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Title:
ATM aberrations in chronic lymphocytic leukemia: del(11q) rather than ATM mutations is an adverse-prognostic biomarker | Leukemia
Description:
Despite the well-established adverse impact of del(11q) in chronic lymphocytic leukemia (CLL), the prognostic significance of somatic ATM mutations remains uncertain. We evaluated the effects of ATM aberrations (del(11q) and/or ATM mutations) on time-to-first-treatment (TTFT) in 3631 untreated patients with CLL, in the context of IGHV gene mutational status and mutations in nine CLL-related genes. ATM mutations were present in 246 cases (6.8%), frequently co-occurring with del(11q) (112/246 cases, 45.5%). ATM-mutated patients displayed a different spectrum of genetic abnormalities when comparing IGHV-mutated (M-CLL) and unmutated (U-CLL) cases: M-CLL was enriched for SF3B1 and NFKBIE mutations, whereas U-CLL showed mutual exclusivity with trisomy 12 and TP53 mutations. Isolated ATM mutations were rare, affecting 1.2% of Binet A patients and <1% of M-CLL cases. While univariable analysis revealed shorter TTFT for Binet A patients with any ATM aberration compared to ATM-wildtype, multivariable analysis identified only del(11q), trisomy 12, SF3B1, and EGR2 mutations as independent prognosticators of shorter TTFT among Binet A patients and within M-CLL and U-CLL subgroups. These findings highlight del(11q), and not ATM mutations, as a key biomarker of increased risk of early progression and need for therapy, particularly in otherwise indolent M-CLL, providing insights into risk-stratification and therapeutic decision-making.
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atm, mutations, patients, pubmed, cases, article, delq, leukemia, cll, google, scholar, variants, chronic, lymphocytic, fig, ttft, cas, somatic, research, gene, mcll, ucll, clinical, analysis, cohort, impact, ighv, status, data, binet, aberrations, supplementary, central, sfb, nature, putative, cancer, department, genes, mutation, university, prognostic, mutated, significant, survival, spain, shorter, compared, study, table,
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nature portfolio privacy policy joaquín martinez-lopez advertising cox–mantel log-rank test ighv-ighd-ighj gene rearrangements nature hum-boldt-universität zu berlin social media gian matteo rigolin protein language models reprints relapsed/refractory cll favorable-prognostic ighv-mutated cll clinical/translational cancer research cancer research uk relapsed/refractory patients c- versus n-terminal european research initiative double-stranded dna breaks fixed-duration venetoclax-rituximab kaplan-meier survival curves high-resolution genomic profiling putative germline/predicted neutral service array-based genomic screening chronic lymphocytic leukaemia hématologie biologique high-resolution genomic screening multi-center european cohort jana kotaskova hôpital pitié-salpêtrière putative germline/neutral variants kaplan-meier survival analysis high tumor content hematological neoplasms group influence tumor development language permissions swedish research council incliva research insitute paired tumor/germline samples integrates published data project national institute chronic lymphocytic leukemia distinct groups based bi-allelic atm abnormalities full size image combination venetoclax-rituximab compared multi-center composition
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headline:ATM aberrations in chronic lymphocytic leukemia: del(11q) rather than ATM mutations is an adverse-prognostic biomarker
description:Despite the well-established adverse impact of del(11q) in chronic lymphocytic leukemia (CLL), the prognostic significance of somatic ATM mutations remains uncertain. We evaluated the effects of ATM aberrations (del(11q) and/or ATM mutations) on time-to-first-treatment (TTFT) in 3631 untreated patients with CLL, in the context of IGHV gene mutational status and mutations in nine CLL-related genes. ATM mutations were present in 246 cases (6.8%), frequently co-occurring with del(11q) (112/246 cases, 45.5%). ATM-mutated patients displayed a different spectrum of genetic abnormalities when comparing IGHV-mutated (M-CLL) and unmutated (U-CLL) cases: M-CLL was enriched for SF3B1 and NFKBIE mutations, whereas U-CLL showed mutual exclusivity with trisomy 12 and TP53 mutations. Isolated ATM mutations were rare, affecting 1.2% of Binet A patients and <1% of M-CLL cases. While univariable analysis revealed shorter TTFT for Binet A patients with any ATM aberration compared to ATM-wildtype, multivariable analysis identified only del(11q), trisomy 12, SF3B1, and EGR2 mutations as independent prognosticators of shorter TTFT among Binet A patients and within M-CLL and U-CLL subgroups. These findings highlight del(11q), and not ATM mutations, as a key biomarker of increased risk of early progression and need for therapy, particularly in otherwise indolent M-CLL, providing insights into risk-stratification and therapeutic decision-making.
datePublished:2025-04-24T00:00:00Z
dateModified:2025-04-24T00:00:00Z
pageStart:1650
pageEnd:1660
license:http://creativecommons.org/licenses/by/4.0/
sameAs:https://doi.org/10.1038/s41375-025-02615-5
keywords:
Cancer genomics
Chronic lymphocytic leukaemia
Medicine/Public Health
general
Internal Medicine
Intensive / Critical Care Medicine
Cancer Research
Oncology
Hematology
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headline:ATM aberrations in chronic lymphocytic leukemia: del(11q) rather than ATM mutations is an adverse-prognostic biomarker
description:Despite the well-established adverse impact of del(11q) in chronic lymphocytic leukemia (CLL), the prognostic significance of somatic ATM mutations remains uncertain. We evaluated the effects of ATM aberrations (del(11q) and/or ATM mutations) on time-to-first-treatment (TTFT) in 3631 untreated patients with CLL, in the context of IGHV gene mutational status and mutations in nine CLL-related genes. ATM mutations were present in 246 cases (6.8%), frequently co-occurring with del(11q) (112/246 cases, 45.5%). ATM-mutated patients displayed a different spectrum of genetic abnormalities when comparing IGHV-mutated (M-CLL) and unmutated (U-CLL) cases: M-CLL was enriched for SF3B1 and NFKBIE mutations, whereas U-CLL showed mutual exclusivity with trisomy 12 and TP53 mutations. Isolated ATM mutations were rare, affecting 1.2% of Binet A patients and <1% of M-CLL cases. While univariable analysis revealed shorter TTFT for Binet A patients with any ATM aberration compared to ATM-wildtype, multivariable analysis identified only del(11q), trisomy 12, SF3B1, and EGR2 mutations as independent prognosticators of shorter TTFT among Binet A patients and within M-CLL and U-CLL subgroups. These findings highlight del(11q), and not ATM mutations, as a key biomarker of increased risk of early progression and need for therapy, particularly in otherwise indolent M-CLL, providing insights into risk-stratification and therapeutic decision-making.
datePublished:2025-04-24T00:00:00Z
dateModified:2025-04-24T00:00:00Z
pageStart:1650
pageEnd:1660
license:http://creativecommons.org/licenses/by/4.0/
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keywords:
Cancer genomics
Chronic lymphocytic leukaemia
Medicine/Public Health
general
Internal Medicine
Intensive / Critical Care Medicine
Cancer Research
Oncology
Hematology
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name:Central European Institute of Technology, Masaryk University, Brno, Czech Republic
name:Institut dâInvestigacions Biomèdiques August Pi I Sunyer (IDIBAPS), Barcelona, Spain
name:Cancer Research Center (IBMCC) CSIC-University of Salamanca, Salamanca, Spain
name:Instituto de Investigación Biomédica (IBSAL), Salamanca, Spain
name:Department of Hematology, University Hospital of Salamanca, Salamanca, Spain
name:Cancer Research Center (IBMCC) CSIC-University of Salamanca, Salamanca, Spain
name:Instituto de Investigación Biomédica (IBSAL), Salamanca, Spain
name:Department of Hematology, University Hospital of Salamanca, Salamanca, Spain
name:Hematology - Department of Medical Sciences, University of Ferrara, Ferrara, Italy
name:IRCCS Ospedale San Raffaele, Milano, Italy
name:IRCCS Ospedale San Raffaele, Milano, Italy
name:Università Vita-Salute San Raffaele, Milano, Italy
name:Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
name:Molecular Pathology Department, University Hospitals Dorset, Bournemouth, UK
name:Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
name:Hospital Universitario 12 Octubre, Madrid, Spain
name:Spanish National Cancer Research (CNIO), Madrid, Spain
name:Hospital Universitario 12 Octubre, Madrid, Spain
name:Hospital Universitario 12 Octubre, Madrid, Spain
name:Spanish National Cancer Research (CNIO), Madrid, Spain
name:Hospital Universitario 12 Octubre, Madrid, Spain
name:Spanish National Cancer Research (CNIO), Madrid, Spain
name:Cancer Research Center (IBMCC) CSIC-University of Salamanca, Salamanca, Spain
name:Instituto de Investigación Biomédica (IBSAL), Salamanca, Spain
name:Department of Hematology, University Hospital of Salamanca, Salamanca, Spain
name:Hematological Diseases Laboratory, CIMA LAB Diagnostics, University of Navarra, 31008 Pamplona, Spain, IdiSNA, Navarra Institute for Health Research, Pamplona, Spain
name:Hematological Diseases Laboratory, CIMA LAB Diagnostics, University of Navarra, 31008 Pamplona, Spain, IdiSNA, Navarra Institute for Health Research, Pamplona, Spain
name:Clinical Epidemiology Division, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden
name:Molecular Cytogenetics Laboratory, Pathology Department, Hospital del Mar and Translational Research on Hematological Neoplasms Group, Hospital del Mar Research Institute (IMIM), Barcelona, Spain
name:Molecular Cytogenetics Laboratory, Pathology Department, Hospital del Mar and Translational Research on Hematological Neoplasms Group, Hospital del Mar Research Institute (IMIM), Barcelona, Spain
name:Department of Hematology, Oncology and Cancer Immunology, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Hum-boldt-Universität zu Berlin, Berlin, Germany
name:Department of Hematology, Hospital Universitari Vall dâHebron (HUVH), Experimental Hematology, Vall dâHebron Institute of Oncology (VHIO), Department of Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain
name:Department of Hematology, Hospital Universitari Vall dâHebron (HUVH), Experimental Hematology, Vall dâHebron Institute of Oncology (VHIO), Department of Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain
name:Service dâhématologie biologique Hôpital Avicenne Assistance Publique des Hôpitaux de Paris Bobigny France, Bobigny, France
name:Molecular Pathology Department, University Hospitals Dorset, Bournemouth, UK
name:Sorbonne Université, Service dâHématologie Biologique, Hôpital Pitié-Salpêtrière, APHP, Paris, France
name:Department of Oncology and Haematology, University Hospital and University of Zurich, Zurich, Switzerland
name:Department of Hematology, INCLIVA Research Insitute, University of Valencia, Valencia, Spain
name:Hematology - Department of Medical Sciences, University of Ferrara, Ferrara, Italy
name:Cancer Research Center (IBMCC) CSIC-University of Salamanca, Salamanca, Spain
name:Instituto de Investigación Biomédica (IBSAL), Salamanca, Spain
name:Department of Hematology, University Hospital of Salamanca, Salamanca, Spain
name:Department of Biochemistry and Molecular Biology, Pharmacy School, Universidad Complutense de Madrid, Madrid, Spain
name:Department of Internal Medicine, Hematology & Oncology, University Hospital Brno, Brno, Czech Republic
name:Faculty of Medicine, Masaryk University, Brno, Czech Republic
name:Central European Institute of Technology, Masaryk University, Brno, Czech Republic
name:Division of Hematology, Department of Translational Medicine, University of Eastern Piedmont, Novara, Italy
name:Department of Hematology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
name:Department of Hematology, Danish Cancer Institute, Copenhagen, Denmark
name:Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
name:Institut dâInvestigacions Biomèdiques August Pi I Sunyer (IDIBAPS), Barcelona, Spain
name:Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain
name:Hospital ClÃnic of Barcelona, Barcelona, Spain
name:Universitat de Barcelona, Barcelona, Spain
name:Cancer Genomics, School for Cancer Sciences, Faculty of Medicine, University of Southampton, Southampton, UK
name:IRCCS Ospedale San Raffaele, Milano, Italy
name:Università Vita-Salute San Raffaele, Milano, Italy
name:Centre for Research and Technology Hellas, Institute of Applied Biosciences, Thessaloniki, Greece
name:Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
name:Clinical Genetics and Genomics, Karolinska University Hospital, Solna, Sweden
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- https://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=search&term=Silvia%20Bonfiglio income
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- Income figures for https://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=search&term=Zadie%20Davis
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- Earnings of https://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=search&term=Karin%20E.%20Smedby
- https://scholar.google.co.uk/scholar?as_q=&num=10&btnG=Search+Scholar&as_epq=&as_oq=&as_eq=&as_occt=any&as_sauthors=%22Karin%20E.%20Smedby%22&as_publication=&as_ylo=&as_yhi=&as_allsubj=all&hl=en income
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