K., Harbst, K., Soller, M., Kristoffersson, U., Ofverholm, A., Nordling, M., Karlsson, P., Von Wachenfeldt, A., Liljegren, A., Lindblom, A., Bustinza, G. B., Rantala, J., Melin, B., Ardnor, C. E., Emanuelsson, M., Ehrencrona, H., Pigg, M. H., Liedgren, S., Hogervorst, F. B. L., Schmidt, M. K., De Lange, J., Collee, J. M., Van Den Ouweland, A. M. W., Hooning, M. J., Van Asperen, C. J., Tollenaar, R. A., Van Cronenburg, T. C. T. E. F., Kets, C. M., Mensenkamp, A. R., Van Der Luijt, R. B., Aalfs, C. M., Waisfisz, Q., Oosterwijk, J. C., Van Der Hout, H., Mourits, M. J., De Bock, G. H., Peock, S., Miedzybrodzka, Z., Morrison, P., Jeffers, L., Cole, T., Ong, K. R., Hoffman, J., James, M., Paterson, J., Taylor, A., Kennedy, M. J., Barton, D., Porteous, M., Drummond, S., Kivuva, E., Searle, A., Goodman, S., Hill, K., Davidson, R., Murday, V., Bradshaw, N., Snadden, L., Longmuir, M., Watt, C., Gibson, S., Haque, E., Tobias, E., Duncan, A., Jacobs, C., Langman, C., Brady, A., Melville, A., Randhawa, K., Barwell, J., Serra Feliu, G., Ellis, I., Lalloo, F., Taylor, J., Side, L., Male, A., Berlin, C., Collier, R., Claber, O., Jobson, I., Walker, L., Mcleod, D., Halliday, D., Durell, S., Stayner, B., Shanley, S., Rahman, N., Houlston, R., Stormorken, A., Bancroft, E., Page, E., Ardern Jones, A., Kohut, K., Wiggins, J., Castro, E., Killick, E., Martin, S., Rea, G., Kulkarni, A., Quarrell, O., Bardsley, C., Goff, S., Brice, G., Winchester, L., Eddy, C., Tripathi, V., Attard, V., Lehmann, A., Eccles, D., Lucassen, A., Crawford, G., Mcbride, D., Smalley, S., Sinilnikova, O., Barjhoux, L., Verny Pierre, C., Giraud, S., Stoppa Lyonnet, D., Buecher, B., Moncoutier, V., Belotti, M., Tirapo, C., De Pauw, A., Bressac De Paillerets, B., Caron, O., Uhrhammer, N., Bonadona, V., Handallou, S., Bourdon, V., Noguchi, T., Remenieras, A., Eisinger, F., Peyrat, J. P., Fournier, J., Revillion, F., Vennin, P., Adenis, C., Lidereau, R., Demange, L., Muller, D., Fricker, J. P., Barouk Simonet, E., Bonnet, F., Bubien, V., Sevenet, N., Longy, M., Toulas, C., Guimbaud, R., Gladieff, L., Feillel, V., Dreyfus, H., Rebischung, C., Peysselon, M., Coron, F., Faivre, L., Lebrun, M., Kientz, C., Ferrer, S. F., Frenay, M., Mortemousque, I., Coulet, F., Colas, C., Soubrier, F., Sokolowska, J., Bronner, M., Lynch, H. T., Snyder, C. L., Angelakos, M., Maskiell, J., Dite, G., MUMC+: DA KG Lab Centraal Lab (9), RS: GROW - School for Oncology and Reproduction, Biostatistiques santé, 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), Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire Kastler Brossel (LKB (Jussieu)), Fédération de recherche du Département de physique de l'Ecole Normale Supérieure - ENS Paris (FRDPENS), École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS), Institut de biologie et chimie des protéines [Lyon] (IBCP), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Generalitat de Catalunya, Asociación Española Contra el Cáncer, Fundación Ramón Areces, Instituto de Salud Carlos III, Clinical Genetics, Pathology, Medical Oncology, Pediatric Surgery, Department of Obstetrics and Gynecology, Clinicum, Department of Medical and Clinical Genetics, HUS Gynecology and Obstetrics, Epidemiology and Data Science, Human genetics, CCA - Oncogenesis, Universitat de Barcelona, Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Fédération de recherche du Département de physique de l'Ecole Normale Supérieure - ENS Paris (FRDPENS), École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), CCA -Cancer Center Amsterdam, ARD - Amsterdam Reproduction and Development, and Human Genetics
Subjects: SELECTION, Oncology, Cancer Research, Medicin och hälsovetenskap, endocrine system diseases, [SDV]Life Sciences [q-bio], 610 Medizin, Càncer d'ovari, SUSCEPTIBILITY ALLELES, MODIFIERS, ComputingMilieux_LEGALASPECTSOFCOMPUTING, Genome-wide association study, QH426-470, Medical and Health Sciences, SUBTYPES, Breast cancer, 0302 clinical medicine, Human genetics, 3123 Gynaecology and paediatrics, Risk Factors, GENETIC-VARIANTS, Genotype, Naturvetenskap, Malalties hereditàries, INVESTIGATORS, skin and connective tissue diseases, ComputingMilieux_MISCELLANEOUS, Genetics (clinical), POPULATION, Ovarian Neoplasms, Genetics, Subtypes, ddc:610, 0303 health sciences, education.field_of_study, Genètica humana, Susceptibility alleles, BRCA1 Protein, COMMON VARIANTS, Breast Cancer Epidemiology, Middle Aged, Prognosis, BRCA2 Protein, 3. Good health, 030220 oncology & carcinogenesis, Female, Natural Sciences, Genetic diseases, Heterozygote, medicine.medical_specialty, Znf365, education, 3122 Cancers, Population, Breast Neoplasms, Single-nucleotide polymorphism, Biology, Polymorphism, Single Nucleotide, Càncer de mama, 03 medical and health sciences, SDG 3 - Good Health and Well-being, Ovarian cancer, Translational research [ONCOL 3], Internal medicine, medicine, Humans, Genetic Predisposition to Disease, Genetics and epigenetic pathways of disease Translational research [NCMLS 6], Molecular Biology, Selection, ddc:614, Ecology, Evolution, Behavior and Systematics, 030304 developmental biology, Hereditary cancer and cancer-related syndromes [ONCOL 1], Common variants, CONSORTIUM, Modifiers, Biology and Life Sciences, BRCA1, medicine.disease, R1, Genetic-variants, Cancer and Oncology, Mutation, Investigators, 3111 Biomedicine, ZNF365, Consortium, Genome-Wide Association Study
Abstract: This is an open-access article distributed under the terms of the Creative Commons Attribution License.-- CIMBA et al., BRCA1-associated breast and ovarian cancer risks can be modified by common genetic variants. To identify further cancer risk-modifying loci, we performed a multi-stage GWAS of 11,705 BRCA1 carriers (of whom 5,920 were diagnosed with breast and 1,839 were diagnosed with ovarian cancer), with a further replication in an additional sample of 2,646 BRCA1 carriers. We identified a novel breast cancer risk modifier locus at 1q32 for BRCA1 carriers (rs2290854, P = 2.7 × 10(-8), HR = 1.14, 95% CI: 1.09-1.20). In addition, we identified two novel ovarian cancer risk modifier loci: 17q21.31 (rs17631303, P = 1.4 × 10(-8), HR = 1.27, 95% CI: 1.17-1.38) and 4q32.3 (rs4691139, P = 3.4 × 10(-8), HR = 1.20, 95% CI: 1.17-1.38). The 4q32.3 locus was not associated with ovarian cancer risk in the general population or BRCA2 carriers, suggesting a BRCA1-specific association. The 17q21.31 locus was also associated with ovarian cancer risk in 8,211 BRCA2 carriers (P = 2×10(-4)). These loci may lead to an improved understanding of the etiology of breast and ovarian tumors in BRCA1 carriers. Based on the joint distribution of the known BRCA1 breast cancer risk-modifying loci, we estimated that the breast cancer lifetime risks for the 5% of BRCA1 carriers at lowest risk are 28%-50% compared to 81%-100% for the 5% at highest risk. Similarly, based on the known ovarian cancer risk-modifying loci, the 5% of BRCA1 carriers at lowest risk have an estimated lifetime risk of developing ovarian cancer of 28% or lower, whereas the 5% at highest risk will have a risk of 63% or higher. Such differences in risk may have important implications for risk prediction and clinical management for BRCA1 carriers., The study was supported by NIH grant CA128978, an NCI Specialized Program of Research Excellence (SPORE) in Breast Cancer (CA116201), a U.S. Department of Defense Ovarian Cancer Idea award (W81XWH-10-1-0341), grants from the Breast Cancer Research Foundation and the Komen Foundation for the Cure; Cancer Research UK grants C12292/A11174 and C1287/A10118; the European Commission's Seventh Framework Programme grant agreement 223175 (HEALTH-F2-2009-223175). Breast Cancer Family Registry Studies (BCFR): supported by the National Cancer Institute, National Institutes of Health under RFA # CA-06-503 and through cooperative agreements with members of the Breast Cancer Family Registry (BCFR) and Principal Investigators, including Cancer Care Ontario (U01 CA69467), Cancer Prevention Institute of California (U01 CA69417), Columbia University (U01 CA69398), Fox Chase Cancer Center (U01 CA69631), Huntsman Cancer Institute (U01 CA69446), and University of Melbourne (U01 CA69638). The Australian BCFR was also supported by the National Health and Medical Research Council of Australia, the New South Wales Cancer Council, the Victorian Health Promotion Foundation (Australia), and the Victorian Breast Cancer Research Consortium. Melissa C. Southey is a NHMRC Senior Research Fellow and a Victorian Breast Cancer Research Consortium Group Leader. Carriers at FCCC were also identified with support from National Institutes of Health grants P01 CA16094 and R01 CA22435. The New York BCFR was also supported by National Institutes of Health grants P30 CA13696 and P30 ES009089. The Utah BCFR was also supported by the National Center for Research Resources and the National Center for Advancing Translational Sciences, NIH grant UL1 RR025764, and by Award Number P30 CA042014 from the National Cancer Institute. Baltic Familial Breast Ovarian Cancer Consortium (BFBOCC): BFBOCC is partly supported by Lithuania (BFBOCC-LT), Research Council of Lithuania grant LIG-19/2010, and Hereditary Cancer Association (Paveldimo vėžio asociacija)., Latvia (BFBOCC-LV) is partly supported by LSC grant 10.0010.08 and in part by a grant from the ESF Nr.2009/0220/1DP/1.1.1.2.0/09/APIA/VIAA/016.BRCA-gene mutations and breast cancer in South African women (BMBSA): BMBSA was supported by grants from the Cancer Association of South Africa (CANSA) to Elizabeth J. van Rensburg. Beckman Research Institute of the City of Hope (BRICOH): Susan L. Neuhausen was partially supported by the Morris and Horowitz Families Endowed Professorship. BRICOH was supported by NIH R01CA74415 and NIH P30 CA033752. Copenhagen Breast Cancer Study (CBCS): The CBCS study was supported by the NEYE Foundation. Spanish National Cancer Centre (CNIO): This work was partially supported by Spanish Association against Cancer (AECC08), RTICC 06/0020/1060, FISPI08/1120, Mutua Madrileña Foundation (FMMA) and SAF2010-20493. City of Hope Cancer Center (COH): The City of Hope Clinical Cancer Genetics Community Research Network is supported by Award Number RC4A153828 (PI: Jeffrey N. Weitzel) from the National Cancer Institute and the Office of the Director, National Institutes of Health. CONsorzio Studi ITaliani sui Tumori Ereditari Alla Mammella (CONSIT TEAM): CONSIT TEAM was funded by grants from Fondazione Italiana per la Ricerca sul Cancro (Special Project “Hereditary tumors”), Italian Association for Cancer Research (AIRC, IG 8713), Italian Minitry of Health (Extraordinary National Cancer Program 2006, “Alleanza contro il Cancro” and “Progetto Tumori Femminili), Italian Ministry of Education, University and Research (Prin 2008) Centro di Ascolto Donne Operate al Seno (CAOS) association and by funds from Italian citizens who allocated the 5×1000 share of their tax payment in support of the Fondazione IRCCS Istituto Nazionale Tumori, according to Italian laws (INT-Institutional strategic projects ‘5×1000’). German Cancer Research Center (DKFZ): The DKFZ study was supported by the DKFZ. The Hereditary Breast and Ovarian Cancer Research Group Netherlands (HEBON): HEBON is supported by the Dutch Cancer Society grants NKI1998-1854, NKI2004-3088, NKI2007-3756, the NWO grant 91109024, the Pink Ribbon grant 110005, and the BBMRI grant CP46/NWO., Epidemiological study of BRCA1 & BRCA2 mutation carriers (EMBRACE): EMBRACE is supported by Cancer Research UK Grants C1287/A10118 and C1287/A11990. D. Gareth Evans and Fiona Lalloo are supported by an NIHR grant to the Biomedical Research Centre, Manchester. The Investigators at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust are supported by an NIHR grant to the Biomedical Research Centre at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust. Rosalind A. Eeles and Elizabeth Bancroft are supported by Cancer Research UK Grant C5047/A8385. Fox Chase Cancer Canter (FCCC): The authors acknowledge support from The University of Kansas Cancer Center and the Kansas Bioscience Authority Eminent Scholar Program. Andrew K. Godwin was funded by 5U01CA113916, R01CA140323, and by the Chancellors Distinguished Chair in Biomedical Sciences Professorship. German Consortium of Hereditary Breast and Ovarian Cancer (GC-HBOC): The German Consortium of Hereditary Breast and Ovarian Cancer (GC-HBOC) is supported by the German Cancer Aid (grant no 109076, Rita K. Schmutzler) and by the Center for Molecular Medicine Cologne (CMMC). Genetic Modifiers of cancer risk in BRCA1/2 mutation carriers (GEMO): The GEMO study was supported by the Ligue National Contre le Cancer; the Association “Le cancer du sein, parlons-en!” Award and the Canadian Institutes of Health Research for the “CIHR Team in Familial Risks of Breast Cancer” program. Gynecologic Oncology Group (GOG): This study was supported by National Cancer Institute grants to the Gynecologic Oncology Group (GOG) Administrative Office and Tissue Bank (CA 27469), Statistical and Data Center (CA 37517), and GOG's Cancer Prevention and Control Committtee (CA 101165). Drs. Mark H. Greene and Phuong L. Mai were supported by funding from the Intramural Research Program, NCI, NIH. Hospital Clinico San Carlos (HCSC): HCSC was supported by RETICC 06/0020/0021, FIS research grant 09/00859, Instituto de Salud Carlos III, Spanish Ministry of Economy and Competitivity, and the European Regional Development Fund (ERDF)., Helsinki Breast Cancer Study (HEBCS): The HEBCS was financially supported by the Helsinki University Central Hospital Research Fund, Academy of Finland (132473), the Finnish Cancer Society, the Nordic Cancer Union, and the Sigrid Juselius Foundation. Study of Genetic Mutations in Breast and Ovarian Cancer patients in Hong Kong and Asia (HRBCP): HRBCP is supported by The Hong Kong Hereditary Breast Cancer Family Registry and the Dr. Ellen Li Charitable Foundation, Hong Kong. Molecular Genetic Studies of Breast and Ovarian Cancer in Hungary (HUNBOCS): HUNBOCS was supported by Hungarian Research Grant KTIA-OTKA CK-80745 and the Norwegian EEA Financial Mechanism HU0115/NA/2008-3/ÖP-9. Institut Català d'Oncologia (ICO): The ICO study was supported by the Asociación Española Contra el Cáncer, Spanish Health Research Foundation, Ramón Areces Foundation, Carlos III Health Institute, Catalan Health Institute, and Autonomous Government of Catalonia and contract grant numbers: ISCIIIRETIC RD06/0020/1051, PI09/02483, PI10/01422, PI10/00748, 2009SGR290, and 2009SGR283. International Hereditary Cancer Centre (IHCC): Supported by the Polish Foundation of Science. Katarzyna Jaworska is a fellow of International PhD program, Postgraduate School of Molecular Medicine, Warsaw Medical University. Iceland Landspitali–University Hospital (ILUH): The ILUH group was supported by the Icelandic Association “Walking for Breast Cancer Research” and by the Landspitali University Hospital Research Fund. INterdisciplinary HEalth Research Internal Team BReast CAncer susceptibility (INHERIT): INHERIT work was supported by the Canadian Institutes of Health Research for the “CIHR Team in Familial Risks of Breast Cancer” program, the Canadian Breast Cancer Research Alliance grant 019511 and the Ministry of Economic Development, Innovation and Export Trade grant PSR-SIIRI-701. Jacques Simard is Chairholder of the Canada Research Chair in Oncogenetics., Istituto Oncologico Veneto (IOVHBOCS): The IOVHBOCS study was supported by Ministero dell'Istruzione, dell'Università e della Ricerca and Ministero della Salute (“Progetto Tumori Femminili” and RFPS 2006-5-341353,ACC2/R6.9”). Kathleen Cuningham Consortium for Research into Familial Breast Cancer (kConFab): kConFab is supported by grants from the National Breast Cancer Foundation and the National Health and Medical Research Council (NHMRC) and by the Queensland Cancer Fund; the Cancer Councils of New South Wales, Victoria, Tasmania, and South Australia; and the Cancer Foundation of Western Australia. Amanda B. Spurdle is an NHMRC Senior Research Fellow. The Clinical Follow Up Study was funded from 2001–2009 by NHMRC and currently by the National Breast Cancer Foundation and Cancer Australia #628333. Mayo Clinic (MAYO): MAYO is supported by NIH grant CA128978, an NCI Specialized Program of Research Excellence (SPORE) in Breast Cancer (CA116201), a U.S. Department of Defence Ovarian Cancer Idea award (W81XWH-10-1-0341) and grants from the Breast Cancer Research Foundation and the Komen Foundation for the Cure. McGill University (MCGILL): The McGill Study was supported by Jewish General Hospital Weekend to End Breast Cancer, Quebec Ministry of Economic Development, Innovation, and Export Trade. Memorial Sloan-Kettering Cancer Center (MSKCC): The MSKCC study was supported by Breast Cancer Research Foundation, Niehaus Clinical Cancer Genetics Initiative, Andrew Sabin Family Foundation, and Lymphoma Foundation. Modifier Study of Quantitative Effects on Disease (MODSQUAD): MODSQUAD was supported by the European Regional Development Fund and the State Budget of the Czech Republic (RECAMO, CZ.1.05/2.1.00/03.0101). Women's College Research Institute, Toronto (NAROD): NAROD was supported by NIH grant: 1R01 CA149429-01. National Cancer Institute (NCI): Drs. Mark H. Greene and Phuong L. Mai were supported by the Intramural Research Program of the US National Cancer Institute, NIH, and by support services contracts NO2-CP-11019-50 and N02-CP-65504 with Westat, Rockville, MD. National Israeli Cancer Control Center (NICCC): NICCC is supported by Clalit Health Services in Israel. Some of its activities are supported by the Israel Cancer Association and the Breast Cancer Research Foundation (BCRF), NY. N. N. Petrov Institute of Oncology (NNPIO): The NNPIO study has been supported by the Russian Foundation for Basic Research (grants 11-04-00227, 12-04-00928, and 12-04-01490), the Federal Agency for Science and Innovations, Russia (contract 02.740.11.0780), and through a Royal Society International Joint grant (JP090615). The Ohio State University Comprehensive Cancer Center (OSU-CCG): OSUCCG is supported by the Ohio State University Comprehensive Cancer Center., South East Asian Breast Cancer Association Study (SEABASS): SEABASS is supported by the Ministry of Science, Technology and Innovation, Ministry of Higher Education (UM.C/HlR/MOHE/06) and Cancer Research Initiatives Foundation. Sheba Medical Centre (SMC): The SMC study was partially funded through a grant by the Israel Cancer Association and the funding for the Israeli Inherited Breast Cancer Consortium. Swedish Breast Cancer Study (SWE-BRCA): SWE-BRCA collaborators are supported by the Swedish Cancer Society. The University of Chicago Center for Clinical Cancer Genetics and Global Health (UCHICAGO): UCHICAGO is supported by grants from the US National Cancer Institute (NIH/NCI) and by the Ralph and Marion Falk Medical Research Trust, the Entertainment Industry Fund National Women's Cancer Research Alliance, and the Breast Cancer Research Foundation. University of California Los Angeles (UCLA): The UCLA study was supported by the Jonsson Comprehensive Cancer Center Foundation and the Breast Cancer Research Foundation. University of California San Francisco (UCSF): The UCSF study was supported by the UCSF Cancer Risk Program and the Helen Diller Family Comprehensive Cancer Center. United Kingdom Familial Ovarian Cancer Registries (UKFOCR): UKFOCR was supported by a project grant from CRUK to Paul Pharoah. University of Pennsylvania (UPENN): The UPENN study was supported by the National Institutes of Health (NIH) (R01-CA102776 and R01-CA083855), Breast Cancer Research Foundation, Rooney Family Foundation, Susan G. Komen Foundation for the Cure, and the Macdonald Family Foundation. Victorian Familial Cancer Trials Group (VFCTG): The VFCTG study was supported by the Victorian Cancer Agency, Cancer Australia, and National Breast Cancer Foundation. Women's Cancer Research Initiative (WCRI): The WCRI at the Samuel Oschin Comprehensive Cancer Institute, Cedars Sinai Medical Center, Los Angeles, is funded by the American Cancer Society Early Detection Professorship (SIOP-06-258-01-COUN).
Published: 2013

6. Association of PHB 1630 C > T and MTHFR 677 C > T polymorphisms with breast and ovarian cancer risk in BRCA1/2 mutation carriers: results from a multicenter study

Author: Jakubowska, A., Rozkrut, D., Antoniou, A., Hamann, U., Scott, R.J., McGuffog, L., Healy, S., Sinilnikova, O.M., Rennert, G., Lejbkowicz, F., Flugelman, A., Andrulis, I.L., Glendon, G., Ozcelik, H., Thomassen, M., Paligo, M., Aretini, P., Kantala, J., Aroer, B., Wachenfeldt, A. von, Liljegren, A., Loman, N., Herbst, K., Kristoffersson, U., Rosenquist, R., Karlsson, P., Stenmark-Askmalm, M., Melin, B., Nathanson, K.L., Domchek, S.M., Byrski, T., Huzarski, T., Gronwald, J., Menkiszak, J., Cybulski, C., Serrano, P., Osorio, A., Cajal, T.R., Tsitlaidou, M., Benitez, J., Gilbert, M., Rookus, M., Aalfs, C.M., Kluijt, I., Boessenkool-Pape, J.L., Meijers-Heijboer, H.E.J., Oosterwijk, J.C., Asperen, C.J. van, Blok, M.J., Nelen, M.R., Ouweland, A.M.W. van den, Seynaeve, C., Luijt, R.B. van der, Devilee, P., Easton, D.F., Peock, S., Frost, D., Platte, R., Ellis, S.D., Fineberg, E., Evans, D.G., Lalloo, F., Eeles, R., Jacobs, C., Adlard, J., Davidson, R., Eccles, D., Cole, T., Cook, J., Godwin, A., Bove, B., Stoppa-Lyonnet, D., Caux-Moncoutier, V., Belotti, M., Tirapo, C., Mazoyer, S., Barjhoux, L., Boutry-Kryza, N., Pujol, P., Coupier, I., Peyrat, J.P., Vennin, P., Muller, D., Fricker, J.P., Venat-Bouvet, L., Johannsson, O., Isaacs, C., Schmutzler, R., Wappenschmidt, B., Meindl, A., Arnold, N., Varon-Mateeva, R., Niederacher, D., Sutter, C., Deissler, H., Preisler-Adams, S., Simard, J., Soucy, P., Durocher, F., Chenevix-Trench, G., Beesley, J., Chen, X., Rebbeck, T., Couch, F., Wang, X., Lindor, N., Fredericksen, Z., Pankratz, V.S., Peterlongo, P., Bonanni, B., Fortuzzi, S., Peissel, B., Szabo, C., Mai, P.L., Loud, J.T., Lubinski, J., OCGN, SWE BRCA, HEBON, EMBRACE, GEMO Study Collaborators, KConFab, CIMBA, Damage and Repair in Cancer Development and Cancer Treatment (DARE), Targeted Gynaecologic Oncology (TARGON), Human Genetics, CCA -Cancer Center Amsterdam, ARD - Amsterdam Reproduction and Development, Genetica & Celbiologie, Klinische Genetica, RS: GROW - School for Oncology and Reproduction, Clinical Genetics, Medical Oncology, IHS, Human genetics, and CCA - Oncogenesis
Subjects: Oncology, Cancer Research, endocrine system diseases, BRCA1/2 mutation carriers, METHYLENETETRAHYDROFOLATE REDUCTASE MTHFR, Genes, BRCA2, Genes, BRCA1, DCN PAC - Perception action and control, SUSCEPTIBILITY, medicine.disease_cause, Bioinformatics, T+polymorphism%22">PHB 1630 C>T polymorphism, 0302 clinical medicine, PROHIBITIN 3'-UNTRANSLATED REGION, Genotype, Prohibitin, skin and connective tissue diseases, breast/ovarian cancer risk, Ovarian Neoplasms, 0303 health sciences, FOLATE STATUS, CARCINOGENESIS, Penetrance, 3. Good health, 030220 oncology & carcinogenesis, Female, +T+polymorphism%22">PHB 1630 C > T polymorphism, CHROMOSOME-17, Risk, EXPRESSION, medicine.medical_specialty, Heterozygote, Hereditary cancer and cancer-related syndromes Genetics and epigenetic pathways of disease [ONCOL 1], Breast Neoplasms, +T+polymorphism%22">MTHFR 677 C > T polymorphism, Biology, Genomic disorders and inherited multi-system disorders [IGMD 3], 03 medical and health sciences, Breast cancer, SDG 3 - Good Health and Well-being, Translational research [ONCOL 3], Internal medicine, Prohibitins, medicine, Humans, Genetic Predisposition to Disease, Genetics and epigenetic pathways of disease Translational research [NCMLS 6], Methylenetetrahydrofolate Reductase (NADPH2), 030304 developmental biology, Polymorphism, Genetic, Hereditary cancer and cancer-related syndromes [ONCOL 1], Biology and Life Sciences, Genetics and Genomics, medicine.disease, GENE, Minor allele frequency, Repressor Proteins, COMMON MUTATION, T+polymorphism%22">MTHFR 677 C>T polymorphism, Methylenetetrahydrofolate reductase, Mutation, biology.protein, RNA, Carcinogenesis, Ovarian cancer
Abstract: BACKGROUND: The variable penetrance of breast cancer in BRCA1/2 mutation carriers suggests that other genetic or environmental factors modify breast cancer risk. Two genes of special interest are prohibitin (PHB) and methylene-tetrahydrofolate reductase (MTHFR), both of which are important either directly or indirectly in maintaining genomic integrity.METHODS: To evaluate the potential role of genetic variants within PHB and MTHFR in breast and ovarian cancer risk, 4102 BRCA1 and 2093 BRCA2 mutation carriers, and 6211 BRCA1 and 2902 BRCA2 carriers from the Consortium of Investigators of Modifiers of BRCA1 and BRCA2 (CIMBA) were genotyped for the PHB 1630 C>T (rs6917) polymorphism and the MTHFR 677 C>T (rs1801133) polymorphism, respectively.RESULTS: There was no evidence of association between the PHB 1630 C>T and MTHFR 677 C>T polymorphisms with either disease for BRCA1 or BRCA2 mutation carriers when breast and ovarian cancer associations were evaluated separately. Analysis that evaluated associations for breast and ovarian cancer simultaneously showed some evidence that BRCA1 mutation carriers who had the rare homozygote genotype (TT) of the PHB 1630 C>T polymorphism were at increased risk of both breast and ovarian cancer (HR 1.50, 95% CI 1.10-2.04 and HR 2.16, 95% CI 1.24-3.76, respectively). However, there was no evidence of association under a multiplicative model for the effect of each minor allele.CONCLUSION: The PHB 1630TT genotype may modify breast and ovarian cancer risks in BRCA1 mutation carriers. This association need to be evaluated in larger series of BRCA1 mutation carriers. British Journal of Cancer (2012) 106, 2016-2024. doi:10.1038/bjc.2012.160 www.bjcancer.com Published online 15 May 2012 (C) 2012 Cancer Research UK
Published: 2012

7. MyPal ADULT study protocol: a randomised clinical trial of the MyPal ePRO-based early palliative care system in adult patients with haematological malignancies

Author: Helen Α Papadaki, Christos Maramis, Niki Stavroyianni, Charalampos Pontikoglou, Kostas Stamatopoulos, Tina Garani-Papadatos, Richard Rosenquist, Pantelis Natsiavas, Cathy Payne, Michael Doubek, Lydia Scarfò, Sheila Payne, Paolo Ghia, Jana Didi, Julie Ling, Christina Karamanidou, Scarfo, L., Karamanidou, C., Doubek, M., Garani-Papadatos, T., Didi, J., Pontikoglou, C., Ling, J., Payne, C., Papadaki, H. A., Rosenquist, R., Stavroyianni, N., Payne, S., Ghia, P., Natsiavas, P., Maramis, C., and Stamatopoulos, K.
Subjects: Adult, Palliative care, Health informatics, adult palliative care, Participatory design, Humans, Medicine, media_common.cataloged_instance, European union, health informatics, Randomized Controlled Trials as Topic, media_common, Protocol (science), business.industry, Palliative Care, General Medicine, Focus Groups, medicine.disease, Focus group, Digital health, Clinical trial, Sleep Quality, Hematologic Neoplasms, leukaemia, Medical emergency, business, Software
Abstract: IntroductionThe systematic collection of electronic patient-reported outcome (ePRO) in the routine care of patients with chronic haematological malignancies such as chronic lymphocytic leukaemia (CLL) and myelodysplasia syndromes (MDS) can constitute a very ambitious but worthwhile challenge. MyPal is a Horizon 2020 Research & Innovation Action aiming to meet this challenge and foster palliative care for patients with CLL or MDS by leveraging ePRO systems to adapt to the personal needs of patients and caregiver(s).Methods and analysisIn this interventional randomised trial, 300 patients with CLL or MDS will be recruited across Europe. Patients will be randomly allocated to early palliative care using the MyPal system (n=150) versus standard care including general palliative care if needed (n=150). Patients in the experimental arm will be given access to the MyPal digital health platform which consists of purposely designed software available on smartphones and/or tablets. The platform entails different functionalities including physical and psychoemotional symptom reporting via regular questionnaire completion, spontaneous self-reporting, motivational messages, medication management and a personalised search engine for health information. Data on patients’ activity (daily steps and sleep quality) will be automatically collected via wearable devices.Ethics and disseminationThe integration of ePROs via mobile applications has raised ethical concerns regarding inclusion criteria, information provided to participants, free and voluntary consent, and respect for their autonomy. These have been carefully addressed by a multidisciplinary team. Data processing, dissemination and exploitation of the study findings will take place in full compliance with European Union data protection law. A participatory design was adopted in the development of the digital platform involving focus groups and discussions with patients to identify needs and preferences. The protocol was approved by the ethics committees of San Raffaele (8/2020), Thessaloniki ‘George Papanikolaou’ Hospital (849), Karolinska Institutet (20.10.2020), University General Hospital of Heraklion (07/15.4.2020) and University of Brno (01-120220/EK).Trial registration numberNCT04370457.
Published: 2021

8. Prognostic impact of prevalent chronic lymphocytic leukemia stereotyped subsets: analysis within prospective clinical trials of the German CLL Study Group

Author: Kirsten Fischer, Barbara Eichhorst, Richard Rosenquist, Hartmut Döhner, Kostas Stamatopoulos, Paolo Ghia, Eugen Tausch, Michael Hallek, Sonia Jaramillo, Valentin Goede, Manuela Hoechstetter, Sandra Robrecht, Andreas Agathangelidis, Johannes Bloehdorn, Christof Schneider, Stephan Stilgenbauer, Jasmin Bahlo, Jaramillo, S., Agathangelidis, A., Schneider, C., Bahlo, J., Robrecht, S., Tausch, E., Bloehdorn, J., Hoechstetter, M., Fischer, K., Eichhorst, B., Goede, V., Hallek, M., Dohner, H., Rosenquist, R., Ghia, P., Stamatopoulos, K., and Stilgenbauer, S.
Subjects: Oncology, medicine.medical_specialty, Chronic lymphocytic leukemia, Article, 03 medical and health sciences, 0302 clinical medicine, International Prognostic Index, Internal medicine, hemic and lymphatic diseases, Medicine, Humans, Chronic Lymphocytic Leukemia, Stereotyped subset, Prospective Studies, Prospective cohort study, Retrospective Studies, business.industry, Retrospective cohort study, Hematology, medicine.disease, Prognosis, Leukemia, Lymphocytic, Chronic, B-Cell, Clinical trial, Leukemia, 030220 oncology & carcinogenesis, Cohort, Mutation, business, IGHV@, Immunoglobulin Heavy Chains, 030215 immunology
Abstract: Almost one-third of all patients with chronic lymphocytic leukemia (CLL) express stereotyped B-cell receptor immunoglobulins (BcR IG) and can be assigned to distinct subsets, each with a particular BcR IG. The largest stereotyped subsets are #1, #2, #4 and #8, associated with specific clinico-biological characteristics and outcomes in retrospective studies. We assessed the associations and prognostic value of these BcR IG in prospective multicenter clinical trials reflective of two different clinical situations: (i) early-stage patients ('watch and wait' arm of the CLL1 trial) (n=592); (ii) patients in need of treatment, enrolled in three phase III trials (CLL8, CLL10, CLL11), treated with different chemo-immunotherapies (n=1,861). Subset #1 was associated with del(11q), higher CLL International Prognostic Index (CLL-IPI) scores and similar clinical course to CLL with unmutated immunoglobulin heavy variable (IGHV) genes (U-CLL) in both early and advanced stage groups. IGHV-mutated (M-CLL) subset #2 cases had shorter time-to-first-treatment (TTFT) versus other M-CLL cases in the early-stage cohort (hazard ratio [HR]: 4.2, confidence interval [CI]: 2-8.6, P
Published: 2020

9. Genomic arrays identify high-risk chronic lymphocytic leukemia with genomic complexity: a multi-center study

Author: Clemens Mellink, Šárka Pospíšilová, Paolo Ghia, Constantine S. Tam, Mar Bellido, Marie Jarošová, Richard Rosenquist, Eva van den Berg, Jacqueline Schoumans, Claudia Haferlach, Lotta Hansson, Zadie Davis, Blanca Espinet, Anna Puiggros, David Oscier, Eric Eldering, Marian Stevens-Kroef, Jonathan C. Strefford, Panagiotis Baliakas, Karla Plevová, Ana E. Rodríguez-Vicente, Alexander C. Leeksma, Kostas Stamatopoulos, Rebeqa Gunnarsson, Pino J Poddighe, Anne Marie van der Kevie-Kersemaekers, Arnon P. Kater, Meaghan Wall, Florence Nguyen-Khac, Theodoros Moysiadis, Anders Österborg, Anh Nhi Tran, Larry Mansouri, Ilaria Scarpelli, Hidde Posthuma, Gisela Barbany, Loic Ysebaert, Helen Parker, Gilead Sciences, Kay Kendall Leukaemia Fund, Cancer Research UK, Wessex Medical Research, Swedish Research Council, Knut and Alice Wallenberg Foundation, Karolinska Institute, Graduate School, AII - Cancer immunology, CCA - Cancer biology and immunology, Human Genetics, Experimental Immunology, Clinical Haematology, Amsterdam Reproduction & Development (AR&D), Leeksma, A. C., Baliakas, P., Moysiadis, T., Puiggros, A., Plevova, K., van der Kevie-Kersemaekers, A. -M., Posthuma, H., Rodriguez-Vicente, A. E., Tran, A. N., Barbany, G., Mansouri, L., Gunnarsson, R., Parker, H., van den Berg, E., Bellido, M., Davis, Z., Wall, M., Scarpelli, I., Osterborg, A., Hansson, L., Jarosova, M., Ghia, P., Poddighe, P., Espinet, B., Pospisilova, S., Tam, C., Ysebaert, L., Nguyen-Khac, F., Oscier, D., Haferlach, C., Schoumans, J., Stevens-Kroef, M., Eldering, E., Stamatopoulos, K., Rosenquist, R., Strefford, J. C., Mellink, C., Kater, A. P., CCA - Cancer Treatment and quality of life, and Human genetics
Subjects: 0301 basic medicine, Oncology, medicine.medical_specialty, GENES, Genomic complexity, Chronic lymphocytic leukemia, Cancer development and immune defence Radboud Institute for Molecular Life Sciences [Radboudumc 2], FEATURES, ABERRATIONS, Article, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, hemic and lymphatic diseases, medicine, Humans, Chronic Lymphocytic Leukemia, Hematologi, Cytogenetics and Molecular Genetics, Lymphoproliferative Disorders, Chromosome Aberrations, Hematology, business.industry, Hazard ratio, Cytogenetics, Cancer, KARYOTYPE, Genomics, CHEMOTHERAPY, medicine.disease, Leukemia, Lymphocytic, Chronic, B-Cell, CYTOGENETICS, 3. Good health, Leukemia, 030104 developmental biology, 030220 oncology & carcinogenesis, Multiple comparisons problem, SURVIVAL, Medical genetics, business, CLL, HYBRIDIZATION, RESISTANCE
Abstract: Complex karyotype (CK) identified by chromosome-banding analysis (CBA) has shown prognostic value in chronic lymphocytic leukemia (CLL). Genomic arrays offer high-resolution genome-wide detection of copy-number alterations (CNAs) and could therefore be well equipped to detect the presence of a CK. Current knowledge on genomic arrays in CLL is based on outcomes of single center studies, in which different cutoffs for CNA calling were used. To further determine the clinical utility of genomic arrays for CNA assessment in CLL diagnostics, we retrospectively analyzed 2293 arrays from 13 diagnostic laboratories according to established standards. CNAs were found outside regions captured by CLL FISH probes in 34% of patients, and several of them including gains of 8q, deletions of 9p and 18p (p, This study was partly funded by an unrestricted contribution from Janssen Pharmaceuticals and from GILEAD Sciences SA. A.C.L. is supported by the Peters van der Laan foundation. J.C.S. was funded by Bloodwise (11052, 12036), the Kay Kendall Leukaemia Fund (873), Cancer Research UK (C34999/A18087, ECMC C24563/A15581), Wessex Medical Research and the Bournemouth Leukaemia Fund. K.P., M.J., and S.P. are supported by the project MHCR DRO no. 65269705, the research infrastructures NCMG LM2015091, and EATRIS-CZ LM2015064, and the project CEITEC2020 LQ1601, funded by MEYS CR. R.R. is supported by Swedish Cancer Society, the Swedish Research Council, the Knut and Alice Wallenberg Foundation, Karolinska Institutet, Karolinska University Hospital, and Radiumhemmets Forskningsfonder, Stockholm.
Published: 2020

10. Immunoglobulin gene sequence analysis in chronic lymphocytic leukemia: updated ERIC recommendations

Author: Frederic Davi, Andreas Agathangelidis, A. Hadzidimitriou, C. Belessi, Anton W. Langerak, Lesley A Sutton, Nikos Darzentas, Marie-Paule Lefranc, Kostas Stamatopoulos, Paolo Ghia, Panagiotis Baliakas, Véronique Giudicelli, Richard Rosenquist, Rosenquist, R, Ghia, P, Hadzidimitriou, A, Sutton, L-A, Agathangelidis, A, Baliakas, P, Darzentas, N, Giudicelli, V, Lefranc, M-P, Langerak, A W, Belessi, C, Davi, F, Stamatopoulos, K, and Immunology
Subjects: Immunoglobulin gene, Cancer Research, medicine.medical_specialty, Sequence analysis, Chronic lymphocytic leukemia, education, Fusion gene, 03 medical and health sciences, 0302 clinical medicine, hemic and lymphatic diseases, Internal medicine, parasitic diseases, medicine, Humans, Gene, Cancer och onkologi, Hematology, biology, Genes, Immunoglobulin, business.industry, Sequence Analysis, DNA, medicine.disease, Virology, Leukemia, Lymphocytic, Chronic, B-Cell, 3. Good health, Europe, Leukemia, Editorial, Oncology, 030220 oncology & carcinogenesis, Cancer and Oncology, Immunology, biology.protein, Antibody, business, 030215 immunology
Abstract: Immunoglobulin gene sequence analysis in chronic lymphocytic leukemia : updated ERIC recommendations
Published: 2017

11. Inhibition of EZH2 and immune signaling exerts synergistic antitumor effects in chronic lymphocytic leukemia

Author: Elisabetta Ferrero, Konstantia Kotta, Theoni Trangas, Maria Anna Akritidou, Elisavet Chartomatsidou, Alessandra Rovida, Stavroula Ntoufa, Niki Stavroyianni, Daniela Belloni, Richard Rosenquist, Kostas Stamatopoulos, Achilles Anagnostopoulos, Paolo Ghia, Nikos Papakonstantinou, Chartomatsidou, E., Ntoufa, S., Kotta, K., Rovida, A., Akritidou, M. A., Belloni, D., Ferrero, E., Trangas, T., Stavroyianni, N., Anagnostopoulos, A., Rosenquist, R., Ghia, P., Papakonstantinou, N., and Stamatopoulos, K.
Subjects: 0301 basic medicine, medicine.medical_specialty, Indazoles, Indoles, Immune signaling, Pyridones, Chronic lymphocytic leukemia, Down-Regulation, Antineoplastic Agents, Apoptosis, macromolecular substances, Histones, 03 medical and health sciences, 0302 clinical medicine, Piperidines, immune system diseases, Internal medicine, hemic and lymphatic diseases, Antineoplastic Combined Chemotherapy Protocols, medicine, Tumor Microenvironment, Humans, Enhancer of Zeste Homolog 2 Protein, Enzyme Inhibitors, neoplasms, Quinazolinones, B-Lymphocytes, Sulfonamides, Hematology, Chemistry, Adenine, EZH2, Drug Synergism, medicine.disease, Bridged Bicyclo Compounds, Heterocyclic, Stimulus Report, Leukemia, Lymphocytic, Chronic, B-Cell, 030104 developmental biology, Pyrimidines, Purines, 030220 oncology & carcinogenesis, Cancer research, Pyrazoles, Signal transduction, Function (biology), Signal Transduction
Abstract: Key Points Microenvironmental stimuli affect EZH2 expression and function in CLL. Combined B-cell signaling and EZH2 inhibition showed synergistic effects on primary CLL cells.
Published: 2019

12. Immunoglobulin Gene Sequence Analysis In Chronic Lymphocytic Leukemia: From Patient Material To Sequence Interpretation

Author: Lesley-Ann Sutton, Frederic Davi, Anton W. Langerak, Andreas Agathangelidis, Cristina Tresoldi, Kostas Stamatopoulos, Paolo Ghia, Richard Rosenquist, Anastasia Hadzidimitriou, Chrysoula Belessi, Agathangelidis, A., Sutton, L. A., Hadzidimitriou, A., Tresoldi, C., Langerak, A. W., Belessi, C., Davi, F., Rosenquist, R., Stamatopoulos, K., Ghia, P., and Immunology
Subjects: Immunoglobulin gene, Sequence analysis, Chronic lymphocytic leukemia, General Chemical Engineering, Immunoglobulin Variable Region, Somatic hypermutation, Computational biology, Cancer research, Biology, General Biochemistry, Genetics and Molecular Biology, Issue 141, 03 medical and health sciences, 0302 clinical medicine, Sequence Analysis, Protein, medicine, Immunoglobulin, Humans, Neoplastic transformation, Gene, Immunoglobulin heavy variable (IGHV), International immunogenetics information system (IMGT), B cell, Medicinsk genetik, B-Lymphocytes, General Immunology and Microbiology, Base Sequence, Genes, Immunoglobulin, General Neuroscience, Nucleic acid sequence, International ImMunoGene Tics information system (IMGT), medicine.disease, Leukemia, Lymphocytic, Chronic, B-Cell, Chronic lymphocytic leukemia (CLL), Complementarity determining region 3 (CDR3), medicine.anatomical_structure, 030220 oncology & carcinogenesis, Somatic hypermutation (SHM), Medical Genetics, 030215 immunology
Abstract: During B cell maturation, the complex process of immunoglobulin (IG) gene V(D)J recombination coupled with somatic hypermutation (SHM) gives rise to a unique DNA sequence within each individual B cell. Since B cell malignancies result from the clonal expansion of a single cell, IG genes represent a unique molecular signature common to all the malignant cells within an individual patient; thus, IG gene rearrangements can be used as clonal markers. In addition to serving as an important clonal identifier, the IG gene sequence can act as a 'molecular timeline' since it is associated with specific developmental stages and hence reflects the history of the B cell involved in the neoplastic transformation. Moreover, for certain malignancies, in particular chronic lymphocytic leukemia (CLL), the IG gene sequence holds prognostic and potentially predictive capabilities. That said, extrapolating meaningful conclusions from IG gene sequence analysis would be impossible if robust methods and tools were not available to aid in their analysis. This article, drawing on the vast experience of the European Research Initiative on CLL (ERIC), details the technical aspects and essential requirements necessary to ensure reliable and reproducible IG gene sequence analysis in CLL, a test that is now recommended for all CLL patients prior to treatment. More specifically, the various analytical stages are described ranging from the identification of the clonotypic IG gene rearrangement and the determination of the nucleotide sequence to the accurate clinical interpretation of the IG gene sequence data. De två första författarna delar förstaförfattarskapet.
Published: 2018

13. ERIC recommendations for TP53 mutation analysis in chronic lymphocytic leukemia—update on methodological approaches and results interpretation

Author: Richard Rosenquist, Eugen Tausch, Thorsten Zenz, M. Gonzalez Diaz, D. Rossi, Lesley-Ann Sutton, K. Stamatopoulos, Frederic Davi, S. Stilgenbauer, Carsten Utoft Niemann, Carol Moreno, Gianluca Gaidano, Šárka Pospíšilová, David Gonzalez, Arnon P. Kater, Jitka Malčíková, Thierry Soussi, Paolo Ghia, CCA - Cancer biology and immunology, Experimental Immunology, Clinical Haematology, AII - Amsterdam institute for Infection and Immunity, AII - Inflammatory diseases, Malcikova, J., Tausch, E., Rossi, D., Sutton, L. A., Soussi, T., Zenz, T., Kater, A. P., Niemann, C. U., Gonzalez, D., Davi, F., Gonzalez Diaz, M., Moreno, C., Gaidano, G., Stamatopoulos, K., Rosenquist, R., Stilgenbauer, S., Ghia, P., Pospisilova, S., Masaryk University, Universität Ulm - Ulm University [Ulm, Allemagne], Oncology Institute of Southern Switzerland (IOSI), Uppsala University, Karolinska Institutet [Stockholm], Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Cancer Center Karolinska [Karolinska Institutet] (CCK), University hospital of Zurich [Zurich], University of Zürich [Zürich] (UZH), Academic Medical Center - Academisch Medisch Centrum [Amsterdam] (AMC), University of Amsterdam [Amsterdam] (UvA), Rigshospitalet [Copenhagen], Queen's University [Belfast] (QUB), Service d'Hématologie Clinique [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], Universidad de Salamanca, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona [Barcelona] (UAB), CERTH, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS San Raffaele Pisana), Universita Vita Salute San Raffaele (UniSR), Masaryk University [Brno] (MUNI), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Universität Zürich [Zürich] = University of Zurich (UZH), Copenhagen University Hospital, Service d'Hématologie clinique [CHU Pitié-Salpêtrière], 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), Universitat Autònoma de Barcelona (UAB), Universita Vita Salute San Raffaele = Vita-Salute San Raffaele University [Milan, Italie] (UniSR), University of Zurich, and Ghia, P
Subjects: 0301 basic medicine, medicine.medical_specialty, Cancer Research, endocrine system diseases, Chronic lymphocytic leukemia, 2720 Hematology, DNA Mutational Analysis, MEDLINE, [SDV.CAN]Life Sciences [q-bio]/Cancer, 610 Medicine & health, Review, Review Article, Tp53 mutation, 03 medical and health sciences, 0302 clinical medicine, Chemoimmunotherapy, Internal medicine, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], medicine, Journal Article, Humans, In patient, 1306 Cancer Research, Hematologi, Intensive care medicine, neoplasms, Cancer och onkologi, Hematology, business.industry, breakpoint cluster region, High-Throughput Nucleotide Sequencing, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, Clinic for Hematology, medicine.disease, Genes, p53, Leukemia, Lymphocytic, Chronic, B-Cell, 3. Good health, Europe, Leukemia, 030104 developmental biology, Anesthesiology and Pain Medicine, Oncology, 030220 oncology & carcinogenesis, Cancer and Oncology, 10032 Clinic for Oncology and Hematology, 2730 Oncology, business
Abstract: Altres ajuts: Supported by the IMI 2 HARMONY JU under GA No 116026, this JU receives support from the EU's H2020 R&I program and EFPIA. Further supported by the EU Horizon 2020 projects MEDGENET 692298, AEGLE 644906, projects CEITEC 2020 (LQ1601), NCMG research infrastructure (LM2015091 funded by MEYS CR), project FNBr 65269705, FM MU ROZV/24/LF/2016, DFG (SFB1074, projects B1 and B2, and EU (FIRE CLL)), and the Swedish Cancer Society and the Swedish Research Council. Publication reflects only the authors' views and the Commission is not responsible for any use that may be made of the information it contains. In chronic lymphocytic leukemia (CLL), TP53 gene defects, due to deletion of the 17p13 locus and/or mutation(s) within the TP53 gene, are associated with resistance to chemoimmunotherapy and a particularly dismal clinical outcome. On these grounds, analysis of TP53 aberrations has been incorporated into routine clinical diagnostics to improve patient stratification and optimize therapeutic decisions. The predictive implications of TP53 aberrations have increasing significance in the era of novel targeted therapies, i.e., inhibitors of B-cell receptor (BcR) signaling and anti-apoptotic BCL2 family members, owing to their efficacy in patients with TP53 defects. In this report, the TP53 Network of the European Research Initiative on Chronic Lymphocytic Leukemia (ERIC) presents updated recommendations on the methodological approaches for TP53 mutation analysis. Moreover, it provides guidance to ensure that the analysis is performed in a timely manner for all patients requiring treatment and that the data is interpreted and reported in a consistent, standardized, and accurate way. Since next-generation sequencing technologies are gaining prominence within diagnostic laboratories, this report also offers advice and recommendations for the interpretation of TP53 mutation data generated by this methodology.
Published: 2018
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14. Not all IGHV3-21 chronic lymphocytic leukemias are equal: prognostic considerations

Author: Eva Minga, Karin E. Smedby, Lesley-Ann Sutton, Nicholas Chiorazzi, Myriam Boudjogra, Kostas Stamatopoulos, Karla Plevová, Lone Bredo Pedersen, Zadie Davis, Lydia Scarfò, Andreas Agathangelidis, Monica Facco, Achilles Anagnostopoulos, Maria Chatzouli, Chrysoula Belessi, Athina Tsanousa, Panagiotis Baliakas, Kirsten van Lom, Lefteris Angelis, Yorick Sandberg, Gunnar Juliusson, Diane F. Jelinek, Fie Juhl Vojdeman, Anne Gardiner, Panagiotis Panagiotidis, Anton W. Langerak, Florence Nguyen-Khac, Hana Skuhrová Francová, Frederic Davi, Denis Moreno, Silvio Veronese, Richard Rosenquist, Marie-Paule Lefranc, Nikos Darzentas, Šárka Pospíšilová, Véronique Giudicelli, Xiao-Jie Yan, Charles C. Chu, Christian H. Geisler, Larry Mansouri, David Oscier, Mark Catherwood, Marco Montillo, Anastasia Hadzidimitriou, Livio Trentin, Paolo Ghia, Tait D. Shanafelt, Tatiana Tzenou, Baliakas, P, Agathangelidis, A, Hadzidimitriou, A, Sutton, La, Minga, E, Tsanousa, A, Scarfò, L, Davis, Z, Yan, Xj, Shanafelt, T, Plevova, K, Sandberg, Y, Vojdeman, Fj, Boudjogra, M, Tzenou, T, Chatzouli, M, Chu, Cc, Veronese, S, Gardiner, A, Mansouri, L, Smedby, Ke, Pedersen, Lb, Moreno, D, Van Lom, K, Giudicelli, V, Francova, H, Nguyen Khac, F, Panagiotidis, P, Juliusson, G, Angelis, L, Anagnostopoulos, A, Lefranc, Mp, Facco, M, Trentin, L, Catherwood, M, Montillo, M, Geisler, Ch, Langerak, Aw, Pospisilova, S, Chiorazzi, N, Oscier, D, Jelinek, Df, Darzentas, N, Belessi, C, Davi, F, Ghia, PAOLO PROSPERO, Rosenquist, R, Stamatopoulos K. Ghia P., is Co senior author, Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden, Università Vita-Salute San Raffaele, Milan, Italy, Division of Molecular Oncology and Department of Onco-Hematology, Istituto di Ricovero e Cura a Carattere Scientifico, San Raffaele Scientific Institute, Milan, Italy, Institute of Applied Biosciences, Centre for Research and Technology-Hellas, Thessaloniki, Greece, Department of Informatics, Aristotle University of Thessaloniki, Thessaloniki, Greece, Department of Haematology, Royal Bournemouth Hospital, Bournemouth, United Kingdom, The Feinstein Institute for Medical Research, Mayo Clinic [Rochester], Central European Institute of Technology [Brno] (CEITEC MU), Brno University of Technology [Brno] (BUT), Erasmus University Medical Center [Rotterdam] (Erasmus MC), Department of Hematology, Rigshospitalet, Copenhagen, Denmark, Service d'Hématologie Biologique [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), First Department of Propaedeutic Medicine, University of Athens, Athens, Greece, Hematology Department, Nikea General Hospital, Piraeus, Greece, Fondazione IRCCS Ca' Granda - Ospedale Maggiore Policlinico, Department of Medicine, Solna, Clinical Epidemiology Unit, Karolinska Institutet, Stockholm, Sweden, Institut de génétique humaine (IGH), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Lund University and Hospital Department of Hematology, Lund Stem Cell Center, Lund, Sweden, Hematology Department and Hematopoietic Cell Transplantation Unit, Georgios Papanicolaou Hospital, Thessaloniki, Greece, Universita degli Studi di Padova, Department of Hemato-Oncology, Belfast City Hospital, Belfast, United Kingdom, Immunology, and Hematology
Subjects: Male, Oncology, medicine.medical_specialty, Chronic lymphocytic leukemia, Immunology, B-cell receptor, Gene Rearrangement, B-Lymphocyte, Heavy Chain, Antineoplastic Agents, Biology, Biochemistry, Time-to-Treatment, Genetic Heterogeneity, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, medicine, Humans, 10. No inequality, ComputingMilieux_MISCELLANEOUS, Survival analysis, Aged, 030304 developmental biology, [SDV.GEN]Life Sciences [q-bio]/Genetics, B-Lymphocytes, 0303 health sciences, Lymphoid Neoplasia, Hematology, Gene Expression Regulation, Leukemic, Genetic heterogeneity, Cell Biology, Middle Aged, Prognosis, medicine.disease, Leukemia, Lymphocytic, Chronic, B-Cell, Survival Analysis, Treatment Outcome, 030220 oncology & carcinogenesis, biology.protein, Immunoglobulin heavy chain, Female, Somatic Hypermutation, Immunoglobulin, Antibody, Immunoglobulin Heavy Chains, IGHV@
Abstract: An unresolved issue in chronic lymphocytic leukemia (CLL) is whether IGHV3-21 gene usage, in general, or the expression of stereotyped B-cell receptor immunoglobulin defining subset # 2 (IGHV3-21/IGLV3-21), in particular, determines outcome for IGHV3-21-utilizing cases. We reappraised this issue in 8593 CLL patients of whom 437 (5%) used the IGHV3-21 gene with 254/437 (58%) classified as subset # 2. Within subset # 2, immunoglobulin heavy variable (IGHV)-mutated cases predominated, whereas non-subset # 2/IGHV3-21 was enriched for IGHV-unmutated cases (P =.002). Subset # 2 exhibited significantly shorter time-to-first-treatment (TTFT) compared with non-subset # 2/IGHV3-21 (22 vs 60 months, P =.001). No such difference was observed between non-subset # 2/IGHV3-21 vs the remaining CLL with similar IGHV mutational status. In conclusion, IGHV3-21 CLL should not be axiomatically considered a homogeneous entity with adverse prognosis, given that only subset # 2 emerges as uniformly aggressive, contrasting non-subset # 2/IGVH3-21 patients whose prognosis depends on IGHV mutational status as the remaining CLL.
Published: 2015

15. Targeted next-generation sequencing in chronic lymphocytic leukemia: a high-throughput yet tailored approach will facilitate implementation in a clinical setting

Author: Jitka Malčíková, Emma Young, Veronika Navrkalová, Šárka Pospíšilová, Martin Trbušek, Kostas Stamatopoulos, Frederic Davi, Diego Cortese, Panagiotis Panagiotidis, Chrysoula Belessi, Alice F. Muggen, Anton W. Langerak, Richard Rosenquist, Lesley-Ann Sutton, Viktor Ljungström, Paolo Ghia, Larry Mansouri, Immunology, Sutton, La, Ljungström, V, Mansouri, L, Young, E, Cortese, D, Navrkalova, V, Malcikova, J, Muggen, Af, Trbusek, M, Panagiotidis, P, Davi, F, Belessi, C, Langerak, Aw, Ghia, PAOLO PROSPERO, Pospisilova, S, Stamatopoulos, K, and Rosenquist, R.
Subjects: Chronic lymphocytic leukemia, Gene Expression, Computational biology, Biology, medicine.disease_cause, DNA sequencing, symbols.namesake, Gene Frequency, medicine, Humans, Receptor, Notch1, Allele, Allele frequency, Alleles, Sanger sequencing, Genetics, Mutation, High-Throughput Nucleotide Sequencing, Articles, Hematology, Ribonucleoprotein, U2 Small Nuclear, Phosphoproteins, Prognosis, medicine.disease, Leukemia, Lymphocytic, Chronic, B-Cell, Neoplasm Proteins, Leukemia, Myeloid Differentiation Factor 88, symbols, RNA Splicing Factors, Tumor Suppressor Protein p53, IGHV@
Abstract: Next- generation sequencing has revealed novel recurrent mutations in chronic lymphocytic leukemia, particularly in patients with aggressive disease. Here, we explored targeted re- sequencing as a novel strategy to assess the mutation status of genes with prognostic potential. To this end, we utilized HaloPlex targeted enrichment technology and designed a panel including nine genes: ATM, BIRC3, MYD88, NOTCH1, SF3B1 and TP53, which have been linked to the prognosis of chronic lymphocytic leukemia, and KLHL6, POT1 and XPO1, which are less characterized but were found to be recurrently mutated in various sequencing studies. A total of 188 chronic lymphocytic leukemia patients with poor prognostic features ( unmutated IGHV, n= 137; IGHV3- 21 subset # 2, n= 51) were sequenced on the HiSeq 2000 and data were analyzed using well- established bioinformatics tools. Using a conservative cutoff of 10% for the mutant allele, we found that 114/ 180 ( 63%) patients carried at least one mutation, with mutations in ATM, BIRC3, NOTCH1, SF3B1 and TP53 accounting for 149/ 177 ( 84%) of all mutations. We selected 155 mutations for Sanger validation ( variant allele frequency, 10- 99%) and 93% ( 144/ 155) of mutations were confirmed; notably, all 11 discordant variants had a variant allele frequency between 11- 27%, hence at the detection limit of conventional Sanger sequencing. Technical precision was assessed by repeating the entire HaloPlex procedure for 63 patients; concordance was found for 77/ 82 ( 94%) mutations. In summary, this study demonstrates that targeted next- generation sequencing is an accurate and reproducible technique potentially suitable for routine screening, eventually as a stand- alone test without the need for confirmation by Sanger sequencing.
Published: 2015

16. Distinct patterns of novel gene mutations in poor-prognostic stereotyped subsets of chronic lymphocytic leukemia: the case of SF3B1 and subset #2

Author: Jitka Malčíková, Richard Rosenquist, Panagiotis Panagiotidis, C. Belessi, Tatiana Tzenou, P. F. Di Celle, Karla Plevová, Šárka Pospíšilová, Nicola Cahill, Anthonie Willem Langerak, Larry Mansouri, Nicholas Chiorazzi, Christian H. Geisler, Kostas Stamatopoulos, Lone B. Pedersen, Zadie Davis, Lesley-Ann Sutton, Diego Cortese, David Oscier, Panagiotis Baliakas, Evangelia Stalika, Paolo Ghia, Lydia Scarfò, Andreas Agathangelidis, Frederic Davi, Jonathan C. Strefford, Strefford, Jc, Sutton, La, Baliakas, P, Agathangelidis, A, Malcikova, J, Plevova, K, Scarfo, L, Davis, Z, Stalika, E, Cortese, D, Cahill, N, Pedersen, Lb, di Celle, Pf, Tzenou, T, Geisler, C, Panagiotidis, P, Langerak, Aw, Chiorazzi, N, Pospisilova, S, Oscier, D, Davi, F, Belessi, C, Mansouri, L, Ghia, PAOLO PROSPERO, Stamatopoulos, K, Rosenquist R. P., Ghia is joint last author, and Immunology
Subjects: Cancer Research, Chronic lymphocytic leukemia, Ubiquitin-Protein Ligases, Biology, medicine.disease_cause, Somatic evolution in cancer, Polymerase Chain Reaction, law.invention, Inhibitor of Apoptosis Proteins, Cohort Studies, 03 medical and health sciences, 0302 clinical medicine, Antigen, law, medicine, Biomarkers, Tumor, Humans, Receptor, Notch1, Survival rate, Gene, Polymerase chain reaction, 030304 developmental biology, 0303 health sciences, Mutation, Hematology, DNA, Neoplasm, Ribonucleoprotein, U2 Small Nuclear, medicine.disease, Phosphoproteins, Prognosis, Leukemia, Lymphocytic, Chronic, B-Cell, Baculoviral IAP Repeat-Containing 3 Protein, Survival Rate, Leukemia, Oncology, 030220 oncology & carcinogenesis, Immunology, RNA Splicing Factors, Follow-Up Studies
Abstract: Recent studies have revealed recurrent mutations of the NOTCH1, SF3B1 and BIRC3 genes in chronic lymphocytic leukemia (CLL), especially among aggressive, chemorefractory cases. Nevertheless, it is currently unknown whether their presence may differ in subsets of patients carrying stereotyped B-cell receptors and also exhibiting distinct prognoses. Here, we analyzed the mutation status of NOTCH1, SF3B1 and BIRC3 in three subsets with particularly poor prognosis, that is, subset # 1, # 2 and # 8, aiming to explore links between genetic aberrations and immune signaling. A remarkably higher frequency of SF3B1 mutations was revealed in subset # 2 (44%) versus subset # 1 and # 8 (4.6% and 0%, respectively; P
Published: 2013

17. An Immunogenetic Signature of Ongoing Antigen Interactions in Splenic Marginal Zone Lymphoma Expressing IGHV1-2*04 Receptors

Author: Theodora Papadaki, Evdoxia Papadopoulou, Šárka Pospíšilová, Andreas Agathangelidis, Alexandra Traverse-Glehen, George Papadopoulos, Lesley-Ann Sutton, Zadie Davis, David Oscier, George Kanellis, Dimitros Tzovaras, Kostas Stamatopoulos, Maria Karypidou, David Gonzalez, Miguel A. Piris, Anastasia Hadzidimitriou, Nikos Darzentas, Vasileios Bikos, Achilles Anagnostopoulos, Paolo Ghia, Estella Matutes, Aliki Xochelli, Patricia Algara, Manuela Mollejo, Maurilio Ponzoni, Richard Rosenquist, Chrysoula Belessi, Panagiotis Baliakas, Evangelia Stalika, Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Bikos, V, Karypidou, M, Stalika, E, Baliakas, P, Xochelli, A, Sutton, La, Papadopoulos, G, Agathangelidis, A, Papadopoulou, E, Davis, Z, Algara, P, Kanellis, G, Traverse Glehen, A, Mollejo, M, Anagnostopoulos, A, Ponzoni, M, Gonzalez, D, Pospisilova, S, Matutes, E, Piris, Ma, Papadaki, T, Ghia, PAOLO PROSPERO, Rosenquist, R, Oscier, D, Darzentas, N, Tzovaras, D, Belessi, C, Hadzidimitriou, A, and Stamatopoulos, K.
Subjects: 0301 basic medicine, Cancer Research, Lymphoma, Amino Acid Motifs, Gene Rearrangement, B-Lymphocyte, Heavy Chain, Immunoglobulin Variable Region, Marginal Zone, immunology, Models, London, Receptors, genetics, Genetics, Gene Rearrangement, B-Lymphocyte, Hematology, 3. Good health, medicine.anatomical_structure, Oncology, Italy, Antigen, France, IGHV@, Immunoglobulin Heavy Chains, Patients, Somatic hypermutation, Receptors, Antigen, B-Cell, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, Immunoglobulin light chain, chemistry, Models, Biological, 03 medical and health sciences, medicine, Humans, Splenic marginal zone lymphoma, Amino Acid Sequence, Antigens, B cell, Alleles, Gene Expression Profiling, Splenic Neoplasms, B-Cell, Gene rearrangement, Lymphoma, B-Cell, Marginal Zone, medicine.disease, Biological, Complementarity Determining Regions, Gene expression profiling, 030104 developmental biology, Amino Acid Substitution, Immunology, Mutation, Heavy Chain, Immunoglobulin heavy chain, pathology, Laboratories, Transcriptome
Abstract: Purpose: Prompted by the extensive biases in the immunoglobulin (IG) gene repertoire of splenic marginal-zone lymphoma (SMZL), supporting antigen selection in SMZL ontogeny, we sought to investigate whether antigen involvement is also relevant post-transformation. Experimental Design: We conducted a large-scale subcloning study of the IG rearrangements of 40 SMZL cases aimed at assessing intraclonal diversification (ID) due to ongoing somatic hypermutation (SHM). Results: ID was identified in 17 of 21 (81%) rearrangements using the immunoglobulin heavy variable (IGHV)1-2*04 gene versus 8 of 19 (40%) rearrangements utilizing other IGHV genes (P = 0.001). ID was also evident in most analyzed IG light chain gene rearrangements, albeit was more limited compared with IG heavy chains. Identical sequence changes were shared by subclones from different patients utilizing the IGHV1-2*04 gene, confirming restricted ongoing SHM profiles. Non-IGHV1-2*04 cases displayed both a lower number of ongoing SHMs and a lack of shared mutations (per group of cases utilizing the same IGHV gene). Conclusions: These findings support ongoing antigen involvement in a sizable portion of SMZL and further argue that IGHV1-2*04 SMZL may represent a distinct molecular subtype of the disease. Clin Cancer Res; 22(8); 2032–40. ©2015 AACR.
Published: 2016

18. Innovation in the prognostication of chronic lymphocytic leukemia: how far beyond TP53 gene analysis can we go?

Author: Emili Montserrat, Lesley-Ann Sutton, Eugen Tausch, Davide Rossi, Jitka Malčíková, Kostas Stamatopoulos, Paolo Ghia, Richard Rosenquist, Carol Moreno, Gianluca Gaidano, Šárka Pospíšilová, Pospisilova, S, Sutton, La, Malcikova, J, Tausch, E, Rossi, D, Montserrat, E, Moreno, C, Stamatopoulos, K, Gaidano, G, Rosenquist, R, and Ghia, P
Subjects: medicine.medical_specialty, endocrine system diseases, Class I Phosphatidylinositol 3-Kinases, Chronic lymphocytic leukemia, Gene Expression, Antineoplastic Agents, medicine.disease_cause, Bioinformatics, Somatic evolution in cancer, 03 medical and health sciences, 0302 clinical medicine, Gene Frequency, Piperidines, hemic and lymphatic diseases, Internal medicine, medicine, Agammaglobulinaemia Tyrosine Kinase, Biomarkers, Tumor, Humans, Molecular Targeted Therapy, Allele, neoplasms, Allele frequency, Gene, Alleles, Quinazolinones, Mutation, Sulfonamides, Hematology, business.industry, Adenine, Editorials, High-Throughput Nucleotide Sequencing, Protein-Tyrosine Kinases, medicine.disease, Bridged Bicyclo Compounds, Heterocyclic, Prognosis, Leukemia, Lymphocytic, Chronic, B-Cell, Leukemia, Pyrimidines, Purines, 030220 oncology & carcinogenesis, Cancer research, Pyrazoles, Tumor Suppressor Protein p53, business, 030215 immunology
Abstract: The prognostication of patients with chronic lymphocytic leukemia (CLL) currently relies on both clinical and biological parameters ([Figure 1][1]). The prime example concerns the TP53 gene, whereby inactivation of TP53 , resulting from either a mutation or chromosome 17p deletion, is associated
Published: 2016

19. Antigen receptor stereotypy in chronic lymphocytic leukemia

Author: Richard Rosenquist, Kostas Stamatopoulos, Andreas Agathangelidis, Paolo Ghia, Stamatopoulos, K., Agathangelidis, A., Rosenquist, R., and Ghia, P.
Subjects: 0301 basic medicine, Cancer Research, Chronic lymphocytic leukemia, Somatic hypermutation, Receptors, Antigen, B-Cell, Complementarity determining region, Biology, 03 medical and health sciences, Genetic Heterogeneity, Antigen, hemic and lymphatic diseases, medicine, Animals, Humans, Genetic heterogeneity, Gene Expression Regulation, Leukemic, breakpoint cluster region, Hematology, medicine.disease, Prognosis, Complementarity Determining Regions, Leukemia, Lymphocytic, Chronic, B-Cell, 3. Good health, Stereotypy (non-human), Leukemia, 030104 developmental biology, Cell Transformation, Neoplastic, Anesthesiology and Pain Medicine, Oncology, Immunology, Somatic Hypermutation, Immunoglobulin, Immunoglobulin Heavy Chains
Abstract: The discovery of almost identical or 'stereotyped' B-cell receptor immunoglobulins (BcR IG) among unrelated patients with chronic lymphocytic leukemia (CLL) cemented the idea of antigen selection in disease ontogeny and evolution. The systematic analysis of the stereotypy phenomenon in CLL revealed that around one-third of CLL patients may be grouped into subsets based on shared sequence motifs within the variable heavy complementarity determining region 3. Stereotyped subsets display a strikingly similar biology of the leukemic clones, referring to many different levels, from the immunogenetic and genetic and extending to the epigenetic and functional levels. Even more importantly, the homogeneity of stereotyped subsets has clinical consequences as patients assigned to the same stereotyped subset generally exhibit an overall similar disease course and outcome. In other words, stereotypy-based patient classification of CLL has already provided a more compartmentalized view of this otherwise heterogeneous disease and can assist in refining prognostication models. While this is relevant only for the one-third of cases expressing stereotyped BcR IG; in principle, however, the findings from further analysis of the stereotyped subsets may also contribute towards improved understanding of the remaining non-stereotyped fraction of CLL patients.
Published: 2016
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20. Whole-exome sequencing in relapsing chronic lymphocytic leukemia: clinical impact of recurrent RPS15 mutations

Author: Larry Mansouri, Anton W. Langerak, Anna Schuh, Tatjana Pandzic, Martin Höglund, Lesley-Ann Sutton, David Oscier, Stuart Blakemore, Karla Plevová, Christiane Pott, Karin E. Smedby, Emma Young, R Clifford, Andreas Agathangelidis, Livio Trentin, Davide Rossi, Viktor Ljungström, Jonathan C. Strefford, Panagiotis Panagiotidis, Jana Kotašková, Šárka Pospíšilová, Paolo Ghia, Tobias Sjöblom, Kostas Stamatopoulos, Stavroula Ntoufa, Niki Stavroyianni, Diego Cortese, Richard Rosenquist, Gianluca Gaidano, Nicholas Chiorazzi, Gunnar Juliusson, Frederic Davi, Panagiotis Baliakas, Chrysoula Belessi, Immunology, Ljungström, V, Cortese, D, Young, E, Pandzic, T, Mansouri, L, Plevova, K, Ntoufa, S, Baliakas, P, Clifford, R, Sutton, La, Blakemore, S, Stavroyianni, N, Agathangelidis, A, Rossi, D, Höglund, M, Kotaskova, J, Juliusson, G, Belessi, C, Chiorazzi, N, Panagiotidis, P, Langerak, Aw, Smedby, Ke, Oscier, D, Gaidano, G, Schuh, A, Davi, F, Pott, C, Strefford, Jc, Trentin, L, Pospisilova, S, Ghia, PAOLO PROSPERO, Stamatopoulos, K, Sjöblom, T, and Rosenquist, R.
Subjects: Ribosomal Proteins, 0301 basic medicine, medicine.medical_specialty, Chronic lymphocytic leukemia, Blotting, Western, DNA Mutational Analysis, Immunology, Mutation, Missense, Cell Separation, Kaplan-Meier Estimate, Biology, Transfection, medicine.disease_cause, Biochemistry, Somatic evolution in cancer, 03 medical and health sciences, Internal medicine, Antineoplastic Combined Chemotherapy Protocols, medicine, Humans, Immunoprecipitation, Exome, Cyclophosphamide, Exome sequencing, Mutation, Lymphoid Neoplasia, Hematology, Cell Biology, medicine.disease, Leukemia, Lymphocytic, Chronic, B-Cell, NFKBIE, 3. Good health, Fludarabine, 030104 developmental biology, Drug Resistance, Neoplasm, Cancer research, Neoplasm Recurrence, Local, Tumor Suppressor Protein p53, Rituximab, Vidarabine, medicine.drug
Abstract: Fludarabine, cyclophosphamide, and rituximab (FCR) is first-line treatment of medically fit chronic lymphocytic leukemia (CLL) patients; however, despite good response rates, many patients eventually relapse. Although recent high-throughput studies have identified novel recurrent genetic lesions in adverse prognostic CLL, the mechanisms leading to relapse after FCR therapy are not completely understood. To gain insight into this issue, we performed whole-exome sequencing of sequential samples from 41 CLL patients who were uniformly treated with FCR but relapsed after a median of 2 years. In addition to mutations with known adverse-prognostic impact (TP53, NOTCH1, ATM, SF3B1, NFKBIE, and BIRC3), a large proportion of cases (19.5%) harbored mutations in RPS15, a gene encoding a component of the 40S ribosomal subunit. Extended screening, totaling 1119 patients, supported a role for RPS15 mutations in aggressive CLL, with one-third of RPS15-mutant cases also carrying TP53 aberrations. In most cases, selection of dominant, relapse-specific subclones was observed over time. However, RPS15 mutations were clonal before treatment and remained stable at relapse. Notably, all RPS15 mutations represented somatic missense variants and resided within a 7 amino-acid, evolutionarily conserved region. We confirmed the recently postulated direct interaction between RPS15 and MDM2/MDMX and transient expression of mutant RPS15 revealed defective regulation of endogenous p53 compared with wild-type RPS15. In summary, we provide novel insights into the heterogeneous genetic landscape of CLL relapsing after FCR treatment and highlight a novel mechanism underlying clinical aggressiveness involving a mutated ribosomal protein, potentially representing an early genetic lesion in CLL pathobiology.
Published: 2016

21. Antigen receptor stereotypy across B-cell lymphoproliferations: the case of IGHV4-59/IGKV3-20 receptors with rheumatoid factor activity

Author: Boris Tichy, Agnieszka Janus, Lone Bredo Pedersen, Xavier Brochet, Nikos Darzentas, C. Belessi, M. Ponzoni, Frederic Davi, J. Jurlander, Paolo Ghia, Kostas Stamatopoulos, Achilles Anagnostopoulos, Maria Gounari, P. F. Di Celle, Véronique Giudicelli, Šárka Pospíšilová, Efterpi Kostareli, David Oscier, Anastasia Kouvatsi, Keith M. Thompson, Richard Rosenquist, Letizia Foroni, Marie-Paule Lefranc, Fiona Murray, Kostareli, E, Gounari, M, Janus, A, Murray, F, Brochet, X, Giudicelli, V, Pospisilova, S, Oscier, D, Foroni, L, di Celle, Pf, Tichy, B, Pedersen, Lb, Jurlander, J, Ponzoni, Maurilio, Kouvatsi, A, Anagnostopoulos, A, Thompson, K, Darzentas, N, Lefranc, Mp, Belessi, C, Rosenquist, R, Davi, F, Ghia, PAOLO PROSPERO, Stamatopoulos, K., Institut de génétique humaine (IGH), and Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Cancer Research, medicine.medical_specialty, Molecular Sequence Data, Immunoglobulin Variable Region, Biology, 03 medical and health sciences, 0302 clinical medicine, Rheumatoid Factor, Antigen receptor, medicine, Humans, Rheumatoid factor, Amino Acid Sequence, Receptor, Peptide sequence, ComputingMilieux_MISCELLANEOUS, B cell, 030304 developmental biology, B-Lymphocytes, 0303 health sciences, Hematology, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], Receptors, Antigen, Stereotypy (non-human), medicine.anatomical_structure, Oncology, 030220 oncology & carcinogenesis, Immunology, Medical genetics, [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM]
Abstract: Antigen receptor stereotypy across B-cell lymphoproliferations: the case of IGHV4-59/IGKV3-20 receptors with rheumatoid factor activity
Published: 2011

22. A different ontogenesis for chronic lymphocytic leukemia cases carrying stereotyped antigen receptors: molecular and computational evidence

Author: Katerina Hatzi, Carol Moreno, C. Belessi, Paolo Ghia, Frederic Davi, Richard Rosenquist, Pär Josefsson, Nicholas Chiorazzi, Fiona Murray, Kostas Stamatopoulos, Achilles Anagnostopoulos, Nikolaos Laoutaris, J. Jurlander, A. Hadzidimitriou, Athanasios Tsaftaris, Nikos Darzentas, Darzentas, N, Hadzidimitriou, A, Murray, F, Hatzi, K, Josefsson, P, Laoutaris, N, Moreno, C, Anagnostopoulos, A, Jurlander, J, Tsaftaris, A, Chiorazzi, N., Belessi, C., Ghia, PAOLO PROSPERO, Rosenquist, R, Davi, F, and Stamatopoulos K. Ghia P., is the corresponding author
Subjects: Cancer Research, Chronic lymphocytic leukemia, Molecular Sequence Data, B-cell receptor, Immunoglobulin Variable Region, Receptors, Antigen, B-Cell, Biology, Mice, Immune system, Antigen, hemic and lymphatic diseases, medicine, Animals, Humans, Amino Acid Sequence, Phylogeny, Genetics, Innate immune system, breakpoint cluster region, Hematology, medicine.disease, Complementarity Determining Regions, Leukemia, Lymphocytic, Chronic, B-Cell, B-1 cell, Stereotypy (non-human), Oncology, Immunology, Immunoglobulin Heavy Chains
Abstract: Chronic lymphocytic leukemia (CLL) is uniquely characterized by the existence of subsets of cases with quasi-identical, 'stereotyped' B-cell receptors (BCRs). Herein we investigate this stereotypy in 2662 patients with CLL, the largest series yet, using purpose-built bioinformatics methods based on sequence pattern discovery. Besides improving the identification of 'stereotyped' cases, we demonstrate that CLL actually consists of two different categories, based on the BCR repertoire, with important biological and ontogenetic differences. The first (similar to 30% of cases) shows a very restricted repertoire and is characterized by BCR stereotypy (clustered cases), whereas the second includes cases with heterogeneous BCRs (nonclustered cases). Eleven major CLL clusters were identified with antigen-binding sites defined by just a few critically positioned residues, regardless of the actual immunoglobulin (IG) variable gene used. This situation is closely reminiscent of the receptors expressed by cells participating in innate immune responses. On these grounds, we argue that whereas CLL cases with heterogeneous BCRs likely derive from the conventional B-cell pool, cases with stereotyped BCRs could derive from progenitor cells evolutionarily adapted to particular antigenic challenges, perhaps intermediate between a true innate immune system and the conventional adaptive B-cell immune system, functionally similar to what has been suggested previously for mouse B1 cells. Leukemia (2010) 24, 125-132; doi:10.1038/leu.2009.186; published online 17 September 2009
Published: 2009

23. Stereotyped patterns of somatic hypermutation in subsets of patients with chronic lymphocytic leukemia: implications for the role of antigen selection in leukemogenesis

Author: Federico Caligaris-Cappio, Fanny Baran-Marzsak, Christos A. Ouzounis, Richard Rosenquist, Dominique Vaur, Athanasios Tsaftaris, Fred Davi, Paolo Ghia, Karin Karlsson, Gerard Tobin, Anastasia Hadzidimitriou, Myriarn Boudjogra, Fiona Murray, Carol Moreno, Nikos Darzentas, Kostas Stamatopoulos, Nikolaos Laoutaris, Chrysoula Belessi, Achilles Anagnostopoulos, Cristina Scielzo, Murray, F, Darzentas, N, Hadzidimitriou, A, Tobin, G, Boudjogra, M, Scielzo, C, Laoutaris, N, Karlsson, K, Baran Marzsak, F, Tsaftaris, A, Moreno, C, Anagnostopoulos, A, Caligaris Cappio, F, Vaur, D, Ouzounis, C, Belessi, C, Ghia, PAOLO PROSPERO, Davi, F, Rosenquist, R, and Stamatopoulos K. Ghia P., is the corresponding author
Subjects: Chronic lymphocytic leukemia, Molecular Sequence Data, Immunology, Somatic hypermutation, Biology, medicine.disease_cause, Biochemistry, Germline, Germline mutation, Antigens, Neoplasm, immune system diseases, hemic and lymphatic diseases, medicine, Humans, Amino Acid Sequence, Amino Acids, Gene, Genetics, Mutation, Binding Sites, Cell Biology, Hematology, medicine.disease, Leukemia, Lymphocytic, Chronic, B-Cell, Cell Transformation, Neoplastic, Immunoglobulin heavy chain, Somatic Hypermutation, Immunoglobulin, IGHV@
Abstract: Somatic hypermutation (SHM) features in a series of 1967 immunoglobulin heavy chain gene (IGH) rearrangements obtained from patients with chronic lymphocytic leukemia (CLL) were examined and compared with IGH sequences from non-CLL B cells available in public databases. SHM analysis was performed for all 1290 CLL sequences in this cohort with less than 100% identity to germ line. At the cohort level, SHM patterns were typical of a canonical SHM process. However, important differences emerged from the analysis of certain subgroups of CLL sequences defined by: (1) IGHV gene usage, (2) presence of stereotyped heavy chain complementarity-determining region 3 (HCDR3) sequences, and (3) mutational load. Recurrent, “stereotyped” amino acid changes occurred across the entire IGHV region in CLL subsets carrying stereotyped HCDR3 sequences, especially those expressing the IGHV3-21 and IGHV4-34 genes. These mutations are underrepresented among non-CLL sequences and thus can be considered as CLL-biased. Furthermore, it was shown that even a low level of mutations may be functionally relevant, given that stereotyped amino acid changes can be found in subsets of minimally mutated cases. The precise targeting and distinctive features of somatic hypermutation (SHM) in selected subgroups of CLL patients provide further evidence for selection by specific antigenic element(s).
Published: 2008

24. Genetics and prognostication in splenic marginal zone lymphoma: Revelations from deep sequencing

Author: Richard Rosenquist, David Gonzalez de Castro, Renata Walewska, Anton Parker, Christina Kalpadakis, Neil McIver-Brown, Marina Parry, Claire Dearden, Francesco Forconi, Andrew Collins, Jonathan C. Strefford, Kostas Stamatopoulos, David G. Oscier, Achilles Anagnostopoulos, Jun Wang, Gerassimos A. Pangalis, Margaret Ashton-Key, Zadie Davis, Matthew J. J. Rose-Zerilli, Paolo Ghia, Jane Gibson, Estella Matutes, Anne Gardiner, Viktor Ljungström, Guy Pratt, Claudia Fazi, Aliki Xochelli, Helen Parker, Parry, M, Rose Zerilli, Mj, Ljungström, V, Gibson, J, Wang, J, Walewska, R, Parker, H, Parker, A, Davis, Z, Gardiner, A, McIver Brown, N, Kalpadakis, C, Xochelli, A, Anagnostopoulos, A, Fazi, C, Gonzalez de Castro, D, Dearden, C, Pratt, G, Rosenquist, R, Ashton Key, M, Forconi, F, Collins, A, Ghia, PAOLO PROSPERO, Matutes, E, Pangalis, G, Stamatopoulos, K, Oscier, D, and Strefford, Jc
Subjects: Adult, Genetic Markers, Male, Cancer Research, Oncology, DNA Mutational Analysis, Kruppel-Like Transcription Factors, Biology, Gene mutation, medicine.disease_cause, Article, Cohort Studies, Germline mutation, Risk Factors, medicine, Humans, Clinical significance, Receptor, Notch2, Splenic marginal zone lymphoma, Tumor Necrosis Factor alpha-Induced Protein 3, Aged, Aged, 80 and over, Genetics, Mutation, Splenic Neoplasms, Intracellular Signaling Peptides and Proteins, High-Throughput Nucleotide Sequencing, Nuclear Proteins, Cancer, Lymphoma, B-Cell, Marginal Zone, Middle Aged, Prognosis, medicine.disease, Neoplasm Proteins, Lymphoma, DNA-Binding Proteins, Treatment Outcome, Multivariate Analysis, Myeloid Differentiation Factor 88, Female, Tumor Suppressor Protein p53, IGHV@, Transcription Factors
Abstract: Purpose: Mounting evidence supports the clinical significance of gene mutations and immunogenetic features in common mature B-cell malignancies. Experimental Design: We undertook a detailed characterization of the genetic background of splenic marginal zone lymphoma (SMZL), using targeted resequencing and explored potential clinical implications in a multinational cohort of 175 patients with SMZL. Results: We identified recurrent mutations in TP53 (16%), KLF2 (12%), NOTCH2 (10%), TNFAIP3 (7%), MLL2 (11%), MYD88 (7%), and ARID1A (6%), all genes known to be targeted by somatic mutation in SMZL. KLF2 mutations were early, clonal events, enriched in patients with del(7q) and IGHV1-2*04 B-cell receptor immunoglobulins, and were associated with a short median time to first treatment (0.12 vs. 1.11 years; P = 0.01). In multivariate analysis, mutations in NOTCH2 [HR, 2.12; 95% confidence interval (CI), 1.02–4.4; P = 0.044] and 100% germline IGHV gene identity (HR, 2.19; 95% CI, 1.05–4.55; P = 0.036) were independent markers of short time to first treatment, whereas TP53 mutations were an independent marker of short overall survival (HR, 2.36; 95 % CI, 1.08–5.2; P = 0.03). Conclusions: We identify key associations between gene mutations and clinical outcome, demonstrating for the first time that NOTCH2 and TP53 gene mutations are independent markers of reduced treatment-free and overall survival, respectively. Clin Cancer Res; 21(18); 4174–83. ©2015 AACR.
Published: 2015

25. Functional loss of IκBε leads to NF-κB deregulation in aggressive chronic lymphocytic leukemia

Author: Viktor Ljungström, Frederic Davi, Kostas Stamatopoulos, Diego Cortese, Nicholas Chiorazzi, Johan Rung, Šárka Pospíšilová, Xiao-Jie Yan, Antonia Kalushkova, Gunnar Juliusson, Karin E. Smedby, Gunilla Enblad, Jonathan C. Strefford, Karla Plevová, Sina Bondza, Lesley-Ann Sutton, Brigitta Sander, Linda Arngården, Rebeqa Gunnarsson, Anton W. Langerak, Larry Mansouri, Jimmy Larsson, Erin Young, Richard Rosenquist, Elin Falk-Sörqvist, Helena Jernberg-Wiklund, Marcus Lars Vittorio Nilsson, Alice F. Muggen, Paolo Ghia, Sujata Bhoi, Ola Söderberg, Chrysoula Belessi, Mats Hellström, Peter Lönn, Mansouri, L, Sutton, La, Ljungström, V, Bondza, S, Arngården, L, Bhoi, S, Larsson, J, Cortese, D, Kalushkova, A, Plevova, K, Young, E, Gunnarsson, R, Falk Sörqvist, E, Lönn, P, Muggen, Af, Yan, Xj, Sander, B, Enblad, G, Smedby, Ke, Juliusson, G, Belessi, C, Rung, J, Chiorazzi, N, Strefford, Jc, Langerak, Aw, Pospisilova, S, Davi, F, Hellström, M, Jernberg Wiklund, H, Ghia, PAOLO PROSPERO, Söderberg, O, Stamatopoulos, K, Nilsson, M, and Rosenquist, R.
Subjects: Cell- och molekylärbiologi, Chronic lymphocytic leukemia, Immunology, B-cell receptor, Biology, Frameshift mutation, 03 medical and health sciences, NFKBIE Gene, 0302 clinical medicine, hemic and lymphatic diseases, medicine, Humans, Immunology and Allergy, B cell, 030304 developmental biology, 0303 health sciences, Gene Expression Regulation, Leukemic, Brief Definitive Report, NF-kappa B, breakpoint cluster region, Hematology, medicine.disease, Leukemia, Lymphocytic, Chronic, B-Cell, NFKBIE, I-kappa B Kinase, 3. Good health, Leukemia, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Cancer research, Cell and Molecular Biology
Abstract: Mansouri et al. applied targeted deep sequencing to identify mutations within NF-κB core complex genes in CLL. NFKBIE, the gene encoding the inhibitory IκBε molecule, was most frequently mutated, especially in poor-prognostic subgroups of CLL. The authors show that NFKBIE mutations were associated with significantly reduced IkBε expression and p65 inhibition, ultimately leading to NF-κB activation and a more aggressive disease., NF-κB is constitutively activated in chronic lymphocytic leukemia (CLL); however, the implicated molecular mechanisms remain largely unknown. Thus, we performed targeted deep sequencing of 18 core complex genes within the NF-κB pathway in a discovery and validation CLL cohort totaling 315 cases. The most frequently mutated gene was NFKBIE (21/315 cases; 7%), which encodes IκBε, a negative regulator of NF-κB in normal B cells. Strikingly, 13 of these cases carried an identical 4-bp frameshift deletion, resulting in a truncated protein. Screening of an additional 377 CLL cases revealed that NFKBIE aberrations predominated in poor-prognostic patients and were associated with inferior outcome. Minor subclones and/or clonal evolution were also observed, thus potentially linking this recurrent event to disease progression. Compared with wild-type patients, NFKBIE-deleted cases showed reduced IκBε protein levels and decreased p65 inhibition, along with increased phosphorylation and nuclear translocation of p65. Considering the central role of B cell receptor (BcR) signaling in CLL pathobiology, it is notable that IκBε loss was enriched in aggressive cases with distinctive stereotyped BcR, likely contributing to their poor prognosis, and leading to an altered response to BcR inhibitors. Because NFKBIE deletions were observed in several other B cell lymphomas, our findings suggest a novel common mechanism of NF-κB deregulation during lymphomagenesis.
Published: 2015
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26. Recurrent mutations refine prognosis in chronic lymphocytic leukemia

Author: Kostas Stamatopoulos, Achilles Anagnostopoulos, Karin E. Smedby, Diego Cortese, Neus Villamor, Alba Navarro, C. Belessi, La. Sutton, E. Minga, Larry Mansouri, Gianluca Gaidano, Eugen Tausch, Paolo Ghia, Richard Rosenquist, Veronika Navrkalová, Šárka Pospíšilová, Jana Kminkova, Julio Delgado, Anastasia Hadzidimitriou, Lydia Scarfò, Gunnar Juliusson, Andreas Agathangelidis, Davide Rossi, Jonathan C. Strefford, Zadie Davis, Antonios M. Makris, Matthew J. J. Rose-Zerilli, David Oscier, Stephan Stilgenbauer, Panagiotis Baliakas, Elias Campo, Barbara Kantorová, Marta Larrayoz, Evangelia Stalika, Baliakas, P., Hadzidimitriou, A., Sutton, L. -A., Rossi, D., Minga, E., Villamor, N., Larrayoz, M., Kminkova, J., Agathangelidis, A., Davis, Z., Tausch, E., Stalika, E., Kantorova, B., Mansouri, L., Scarfo', L., Cortese, D., Navrkalova, V., Rose-Zerilli, M. J. J., Smedby, K. E., Juliusson, G., Anagnostopoulos, A., Makris, A. M., Navarro, A., Delgado, J., Oscier, D., Belessi, C., Stilgenbauer, S., Ghia, P., Pospisilova, S., Gaidano, G., Campo, E., Strefford, J. C., Stamatopoulos, K., and Rosenquist, R.
Subjects: Oncology, Male, Cancer Research, Time Factors, Chronic lymphocytic leukemia, DNA Mutational Analysis, medicine.disease_cause, 0302 clinical medicine, Recurrence, hemic and lymphatic diseases, Receptor, Notch1, 0303 health sciences, Mutation, Hematology, Middle Aged, Prognosis, 3. Good health, Europe, Leukemia, 030220 oncology & carcinogenesis, Female, RNA Splicing Factors, IGHV@, medicine.medical_specialty, Polymorphism, Single Nucleotide, 03 medical and health sciences, Cytogenetics, Internal medicine, medicine, Humans, Clinical significance, neoplasms, 030304 developmental biology, Aged, business.industry, Ribonucleoprotein, U2 Small Nuclear, medicine.disease, Phosphoproteins, Leukemia, Lymphocytic, Chronic, B-Cell, Lymphoma, Immunology, Multivariate Analysis, Tumor Suppressor Protein p53, business, Trisomy, Gene Deletion
Abstract: Through the European Research Initiative on chronic lymphocytic leukemia (CLL) (ERIC), we screened 3490 patients with CLL for mutations within the NOTCH1 (n=3334), SF3B1 (n=2322), TP53 (n=2309), MYD88 (n=1080) and BIRC3 (n=919) genes, mainly at diagnosis (75%) and before treatment (>90%). BIRC3 mutations (2.5%) were associated with unmutated IGHV genes (U-CLL), del(11q) and trisomy 12, whereas MYD88 mutations (2.2%) were exclusively found among M-CLL. NOTCH1, SF3B1 and TP53 exhibited variable frequencies and were mostly enriched within clinically aggressive cases. Interestingly, as the timespan between diagnosis and mutational screening increased, so too did the incidence of SF3B1 mutations; no such increase was observed for NOTCH1 mutations. Regarding the clinical impact, NOTCH1 mutations, SF3B1 mutations and TP53 aberrations (deletion/mutation, TP53ab) correlated with shorter time-to-first-treatment (P
Published: 2014
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27. The microenvironment in lymphomas--dissecting the complex crosstalk between tumor cells and 'by-stander' cells

Author: Frederic Davi, Paolo Ghia, Richard Rosenquist, Rosenquist, R, Davi, F, and Ghia, PAOLO PROSPERO
Subjects: Cancer Research, Tumor microenvironment, Stromal cell, Lymphocytosis, Lymphoma, Chronic lymphocytic leukemia, Biology, medicine.disease, Crosstalk (biology), Immune system, immune system diseases, hemic and lymphatic diseases, Immunology, Monoclonal, medicine, Tumor Microenvironment, Humans, medicine.symptom, Signal Transduction
Abstract: In lymphomas, it is increasingly apparent that the microenvironment is an essential player not only for lymphoma pathogenesis but also for disease progression and therapy resistance. In recent years, we have begun to understand the complex crosstalk between the neoplastic cells and other immune cells, such as T and NK cells, and stromal cells, as well as the signaling pathways that become aberrantly activated through this dialogue (e.g. B-cell receptor, Toll-like receptor and NF-kappa B signaling). In this series of reviews, the intricate interplay between lymphoma cells and 'by-stander' cells will be illustrated in representative lymphoma entities, namely Hodgkin lymphomas, follicular lymphomas, marginal-zone lymphomas, chronic lymphocytic leukemia, and T-cell lymphomas, where the crucial role played by the microenvironment has become particularly evident. Furthermore, important clues to the pathobiology of lymphomas have emerged from (i) the recognition of pre-malignant conditions, such as monoclonal B-cell lymphocytosis or in situ lymphomas, (ii) the identification of microbial and/or auto-antigens that are linked to particular entities, as well as (iii) the established increased risk of lymphomas in certain autoimmune/inflammatory conditions, all critical aspects that will be further elaborated in this thematic issue. Our increasing knowledge of these interactions and associations has finally allowed us to design targeted or immune-mediated strategies to interfere with the lymphoma microenvironment, thereby opening promising therapeutic avenues on the road to cure for these yet incurable diseases. (C) 2013 Elsevier Ltd. All rights reserved.
Published: 2013

28. Prognostic relevance of MYD88 mutations in CLL: the jury is still out

Author: Richard Rosenquist, Lesley-Ann Sutton, Davide Rossi, Paolo Ghia, Lydia Scarfò, Andreas Agathangelidis, Gianluca Gaidano, Šárka Pospíšilová, Jana Kminkova, Anastasia Hadzidimitriou, Kostas Stamatopoulos, Panagiotis Baliakas, Baliakas, P, Hadzidimitriou, A, Agathangelidis, A, Rossi, D, Sutton, La, Kminkova, J, Scarfo, L, Pospisilova, S, Gaidano, G, Stamatopoulos, K, Ghia, P, and Rosenquist, R
Subjects: Adult, Male, Chronic lymphocytic leukemia, Immunology, Kaplan-Meier Estimate, medicine.disease_cause, Biochemistry, Genome, 03 medical and health sciences, Exon, 0302 clinical medicine, hemic and lymphatic diseases, Biomarkers, Tumor, medicine, Humans, Gene, Aged, 030304 developmental biology, Aged, 80 and over, Genetics, 0303 health sciences, Mutation, business.industry, Cell Biology, Hematology, Middle Aged, Prognosis, medicine.disease, Leukemia, Lymphocytic, Chronic, B-Cell, 3. Good health, Leukemia, 030220 oncology & carcinogenesis, Myeloid Differentiation Factor 88, Female, business, IGHV@
Abstract: Genome surveys have offered a comprehensive view of the genetic landscape of chronic lymphocytic leukemia (CLL), identifying several recurrently mutated genes, including myeloid differentiation primary response 88 (MYD88). The predominant mutation concerns a p.L265P substitution within exon 5,1,2 which leads to constitutive nuclear factor kappaB stimulation, thus conferring a proliferation and survival advantage to the mutant cells.1 MYD88 mutations reach up to 2% to 5% in CLL and are strikingly enriched among patients expressing mutated IGHV genes (M-CLL).
Published: 2015

29. ERIC recommendations on IGHV gene mutational status analysis in chronic lymphocytic leukemia

Author: Chrysoula Belessi, S. Stilgenbauer, Carol Moreno, Paolo Ghia, Richard Rosenquist, Kostas Stamatopoulos, Frederic Davi, Freda K. Stevenson, Ghia, PAOLO PROSPERO, Stamatopoulos, K, Belessi, C, Moreno, C, Stilgenbauer, S, Stevenson, F, Davi, F, and Rosenquist, R.
Subjects: Cancer Research, International Cooperation, Chronic lymphocytic leukemia, education, Immunoglobulin Variable Region, hemic and lymphatic diseases, parasitic diseases, medicine, Humans, Mutational status, Gene, Genes, Immunoglobulin, business.industry, Hematology, medicine.disease, Leukemia, Lymphocytic, Chronic, B-Cell, Europe, Leukemia, Oncology, Mutation, Practice Guidelines as Topic, Immunology, Immunoglobulin Heavy Chains, business, IGHV@
Abstract: ERIC recommendations on IGHV gene mutational status analysis in chronic lymphocytic leukemia
Published: 2006

30. Stereotyped B-cell receptors in one-third of chronic lymphocytic leukemia: a molecular classification with implications for targeted therapies

Author: Lone Bredo Pedersen, Frederic Davi, Nikos Darzentas, Andreas Agathangelidis, Anton W. Langerak, Boris Tichy, Chrysoula Belessi, Karin E. Smedby, Lisa Bonello, Šárka Pospíšilová, Richard Rosenquist, Kostas Stamatopoulos, Ellen J. van Gastel-Mol, Nicola Cahill, Achilles Anagnostopoulos, Xiao-Jie Yan, Athanasios Tsaftaris, Christian H. Geisler, Agnieszka Janus, Charles C. Chu, Xavier Brochet, Cristina Tresoldi, Marie-Paule Lefranc, Hélène Merle-Béral, Gunnar Juliusson, Nikolaos Laoutaris, David Oscier, Jesper Jurlander, Paola Francia di Celle, Paolo Ghia, Fiona Murray, Anastasia Hadzidimitriou, Letizia Foroni, Zadie Davis, Nicholas Chiorazzi, Véronique Giudicelli, Agathangelidis, A, Darzentas, N, Hadzidimitriou, A, Brochet, X, Murray, F, Yan X., J, Davis, Z, van Gastel Mol, Ej, Tresoldi, C, Chu, Cc, Cahill, N, Giudicelli, V, Tichy, B, Pedersen, Lb, Foroni, L, Bonello, L, Janus, A, Smedby, K, Anagnostopoulos, A, Merle Beral, H, Laoutaris, N, Juliusson, G, Francia di Celle, P, Pospisilova, S, Jurlander, J, Geisler, C, Tsaftaris, A, Lefranc M., P, Langerak, Aw, Oscier, Dg, Chiorazzi, N, Belessi, C, Davi, F, Rosenquist, R, Ghia, PAOLO PROSPERO, Stamatopoulos K. Ghia P., is the corresponding author, and Immunology
Subjects: Chronic lymphocytic leukemia, B-cell receptor, Immunology, Molecular Sequence Data, Amino Acid Sequence, Gene Rearrangement, B-Lymphocyte, Humans, Immunoglobulin Heavy Chains, Immunoglobulin Variable Region, Immunophenotyping, Leukemia, Lymphocytic, Chronic, B-Cell, Models, Biological, Molecular Diagnostic Techniques, Receptors, Antigen, B-Cell, Somatic Hypermutation, Immunoglobulin, Molecular Targeted Therapy, Hematology, Biochemistry, Cell Biology, Somatic hypermutation, Computational biology, Biology, Models, hemic and lymphatic diseases, Receptors, medicine, Immunoglobulin, Chronic, Gene Rearrangement, Leukemia, Lymphoid Neoplasia, breakpoint cluster region, B-Lymphocyte, B-Cell, Gene rearrangement, medicine.disease, Biological, Somatic Hypermutation, Lymphocytic, Stereotypy (non-human), Antigen
Abstract: Mounting evidence indicates that grouping of chronic lymphocytic leukemia (CLL) into distinct subsets with stereotyped BCRs is functionally and prognostically relevant. However, several issues need revisiting, including the criteria for identification of BCR stereotypy and its actual frequency as well as the identification of “CLL-biased” features in BCR Ig stereotypes. To this end, we examined 7596 Ig VH (IGHV-IGHD-IGHJ) sequences from 7424 CLL patients, 3 times the size of the largest published series, with an updated version of our purpose-built clustering algorithm. We document that CLL may be subdivided into 2 distinct categories: one with stereotyped and the other with nonstereotyped BCRs, at an approximate ratio of 1:2, and provide evidence suggesting a different ontogeny for these 2 categories. We also show that subset-defining sequence patterns in CLL differ from those underlying BCR stereotypy in other B-cell malignancies. Notably, 19 major subsets contained from 20 to 213 sequences each, collectively accounting for 943 sequences or one-eighth of the cohort. Hence, this compartmentalized examination of VH sequences may pave the way toward a molecular classification of CLL with implications for targeted therapeutic interventions, applicable to a significant number of patients assigned to the same subset.
Published: 2012

31. Is there a role for antigen selection in mantle cell lymphoma? Immunogenetic support from a series of 807 cases

Author: Kheira Beldjord, Athanasios Tsaftaris, Arne Kolstad, Antonis Dagklis, Richard Rosenquist, Patricia J. T. A. Groenen, Nikos Darzentas, Theodora Papadaki, Christiane Pott, Anastasia Hadzidimitriou, Maurilio Ponzoni, Andreas Agathangelidis, Elias Campo, Christian H. Geisler, Fiona Murray, Paul D. M. Rombout, Martin Dreyling, Alba Navarro Lopez, Frederic Davi, Birgitta Sander, Marie Hélène Delfau-Larue, Kostas Stamatopoulos, Achilles Anagnostopoulos, Paolo Ghia, Lone Bredo Pedersen, Andreas Rosenwald, Penelope Mavragani-Tsipidou, Hadzidimitriou, A, Agathangelidis, A, Darzentas, N, Murray, F, Delfau Larue, Mh, Pedersen, Lb, Lopez, An, Dagklis, A, Rombout, P, Beldjord, K, Kolstad, A, Dreyling, Mh, Anagnostopoulos, A, Tsaftaris, A, Mavragani Tsipidou, P, Rosenwald, A, Ponzoni, Maurilio, Groenen, P, Ghia, PAOLO PROSPERO, Sander, B, Papadaki, T, Campo, E, Geisler, C, Rosenquist, R, Davi, F, Pott, C, and Stamatopoulos, K.
Subjects: Immunoglobulin gene, Chronic lymphocytic leukemia, Immunology, Molecular Sequence Data, Gene Rearrangement, B-Lymphocyte, Heavy Chain, Immunoglobulin Variable Region, Somatic hypermutation, Lymphoma, Mantle-Cell, Biology, Biochemistry, Cohort Studies, Epitopes, Translational research [ONCOL 3], medicine, Immunogenetics, Cluster Analysis, Humans, Amino Acid Sequence, Gene, Genetics, Genes, Immunoglobulin, Repertoire, Cell Biology, Hematology, Gene rearrangement, medicine.disease, Mantle cell lymphoma, IGHV@, Immunoglobulin Heavy Chains
Abstract: We examined 807 productive IGHV-IGHD-IGHJ gene rearrangements from mantle cell lymphoma (MCL) cases, by far the largest series to date. The IGHV gene repertoire was remarkably biased, with IGHV3-21, IGHV4-34, IGHV1-8, and IGHV3-23 accounting for 46.3% of the cohort. Eighty-four of 807 (10.4%) cases, mainly using the IGHV3-21 and IGHV4-34 genes, were found to bear stereotyped heavy complementarity-determining region 3 (VH CDR3) sequences and were placed in 38 clusters. Notably, the MCL stereotypes were distinct from those reported for chronic lymphocytic leukemia. Based on somatic hypermutation (SHM) status, 238/807 sequences (29.5%) carried IGHV genes with 100% germ line identity; the remainder (569/807; 70.5%) exhibited different SHM impact, ranging from minimal (in most cases) to pronounced. Shared replacement mutations across the IGHV gene were identified for certain subgroups, especially those using IGHV3-21, IGHV1-8, and IGHV3-23. Comparison with other entities, in particular CLL, revealed that several of these mutations were "MCL-biased." In conclusion, MCL is characterized by a highly restricted immunoglobulin gene repertoire with stereotyped VH CDR3s and very precise SHM targeting, strongly implying a role for antigen-driven selection of the clonogenic progenitors. Hence, an antigen-driven origin of MCL could be envisaged, at least for subsets of cases. (Blood. 2011; 118(11):3088-3095) We examined 807 productive IGHV-IGHD-IGHJ gene rearrangements from mantle cell lymphoma (MCL) cases, by far the largest series to date. The IGHV gene repertoire was remarkably biased, with IGHV3-21, IGHV4-34, IGHV1-8, and IGHV3-23 accounting for 46.3% of the cohort. Eighty-four of 807 (10.4%) cases, mainly using the IGHV3-21 and IGHV4-34 genes, were found to bear stereotyped heavy complementarity-determining region 3 (VH CDR3) sequences and were placed in 38 clusters. Notably, the MCL stereotypes were distinct from those reported for chronic lymphocytic leukemia. Based on somatic hypermutation (SHM) status, 238/807 sequences (29.5%) carried IGHV genes with 100% germ line identity; the remainder (569/807; 70.5%) exhibited different SHM impact, ranging from minimal (in most cases) to pronounced. Shared replacement mutations across the IGHV gene were identified for certain subgroups, especially those using IGHV3-21, IGHV1-8, and IGHV3-23. Comparison with other entities, in particular CLL, revealed that several of these mutations were "MCL-biased." In conclusion, MCL is characterized by a highly restricted immunoglobulin gene repertoire with stereotyped VH CDR3s and very precise SHM targeting, strongly implying a role for antigen-driven selection of the clonogenic progenitors. Hence, an antigen-driven origin of MCL could be envisaged, at least for subsets of cases. (Blood. 2011; 118(11):3088-3095)
Published: 2011

32. Immunoglobulin sequence analysis and prognostication in CLL: guidelines from the ERIC review board for reliable interpretation of problematic cases

Author: Kathleen N. Potter, A. Hadzidimitriou, Frederic Davi, Anthonie Willem Langerak, Richard Rosenquist, Paolo Ghia, C. Belessi, Fiona Murray, K. Stamatopoulos, Langerak, Aw, Davi, F, Ghia, PAOLO PROSPERO, Hadzidimitriou, A, Murray, F, Potter, Kn, Rosenquist, R, Stamatopoulos, K, Belessi C. Ghia P., is the corresponding author, and Immunology
Subjects: Immunoglobulin gene, Cancer Research, business.industry, European research, Interpretation (philosophy), Immunoglobulins, Hematology, Reference Standards, Prognosis, Data science, Leukemia, Lymphocytic, Chronic, B-Cell, Oncology, hemic and lymphatic diseases, Immunology, Medicine, Humans, business, IGHV@, Reference standards, Sequence Analysis
Abstract: prognostication in chronic lymphocytic leukemia (CLL) and the definition of standardized procedures has allowed reliable and reproducible results. Occasionally, a straightforward interpretation of the sequences is not possible because of the so-called 'problematic sequences' that do not fit the 'classic' interpretation and pose scientific questions at the cross-road between hematology and immunology. Thanks to a dedicated effort within the European Research Initiative on CLL (ERIC), we have now the possibility to present such cases, offer a scientific explanation and propose recommendations in terms of prognostication. Leukemia (2011) 25, 979-984; doi:10.1038/leu.2011.49; published online 1 April 2011
Published: 2011

33. Determination of IGHV gene mutational status in chronic lymphocytic leukemia: bioinformatics advances meet clinical needs

Author: Frederic Davi, Kostas Stamatopoulos, Paolo Ghia, Richard Rosenquist, Chrysoula Belessi, Davi, F, Rosenquist, R, Ghia, PAOLO PROSPERO, Belessi, C, and Stamatopoulos, K.
Subjects: Cancer Research, business.industry, Chronic lymphocytic leukemia, Genes, Immunoglobulin Heavy Chain, Immunoglobulin Variable Region, Computational Biology, Hematology, Bioinformatics, medicine.disease, Leukemia, Lymphocytic, Chronic, B-Cell, Oncology, Mutation, Medicine, Mutational status, Humans, business, IGHV@, Gene
Abstract: Determination of IGHV gene mutational status in chronic lymphocytic leukemia: bioinformatics advances meet clinical needs
Published: 2007

34. Evidence for the Significant Role of Immunoglobulin Light Chains in Antigen Recognition and Selection in Chronic Lymphocytic Leukemia

Author: Cristina Tresoldi, Frederic Davi, Tanja Smilevska, Nikolaos Laoutaris, Anastasia Hadzidimitriou, Richard Rosenquist, Athanasios Tsaftaris, Eleni Arvaniti, Nikos Darzentas, Paolo Ghia, Chrysoula Belessi, Kostas Stamatopoulos, Fiona Murray, Achilles Anagnostopoulos, Hadzidimitriou, A, Darzentas, N, Murray, F, Smilevska, T, Arvaniti, E, Tresoldi, C, Tsaftaris, A, Laoutaris, N, Anagnostopoulos, A, Davi, F, Ghia, PAOLO PROSPERO, Rosenquist, R, Stamatopoulos, K, and Belessi C. Ghia P., is the corresponding author
Subjects: Male, Chronic lymphocytic leukemia, Immunology, Immunoglobulin Variable Region, Somatic hypermutation, Receptors, Antigen, B-Cell, Immunoglobulin light chain, medicine.disease_cause, Immunoglobulin kappa-Chains, Biochemistry, Immunoglobulin lambda-Chains, hemic and lymphatic diseases, medicine, Humans, Genetics, Mutation, biology, Gene Expression Regulation, Leukemic, Receptor editing, Gene rearrangement, Cell Biology, Hematology, medicine.disease, Molecular biology, Leukemia, Lymphocytic, Chronic, B-Cell, Neoplasm Proteins, Amino Acid Substitution, biology.protein, Female, Binding Sites, Antibody, Somatic Hypermutation, Immunoglobulin, Antibody
Abstract: The chronic lymphocytic leukemia (CLL) immunoglobulin (IG) heavy chain repertoire is known to display biased immunoglobulin variable heavy-chain (IGHV) gene usage, remarkable complementarity determining region 3 (HCDR3) stereotypy as well as distinctive somatic hypermutation (SHM) patterns, at least for subsets of cases. Our aim in the present study was to similarly investigate the IG light chain (LC) genes in terms of mutation frequency and targeting and CDR3 stereotypy to elucidate if the LC may play a significant complementary role in antigen recognition in CLL. We thus examined SHM patterns and secondary rearrangements of the IG LC gene loci in a total of 612 IGKV-J and 279 IGLV-J rearrangements from 725 patients with CLL. Firstly, we observed a highly restricted light chain gene usage in the vast majority of CLL cases with stereotyped HCDR3s. In particular, stereotyped IGHV3-21 CLL cases were characterized by a strikingly biased expression of lambda light chains utilizing the IGLV3-21 gene (36/37 cases of subset#2), whereas all 15 subset #4 cases with stereotyped IGHV4-34 IGs carried an IGKV2-30 rearrangement. In addition, subset-biased light chain CDR3 motifs were identified in groups of sequences utilizing the same IGKV or IGLV gene. For example, all 30 IGKV1-39/1D-39 light chains of subset#1 (using stereotyped IGHV1/5/7 genes) carried notably long KCDR3s (10–11 amino acids) generated by significant N region addition and characterized by the frequent introduction of a junctional proline (26/30 cases). Important differences regarding mutational load were observed in groups of sequences utilizing the same IGKV or IGLV gene and/or belonging to subsets with stereotyped B cell receptors (BCRs). In fact, significant differences were observed with regard to mutational status among groups of sequences utilizing different alleles of certain IGK/LV genes (specifically the IGKV1-5, IGLV1-51 and IGLV3-21 genes). At cohort level, the SHM patterns were typical of a canonical SHM process. A clustering of R mutations in KCDR1 was evident for all IGKV subgroups with the notable exception of the IGKV2 subgroup, which exhibited preferential targeting to the KCDR2, especially in IGKV2-30 rearrangements of cases with stereotyped IGHV4-34/IGKV2-30 BCRs (subset#4). Recurrent amino acid changes at certain positions across the entire IGKV/IGLV sequence were observed at a high frequency (27–67% of cases) in a number of stereotyped subsets, especially those expressing the IGHV3-21/IGLV3-21 BCR (subset #2) and the IGHV4-34/IGKV2-30 BCR (subset #4). Comparison with CLL LC sequences carrying heterogeneous K/LCDR3s or non-CLL LC sequences revealed that these distinct amino acid changes are greatly under-represented in such groups and appear therefore to be “subset-biased”. Finally, a significant proportion of CLL cases (63 cases; 26 kappa- and 37 lambda-expressing) with monotypic LC expression were found to carry multiple potentially functional LC rearrangements. Of note, nineteen of these 63 cases (30%) belonged to subsets with stereotyped BCRs. This finding alludes to the possibility of secondary rearrangements most likely occurring in the context of (auto)antigen-driven receptor editing, particularly in the case of stereotyped subsets. In conclusion, SHM targeting in CLL LCs appears to be just as precise and, most likely, functionally driven as in heavy chains. Secondary LC gene rearrangements and subset-biased mutations in CLL LC genes are strong indications that LCs are crucial in shaping the specificity of leukemic BCRs, in association with defined heavy chains. Therefore, CLL is characterized not only by stereotyped HCDR3 and heavy chains but, rather, by stereotyped BCRs involving both chains, which create distinctive antigen binding grooves.
Published: 2008

35. IgG-Switched CLL Has a Distinct Immunogenetic Signature from the Common MD Variant: Ontogenetic Implications

Author: Paolo Ghia, Richard Rosenquist, Lesley-Ann Sutton, Maria Chatzouli, Chrysoula Belessi, Nikos Darzentas, Anna Vardi, Larry Mansouri, Vassiliki Douka, Lydia Scarfò, Andreas Agathangelidis, Kostas Stamatopoulos, Achilles Anagnostopoulos, Vardi, A, Agathangelidis, A, Sutton, La, Chatzouli, M, Scarfo, L, Mansouri, L, Douka, V, Anagnostopoulos, A, Darzentas, N, Rosenquist, R, Ghia, PAOLO PROSPERO, Belessi, C, and Stamatopoulos, K.
Subjects: Adult, Male, Cancer Research, Chronic lymphocytic leukemia, B-cell receptor, Immunoglobulin Variable Region, Somatic hypermutation, Receptors, Antigen, B-Cell, Somatic evolution in cancer, Immunoglobulin D, 03 medical and health sciences, 0302 clinical medicine, immune system diseases, hemic and lymphatic diseases, medicine, Immunogenetics, Humans, Gene Rearrangement, B-Lymphocyte, neoplasms, Gene, 030304 developmental biology, Aged, Genetics, Aged, 80 and over, 0303 health sciences, biology, Repertoire, Middle Aged, medicine.disease, Leukemia, Lymphocytic, Chronic, B-Cell, 3. Good health, Oncology, Immunoglobulin M, 030220 oncology & carcinogenesis, Immunoglobulin G, biology.protein, Female, Somatic Hypermutation, Immunoglobulin, Antibody, Immunoglobulin Heavy Chains
Abstract: Purpose: Immunoglobulin G–switched chronic lymphocytic leukemia (G-CLL) is a rare variant of CLL, whose origin and ontogenetic relationship to the common IgM/IgD (MD-CLL) variant remains undefined. Here, we sought for clues about the ontogeny of G-CLL versus MD-CLL by profiling the relevant IG gene repertoires. Experimental Design: Using purpose-built bioinformatics methods, we performed detailed immunogenetic profiling of a multinational CLL cohort comprising 1,256 cases, of which 1,087 and 169 expressed IG mu/delta and gamma heavy chains, respectively. Results: G-CLL has a highly skewed IG gene repertoire that is distinct from MD-CLL, especially in terms of (i) overuse of the IGHV4-34 and IGHV4-39 genes and (ii) differential somatic hypermutation (SHM) load. Repertoire differences were also found when comparing subgroups with similar SHM status and were mainly attributed to the exclusive representation in G-CLL of two major subsets with quasi-identical (stereotyped) B-cell receptors. These subsets, namely #4 (IGHV4-34/IGKV2-30) and #8 (IGHV4-39/IGKV1(D)-39), were found to display sharply contrasting SHM and clinical behavior. Conclusions: G-CLL exhibits an overall distinct immunogenetic signature from MD-CLL, prompting speculations about distinct ontogenetic derivation and/or immune triggering. The reasons underlying the differential regulation of SHM among G-CLL cases remain to be elucidated. Clin Cancer Res; 20(2); 323–30. ©2013 AACR.
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36. Immunoglobulin heavy variable (IGHV) genes and alleles: new entities, new names and implications for research and prognostication in chronic lymphocytic leukaemia

Author: Nikos Maglaveras, Alessandra Tedeschi, Kostas Stamatopoulos, Ioannis Vlahavas, Nicholas Chiorazzi, E. Minga, Ioanna Chouvarda, Livio Trentin, Christian H. Geisler, Nikos Darzentas, Diane F. Jelinek, Andreas Agathangelidis, Aliki Xochelli, Panagiotis Baliakas, Panagiotis Panagiotidis, Véronique Giudicelli, Ioannis Kavakiotis, Anastasia Hadzidimitriou, Marie-Paule Lefranc, Chrysoula Belessi, Lisa Bonello, Fred Davi, Paolo Ghia, Richard Rosenquist, Anton W. Langerak, Lesley-Ann Sutton, Šárka Pospíšilová, David Oscier, Institute of Applied Biosciences, Institut de génétique humaine (IGH), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Computer Science Department, Aristotle University of Thessaloniki, Xochelli, A, Agathangelidis, A, Kavakiotis, I, Minga, E, Sutton, La, Baliakas, P, Chouvarda, I, Giudicelli, V, Vlahavas, I, Maglaveras, N, Bonello, L, Trentin, L, Tedeschi, A, Panagiotidis, P, Geisler, C, Langerak, Aw, Pospisilova, S, Jelinek, Df, Oscier, D, Chiorazzi, N, Darzentas, N, Davi, F, Ghia, PAOLO PROSPERO, Rosenquist, R, Hadzidimitriou, A, Belessi, C, Lefranc, Mp, Stamatopoulos, K., and Immunology
Subjects: IGHV, Immunology, Somatic hypermutation, CLL, New IGHV gene alleles, New IGHV genes, Prognostication, SHM, Alleles, Amino Acid Sequence, Complementarity Determining Regions, Humans, Leukemia, Lymphocytic, Chronic, B-Cell, Mutation, Sequence Alignment, Prognosis, Genetics, Medicine (all), Sequence alignment, Immunogenetics, Biology, Germline, Chronic, Allele, Gene, ComputingMilieux_MISCELLANEOUS, [SDV.GEN]Life Sciences [q-bio]/Genetics, Leukemia, B-Cell, IGHV, chronic lymphocytic leukaemia, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], Lymphocytic, Human genetics, 3. Good health, IGHV@, chronic lymphocytic leukaemia
Abstract: Ieext generation sequencing studies in Homo sapiens have identified novel immunoglobulin heavy variable (IGHV) genes and alleles necessitating changes in the international ImMunoGeneTics information system (IMGT) GENE-DB and reference directories of IMGT/V-QUEST. In chronic lymphocytic leukaemia (CLL), the somatic hypermutation (SHM) status of the clonotypic rearranged IGHV gene is strongly associated with patient outcome. Correct determination of this parameter strictly depends on the comparison of the nucleotide sequence of the clonotypic rearranged IGHV gene with that of the closest germline counterpart. Consequently, changes in the reference directories could, in principle, affect the correct interpretation of the IGHV mutational status in CLL. To this end, we analyzed 8066 productive IG heavy chain (IGH) rearrangement sequences from our consortium both before and after the latest update of the IMGT/V-QUEST reference directory. Differences were identified in 405 cases (5 % of the cohort). In 291/405 sequences (71.9 %), changes concerned only the IGHV gene or allele name, whereas a change in the percent germline identity (%GI) was noted in 114/405 (28.1 %) sequences; in 50/114 (43.8 %) sequences, changes in the %GI led to a change in the mutational set. In conclusion, recent changes in the IMGT reference directories affected the interpretation of SHM in a sizeable number of IGH rearrangement sequences from CLL patients. This indicates that both physicians and researchers should consider a re-evaluation of IG sequence data, especially for those IGH rearrangement sequences that, up to date, have a GI close to 98 %, where caution is warranted.
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37. MDM2 promotor polymorphism and disease characteristics in chronic lymphocytic leukemia: results of an individual patient data-based meta-analysis

Author: Davide Rossi, Gianluca Gaidano, Peter Söderkvist, Richard Greil, Paolo Ghia, Šárka Pospíšilová, Hartmut Döhner, Richard Rosenquist, Aneela Majid, Anton Parker, Šárka Pavlová, Gareth L. Bond, Stephan Stilgenbauer, Mohd Arifin Kaderi, David Oscier, Zuzana Tvaruzkova, Axel Benner, Emili Montserrat, Thorsten Zenz, Larry Mansouri, Holger Nückel, Olaf Merkel, Ulrich Dührsen, Kerstin Willander, Martin J. S. Dyer, Mats Linderholm, Benner, A, Mansouri, L, Rossi, D, Majid, A, Willander, K, Parker, A, Bond, G, Pavlova, S, Nückel, H, Merkel, O, Ghia, PAOLO PROSPERO, Montserrat, E, Kaderi, Ma, Rosenquist, R, Gaidano, G, Dyer, Mj, Söderkvist, P, Linderholm, M, Oscier, D, Tvaruzkova, Z, Pospisilova, S, Dührsen, U, Greil, R, Döhner, H, Stilgenbauer, S, Zenz, T., and Universitat de Barcelona
Subjects: Oncology, Adult, Male, medicine.medical_specialty, Databases, Factual, Chronic lymphocytic leukemia, Medizin, Single-nucleotide polymorphism, Disease, Biology, Polymorphism, Single Nucleotide, Cohort Studies, 03 medical and health sciences, Young Adult, 0302 clinical medicine, Internal medicine, Genotype, medicine, Genetics, Humans, Adults, Leucèmia limfocítica crònica, Promoter Regions, Genetic, Guideline Articles, 030304 developmental biology, Aged, Aged, 80 and over, 0303 health sciences, Proto-Oncogene Proteins c-mdm2, Hematology, Middle Aged, medicine.disease, Adulthood, Leukemia, Lymphocytic, Chronic, B-Cell, 3. Good health, Log-rank test, Estudi de casos, 030220 oncology & carcinogenesis, Meta-analysis, Cohort, Immunology, Female, Case studies, Genètica, Cohort study
Abstract: A number of single nucleotide polymorphisms have been associated with disease predisposition in chronic lymphocytic leukemia. A single nucleotide polymorphism in the MDM2 promotor region, MDM2SNP309, was shown to soothe the p53 pathway. In the current study, we aimed to clarify the effect of the MDM2SNP309 on chronic lymphocytic leukemia characteristics and outcome. We performed a meta-analysis of data from 2598 individual patients from 10 different cohorts. Patients’ data and genetic analysis for MDM2SNP309 genotype, immunoglobulin heavy chain variable region mutation status and fluorescence in situ hybridization results were collected. There were no differences in overall survival based on the polymorphism (log rank test, stratified by study cohort; P=0.76; GG genotype: cohort-adjusted median overall survival of 151 months; TG: 153 months; TT: 149 months). In a multivariable Cox proportional hazards regression analysis, advanced age, male sex and unmutated immunoglobulin heavy chain variable region genes were associated with inferior survival, but not the MDM2 genotype. The MDM2SNP309 is unlikely to influence disease characteristics and prognosis in chronic lymphocytic leukemia. Studies investigating the impact of individual single nucleotide polymorphisms on prognosis are often controversial. This may be due to selection bias and small sample size. A meta-analysis based on individual patient data provides a reasonable strategy for prognostic factor analyses in the case of small individual studies. Individual patient data-based meta-analysis can, therefore, be a powerful tool to assess genetic risk factors in the absence of large studies.
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