ATM aberrations in chronic lymphocytic leukemia: del(11q) rather than ATM mutations is an adverse-prognostic biomarker

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 patie...

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Autores: Thorvaldsdottir, B, Mansouri, L, Sutton, LA, Nadeu, F, Meggendorfer, M, Parker, H, Brieghel, C, Laidou, S, Moia, R, Rossi, D, Kotaskova, J, Delgado, J, Rodríguez-Vicente, AE, Benito, R, Rigolin, GM, Bonfiglio, S, Scarfò, L, Mattsson, M, Davis, Z, Baliakas, P, Rapado, I, Miras, F, Martinez-Lopez, J, de la Serna, J, Rivas, JMH, Larráyoz, MJ, Calasanz, MJ, Smedby, KE, Espinet, B, Puiggros, A, Bullinger, L, Bosch, F, Tazón-Vega, B, Baran-Marszak, F, Oscier, D, Nguyen-Khac, F, Zenz, T, Terol, MJ, Cuneo, A, Hernández-Sánchez, M, Pospisilova, S, Gaidano, G, Niemann, CU, Campo, E, Strefford, JC, Ghia, P, Stamatopoulos, K, Rosenquist, R
Tipo de documento: artigo
Estado:Versão publicada
Data de publicação:2025
País:España
Recursos:INCLIVA
Repositório:r-INCLIVA. Repositorio Institucional de Producción Científica de INCLIVA
OAI Identifier:oai:incliva.fundanetsuite.com:p20011
Acesso em linha:https://incliva.portalinvestigacion.com/publicaciones/20011
Access Level:Acceso aberto
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spelling ATM aberrations in chronic lymphocytic leukemia: del(11q) rather than ATM mutations is an adverse-prognostic biomarkerThorvaldsdottir, BMansouri, LSutton, LANadeu, FMeggendorfer, MParker, HBrieghel, CLaidou, SMoia, RRossi, DKotaskova, JDelgado, JRodríguez-Vicente, AEBenito, RRigolin, GMBonfiglio, SScarfò, LMattsson, MDavis, ZBaliakas, PRapado, IMiras, FMartinez-Lopez, Jde la Serna, JRivas, JMHLarráyoz, MJCalasanz, MJSmedby, KEEspinet, BPuiggros, ABullinger, LBosch, FTazón-Vega, BBaran-Marszak, FOscier, DNguyen-Khac, FZenz, TTerol, MJCuneo, AHernández-Sánchez, MPospisilova, SGaidano, GNiemann, CUCampo, EStrefford, JCGhia, PStamatopoulos, KRosenquist, RDespite 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.SPRINGERNATURE2025info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttps://incliva.portalinvestigacion.com/publicaciones/20011LEUKEMIAISSN: 08876924ISSNe: 14765551reponame:r-INCLIVA. Repositorio Institucional de Producción Científica de INCLIVAinstname:INCLIVAInglésinfo:eu-repo/semantics/openAccessoai:incliva.fundanetsuite.com:p200112026-06-07T16:35:31Z
dc.title.none.fl_str_mv ATM aberrations in chronic lymphocytic leukemia: del(11q) rather than ATM mutations is an adverse-prognostic biomarker
title ATM aberrations in chronic lymphocytic leukemia: del(11q) rather than ATM mutations is an adverse-prognostic biomarker
spellingShingle ATM aberrations in chronic lymphocytic leukemia: del(11q) rather than ATM mutations is an adverse-prognostic biomarker
Thorvaldsdottir, B
title_short ATM aberrations in chronic lymphocytic leukemia: del(11q) rather than ATM mutations is an adverse-prognostic biomarker
title_full ATM aberrations in chronic lymphocytic leukemia: del(11q) rather than ATM mutations is an adverse-prognostic biomarker
title_fullStr ATM aberrations in chronic lymphocytic leukemia: del(11q) rather than ATM mutations is an adverse-prognostic biomarker
title_full_unstemmed ATM aberrations in chronic lymphocytic leukemia: del(11q) rather than ATM mutations is an adverse-prognostic biomarker
title_sort ATM aberrations in chronic lymphocytic leukemia: del(11q) rather than ATM mutations is an adverse-prognostic biomarker
dc.creator.none.fl_str_mv Thorvaldsdottir, B
Mansouri, L
Sutton, LA
Nadeu, F
Meggendorfer, M
Parker, H
Brieghel, C
Laidou, S
Moia, R
Rossi, D
Kotaskova, J
Delgado, J
Rodríguez-Vicente, AE
Benito, R
Rigolin, GM
Bonfiglio, S
Scarfò, L
Mattsson, M
Davis, Z
Baliakas, P
Rapado, I
Miras, F
Martinez-Lopez, J
de la Serna, J
Rivas, JMH
Larráyoz, MJ
Calasanz, MJ
Smedby, KE
Espinet, B
Puiggros, A
Bullinger, L
Bosch, F
Tazón-Vega, B
Baran-Marszak, F
Oscier, D
Nguyen-Khac, F
Zenz, T
Terol, MJ
Cuneo, A
Hernández-Sánchez, M
Pospisilova, S
Gaidano, G
Niemann, CU
Campo, E
Strefford, JC
Ghia, P
Stamatopoulos, K
Rosenquist, R
author Thorvaldsdottir, B
author_facet Thorvaldsdottir, B
Mansouri, L
Sutton, LA
Nadeu, F
Meggendorfer, M
Parker, H
Brieghel, C
Laidou, S
Moia, R
Rossi, D
Kotaskova, J
Delgado, J
Rodríguez-Vicente, AE
Benito, R
Rigolin, GM
Bonfiglio, S
Scarfò, L
Mattsson, M
Davis, Z
Baliakas, P
Rapado, I
Miras, F
Martinez-Lopez, J
de la Serna, J
Rivas, JMH
Larráyoz, MJ
Calasanz, MJ
Smedby, KE
Espinet, B
Puiggros, A
Bullinger, L
Bosch, F
Tazón-Vega, B
Baran-Marszak, F
Oscier, D
Nguyen-Khac, F
Zenz, T
Terol, MJ
Cuneo, A
Hernández-Sánchez, M
Pospisilova, S
Gaidano, G
Niemann, CU
Campo, E
Strefford, JC
Ghia, P
Stamatopoulos, K
Rosenquist, R
author_role author
author2 Mansouri, L
Sutton, LA
Nadeu, F
Meggendorfer, M
Parker, H
Brieghel, C
Laidou, S
Moia, R
Rossi, D
Kotaskova, J
Delgado, J
Rodríguez-Vicente, AE
Benito, R
Rigolin, GM
Bonfiglio, S
Scarfò, L
Mattsson, M
Davis, Z
Baliakas, P
Rapado, I
Miras, F
Martinez-Lopez, J
de la Serna, J
Rivas, JMH
Larráyoz, MJ
Calasanz, MJ
Smedby, KE
Espinet, B
Puiggros, A
Bullinger, L
Bosch, F
Tazón-Vega, B
Baran-Marszak, F
Oscier, D
Nguyen-Khac, F
Zenz, T
Terol, MJ
Cuneo, A
Hernández-Sánchez, M
Pospisilova, S
Gaidano, G
Niemann, CU
Campo, E
Strefford, JC
Ghia, P
Stamatopoulos, K
Rosenquist, R
author2_role author
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author
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author
author
author
author
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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.
publishDate 2025
dc.date.none.fl_str_mv 2025
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv https://incliva.portalinvestigacion.com/publicaciones/20011
url https://incliva.portalinvestigacion.com/publicaciones/20011
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv SPRINGERNATURE
publisher.none.fl_str_mv SPRINGERNATURE
dc.source.none.fl_str_mv LEUKEMIA
ISSN: 08876924
ISSNe: 14765551
reponame:r-INCLIVA. Repositorio Institucional de Producción Científica de INCLIVA
instname:INCLIVA
instname_str INCLIVA
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