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Different prognostic impact of recurrent gene mutations in chronic lymphocytic leukemia depending on IGHV gene somatic hypermutation status: a study by ERIC in HARMONY
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...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9898037/ https://www.ncbi.nlm.nih.gov/pubmed/36566271 http://dx.doi.org/10.1038/s41375-022-01802-y |
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author | Mansouri, Larry Thorvaldsdottir, Birna Sutton, Lesley-Ann Karakatsoulis, Georgios Meggendorfer, Manja Parker, Helen Nadeu, Ferran Brieghel, Christian Laidou, Stamatia Moia, Riccardo Rossi, Davide Catherwood, Mark Kotaskova, Jana Delgado, Julio Rodríguez-Vicente, Ana E. Benito, Rocío Rigolin, Gian Matteo Bonfiglio, Silvia Scarfo, Lydia Mattsson, Mattias Davis, Zadie Gogia, Ajay Rani, Lata Baliakas, Panagiotis Foroughi-Asl, Hassan Jylhä, Cecilia Skaftason, Aron Rapado, Inmaculada Miras, Fatima Martinez-Lopez, Joaquín de la Serna, Javier Rivas, Jesús María Hernández Thornton, Patrick Larráyoz, María José Calasanz, María José Fésüs, Viktória Mátrai, Zoltán Bödör, Csaba Smedby, Karin E. Espinet, Blanca Puiggros, Anna Gupta, Ritu Bullinger, Lars Bosch, Francesc Tazón-Vega, Bárbara Baran-Marszak, Fanny Oscier, David Nguyen-Khac, Florence Zenz, Thorsten Terol, Maria Jose Cuneo, Antonio Hernández-Sánchez, María Pospisilova, Sarka Mills, Ken Gaidano, Gianluca Niemann, Carsten U. Campo, Elias Strefford, Jonathan C. Ghia, Paolo Stamatopoulos, Kostas Rosenquist, Richard |
author_facet | Mansouri, Larry Thorvaldsdottir, Birna Sutton, Lesley-Ann Karakatsoulis, Georgios Meggendorfer, Manja Parker, Helen Nadeu, Ferran Brieghel, Christian Laidou, Stamatia Moia, Riccardo Rossi, Davide Catherwood, Mark Kotaskova, Jana Delgado, Julio Rodríguez-Vicente, Ana E. Benito, Rocío Rigolin, Gian Matteo Bonfiglio, Silvia Scarfo, Lydia Mattsson, Mattias Davis, Zadie Gogia, Ajay Rani, Lata Baliakas, Panagiotis Foroughi-Asl, Hassan Jylhä, Cecilia Skaftason, Aron Rapado, Inmaculada Miras, Fatima Martinez-Lopez, Joaquín de la Serna, Javier Rivas, Jesús María Hernández Thornton, Patrick Larráyoz, María José Calasanz, María José Fésüs, Viktória Mátrai, Zoltán Bödör, Csaba Smedby, Karin E. Espinet, Blanca Puiggros, Anna Gupta, Ritu Bullinger, Lars Bosch, Francesc Tazón-Vega, Bárbara Baran-Marszak, Fanny Oscier, David Nguyen-Khac, Florence Zenz, Thorsten Terol, Maria Jose Cuneo, Antonio Hernández-Sánchez, María Pospisilova, Sarka Mills, Ken Gaidano, Gianluca Niemann, Carsten U. Campo, Elias Strefford, Jonathan C. Ghia, Paolo Stamatopoulos, Kostas Rosenquist, Richard |
author_sort | Mansouri, Larry |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-9898037 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-98980372023-02-05 Different prognostic impact of recurrent gene mutations in chronic lymphocytic leukemia depending on IGHV gene somatic hypermutation status: a study by ERIC in HARMONY Mansouri, Larry Thorvaldsdottir, Birna Sutton, Lesley-Ann Karakatsoulis, Georgios Meggendorfer, Manja Parker, Helen Nadeu, Ferran Brieghel, Christian Laidou, Stamatia Moia, Riccardo Rossi, Davide Catherwood, Mark Kotaskova, Jana Delgado, Julio Rodríguez-Vicente, Ana E. Benito, Rocío Rigolin, Gian Matteo Bonfiglio, Silvia Scarfo, Lydia Mattsson, Mattias Davis, Zadie Gogia, Ajay Rani, Lata Baliakas, Panagiotis Foroughi-Asl, Hassan Jylhä, Cecilia Skaftason, Aron Rapado, Inmaculada Miras, Fatima Martinez-Lopez, Joaquín de la Serna, Javier Rivas, Jesús María Hernández Thornton, Patrick Larráyoz, María José Calasanz, María José Fésüs, Viktória Mátrai, Zoltán Bödör, Csaba Smedby, Karin E. Espinet, Blanca Puiggros, Anna Gupta, Ritu Bullinger, Lars Bosch, Francesc Tazón-Vega, Bárbara Baran-Marszak, Fanny Oscier, David Nguyen-Khac, Florence Zenz, Thorsten Terol, Maria Jose Cuneo, Antonio Hernández-Sánchez, María Pospisilova, Sarka Mills, Ken Gaidano, Gianluca Niemann, Carsten U. Campo, Elias Strefford, Jonathan C. Ghia, Paolo Stamatopoulos, Kostas Rosenquist, Richard Leukemia Article 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. Nature Publishing Group UK 2022-12-24 2023 /pmc/articles/PMC9898037/ /pubmed/36566271 http://dx.doi.org/10.1038/s41375-022-01802-y Text en © The Author(s) 2022, corrected publication 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Mansouri, Larry Thorvaldsdottir, Birna Sutton, Lesley-Ann Karakatsoulis, Georgios Meggendorfer, Manja Parker, Helen Nadeu, Ferran Brieghel, Christian Laidou, Stamatia Moia, Riccardo Rossi, Davide Catherwood, Mark Kotaskova, Jana Delgado, Julio Rodríguez-Vicente, Ana E. Benito, Rocío Rigolin, Gian Matteo Bonfiglio, Silvia Scarfo, Lydia Mattsson, Mattias Davis, Zadie Gogia, Ajay Rani, Lata Baliakas, Panagiotis Foroughi-Asl, Hassan Jylhä, Cecilia Skaftason, Aron Rapado, Inmaculada Miras, Fatima Martinez-Lopez, Joaquín de la Serna, Javier Rivas, Jesús María Hernández Thornton, Patrick Larráyoz, María José Calasanz, María José Fésüs, Viktória Mátrai, Zoltán Bödör, Csaba Smedby, Karin E. Espinet, Blanca Puiggros, Anna Gupta, Ritu Bullinger, Lars Bosch, Francesc Tazón-Vega, Bárbara Baran-Marszak, Fanny Oscier, David Nguyen-Khac, Florence Zenz, Thorsten Terol, Maria Jose Cuneo, Antonio Hernández-Sánchez, María Pospisilova, Sarka Mills, Ken Gaidano, Gianluca Niemann, Carsten U. Campo, Elias Strefford, Jonathan C. Ghia, Paolo Stamatopoulos, Kostas Rosenquist, Richard Different prognostic impact of recurrent gene mutations in chronic lymphocytic leukemia depending on IGHV gene somatic hypermutation status: a study by ERIC in HARMONY |
title | Different prognostic impact of recurrent gene mutations in chronic lymphocytic leukemia depending on IGHV gene somatic hypermutation status: a study by ERIC in HARMONY |
title_full | Different prognostic impact of recurrent gene mutations in chronic lymphocytic leukemia depending on IGHV gene somatic hypermutation status: a study by ERIC in HARMONY |
title_fullStr | Different prognostic impact of recurrent gene mutations in chronic lymphocytic leukemia depending on IGHV gene somatic hypermutation status: a study by ERIC in HARMONY |
title_full_unstemmed | Different prognostic impact of recurrent gene mutations in chronic lymphocytic leukemia depending on IGHV gene somatic hypermutation status: a study by ERIC in HARMONY |
title_short | Different prognostic impact of recurrent gene mutations in chronic lymphocytic leukemia depending on IGHV gene somatic hypermutation status: a study by ERIC in HARMONY |
title_sort | different prognostic impact of recurrent gene mutations in chronic lymphocytic leukemia depending on ighv gene somatic hypermutation status: a study by eric in harmony |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9898037/ https://www.ncbi.nlm.nih.gov/pubmed/36566271 http://dx.doi.org/10.1038/s41375-022-01802-y |
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