Different prognostic impact of recurrent gene mutations in chronic lymphocytic leukemia depending on IGHV gene somatic hypermutation status: a study by ERIC in HARMONY
Por:
Mansouri L, Thorvaldsdottir B, Sutton LA, Karakatsoulis G, Meggendorfer M, Parker H, Nadeu F, Brieghel C, Laidou S, Moia R, Rossi D, Catherwood M, Kotaskova J, Delgado J, Rodríguez-Vicente AE, Benito R, Rigolin GM, Bonfiglio S, Scarfo L, Mattsson M, Davis Z, Gogia A, Rani L, Baliakas P, Foroughi-Asl H, Jylhä C, Skaftason A, Rapado I, Miras F, Martinez-Lopez J, de la Serna J, Rivas JMH, Thornton P, Larráyoz MJ, Calasanz MJ, Fésüs V, Mátrai Z, Bödör C, Smedby KE, Espinet B, Puiggros A, Gupta R, Bullinger L, Bosch F, Tazón-Vega B, Baran-Marszak F, Oscier D, N'Guyen-Khac F, Zenz T, Terol MJ, Cuneo A, Hernández-Sánchez M, Pospisilova S, Mills K, Gaidano G, Niemann CU, Campo E, Strefford JC, Ghia P, Stamatopoulos K, Rosenquist R
Publicada:
1 feb 2023
Ahead of Print:
1 dic 2022
Resumen:
Recent evidence suggests that the prognostic impact of gene mutations in patients with chronic lymphocytic leukemia (CLL) may differ depending on the immunoglobulin heavy variable (IGHV) gene somatic hypermutation (SHM) status. In this study, we assessed the impact of nine recurrently mutated genes (BIRC3, EGR2, MYD88, NFKBIE, NOTCH1, POT1, SF3B1, TP53, and XPO1) in pre-treatment samples from 4580 patients with CLL, using time-to-first-treatment (TTFT) as the primary end-point in relation to IGHV gene SHM status. Mutations were detected in 1588 (34.7%) patients at frequencies ranging from 2.3-9.8% with mutations in NOTCH1 being the most frequent. In both univariate and multivariate analyses, mutations in all genes except MYD88 were associated with a significantly shorter TTFT. In multivariate analysis of Binet stage A patients, performed separately for IGHV-mutated (M-CLL) and unmutated CLL (U-CLL), a different spectrum of gene alterations independently predicted short TTFT within the two subgroups. While SF3B1 and XPO1 mutations were independent prognostic variables in both U-CLL and M-CLL, TP53, BIRC3 and EGR2 aberrations were significant predictors only in U-CLL, and NOTCH1 and NFKBIE only in M-CLL. Our findings underscore the need for a compartmentalized approach to identify high-risk patients, particularly among M-CLL patients, with potential implications for stratified management.
Filiaciones:
Mansouri L:
Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
Thorvaldsdottir B:
Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
Sutton LA:
Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
Karakatsoulis G:
Centre for Research and Technology Hellas, Institute of Applied Biosciences, Thessaloniki, Greece
Department of Mathematics, University of Ioannina, Ioannina, Greece
Meggendorfer M:
MLL Munich Leukemia Laboratory, Munich, Germany
Parker H:
Cancer Genomics, School for Cancer Sciences, Faculty of Medicine, University of Southampton, Southampton, UK
Nadeu F:
Institut d'Investigacions Biomèdiques August Pi I Sunyer (IDIBAPS), Barcelona, Spain
Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain
Brieghel C:
Department of Hematology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
Laidou S:
Centre for Research and Technology Hellas, Institute of Applied Biosciences, Thessaloniki, Greece
Moia R:
Division of Hematology, Department of Translational Medicine, Università del Piemonte Orientale, Novara, Italy
Rossi D:
Division of Hematology, Oncology Institute of Southern Switzerland, Bellinzona, Switzerland
Laboratory of Experimental Hematology, Institute of Oncology Research, Bellinzona, Switzerland
Catherwood M:
Patrick G Johnston Centre for Cancer Research, Queen's University Belfast, Belfast, UK
Kotaskova J:
Department of Internal Medicine-Hematology and Oncology, University Hospital Brno, Brno, Czech Republic
Faculty of Medicine, Masaryk University, Brno, Czech Republic
Central European Institute of Technology, Masaryk University, Brno, Czech Republic
Delgado J:
Institut d'Investigacions Biomèdiques August Pi I Sunyer (IDIBAPS), Barcelona, Spain
Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain
Hospital Clinic of Barcelona, Barcelona, Spain
Universitat de Barcelona, Barcelona, Spain
Rodríguez-Vicente AE:
Cancer Research Center (IBMCC) CSIC-University of Salamanca, Salamanca, Spain
Instituto de Investigación Biomédica (IBSAL), Salamanca, Spain
Department of Hematology, University Hospital of Salamanca, Salamanca, Spain
Benito R:
Cancer Research Center (IBMCC) CSIC-University of Salamanca, Salamanca, Spain
Instituto de Investigación Biomédica (IBSAL), Salamanca, Spain
Department of Hematology, University Hospital of Salamanca, Salamanca, Spain
Rigolin GM:
Hematology-Department of Medical Sciences, University of Ferrara, Ferrara, Italy
Bonfiglio S:
Università Vita Salute San Raffaele and IRCCS Ospedale San Raffaele, Milano, Italy
Scarfo L:
Università Vita Salute San Raffaele and IRCCS Ospedale San Raffaele, Milano, Italy
Mattsson M:
Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
Davis Z:
Molecular Pathology Department, University Hospitals Dorset, Bournemouth, UK
Gogia A:
All India Institute of Medical Sciences (AIIMS), New Delhi, India
Rani L:
All India Institute of Medical Sciences (AIIMS), New Delhi, India
Baliakas P:
Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
Foroughi-Asl H:
Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
Jylhä C:
Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
Skaftason A:
Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
Rapado I:
Hospital Universitario 12 Octubre, Madrid, Spain
Spanish National Cancer Research (CNIO), Madrid, Spain
Miras F:
Hospital Universitario 12 Octubre, Madrid, Spain
Martinez-Lopez J:
Hospital Universitario 12 Octubre, Madrid, Spain
Spanish National Cancer Research (CNIO), Madrid, Spain
de la Serna J:
Hospital Universitario 12 Octubre, Madrid, Spain
Spanish National Cancer Research (CNIO), Madrid, Spain
Rivas JMH:
Cancer Research Center (IBMCC) CSIC-University of Salamanca, Salamanca, Spain
Instituto de Investigación Biomédica (IBSAL), Salamanca, Spain
Department of Hematology, University Hospital of Salamanca, Salamanca, Spain
Thornton P:
Haematology Department, Beaumont Hospital, Dublin, Ireland
Larráyoz MJ:
Hematological Diseases Laboratory, CIMA LAB Diagnostics, University of Navarra, Pamplona, Spain
IdiSNA, Navarra Institute for Health Research, Pamplona, Spain
Calasanz MJ:
Hematological Diseases Laboratory, CIMA LAB Diagnostics, University of Navarra, Pamplona, Spain
IdiSNA, Navarra Institute for Health Research, Pamplona, Spain
Fésüs V:
HCEMM-SE Molecular Oncohematology Research Group, Department of Pathology and Experimental Cancer Research, Semmelweis University, Budapest, Hungary
Mátrai Z:
Central Hospital of Southern Pest-National Institute of Hematology and Infectious Diseases, Budapest, Hungary
Bödör C:
HCEMM-SE Molecular Oncohematology Research Group, Department of Pathology and Experimental Cancer Research, Semmelweis University, Budapest, Hungary
Smedby KE:
Clinical Epidemiology Division, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden
Espinet B:
Molecular Cytogenetics Laboratory, Pathology Department, Hospital del Mar and Translational Research on Hematological Neoplasms Group, Hospital del Mar Research Institute (IMIM), Barcelona, Spain
Puiggros A:
Molecular Cytogenetics Laboratory, Pathology Department, Hospital del Mar and Translational Research on Hematological Neoplasms Group, Hospital del Mar Research Institute (IMIM), Barcelona, Spain
Gupta R:
All India Institute of Medical Sciences (AIIMS), New Delhi, India
Bullinger L:
Department of Hematology, Oncology and Cancer Immunology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, Germany
Bosch F:
Department of Hematology, Hospital Universitari Vall d'Hebron (HUVH), Experimental Hematology, Vall d'Hebron Institute of Oncology (VHIO), Department of Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain
Tazón-Vega B:
Department of Hematology, Hospital Universitari Vall d'Hebron (HUVH), Experimental Hematology, Vall d'Hebron Institute of Oncology (VHIO), Department of Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain
Baran-Marszak F:
Service d'hématologie Biologique Hôpital Avicenne Assistance Publique des Hôpitaux de Paris, Bobigny, France
Oscier D:
Molecular Pathology Department, University Hospitals Dorset, Bournemouth, UK
N'Guyen-Khac F:
Sorbonne Université, Service d'Hématologie Clinique, Hôpital Pitié-Salpêtrière, APHP, Paris, France
Zenz T:
Department of Oncology and Haematology, University Hospital and University of Zurich, Zurich, Switzerland
Terol MJ:
Department of Hematology, INCLIVA Research Insitute, University of Valencia, Valencia, Spain
Cuneo A:
Hematology-Department of Medical Sciences, University of Ferrara, Ferrara, Italy
Hernández-Sánchez M:
Cancer Research Center (IBMCC) CSIC-University of Salamanca, Salamanca, Spain
Instituto de Investigación Biomédica (IBSAL), Salamanca, Spain
Department of Hematology, University Hospital of Salamanca, Salamanca, Spain
Pospisilova S:
Department of Internal Medicine-Hematology and Oncology, University Hospital Brno, Brno, Czech Republic
Faculty of Medicine, Masaryk University, Brno, Czech Republic
Central European Institute of Technology, Masaryk University, Brno, Czech Republic
Mills K:
Patrick G Johnston Centre for Cancer Research, Queen's University Belfast, Belfast, UK
Gaidano G:
Division of Hematology, Department of Translational Medicine, Università del Piemonte Orientale, Novara, Italy
Niemann CU:
Department of Hematology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
Campo E:
Institut d'Investigacions Biomèdiques August Pi I Sunyer (IDIBAPS), Barcelona, Spain
Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain
Hospital Clinic of Barcelona, Barcelona, Spain
Universitat de Barcelona, Barcelona, Spain
Strefford JC:
Cancer Genomics, School for Cancer Sciences, Faculty of Medicine, University of Southampton, Southampton, UK
Ghia P:
Università Vita Salute San Raffaele and IRCCS Ospedale San Raffaele, Milano, Italy
Stamatopoulos K:
Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
Centre for Research and Technology Hellas, Institute of Applied Biosciences, Thessaloniki, Greece
Rosenquist R:
Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
Clinical Genetics, Karolinska University Hospital, Solna, Sweden.
Green Published, hybrid
FULL TEXT
 |
Published Version |
|
| No Accesible |
|