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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Detalhes bibliográficos
Autores: Thorvaldsdottir, Birna, Mansouri, Larry, Sutton, Lesley-Ann, Nadeu, Ferran, Meggendorfer, Manja, Parker, Helen, Brieghel, Christian, Laidou, Stamatia, Moia, Riccardo, Rossi, Davide, Kotaskova, Jana, Delgado, Julio, Rodríguez-Vicente, Ana Eugenia, Benito, Rocío, Rigolin, Gian Matteo, Bonfiglio, Silvia, Scarfò, Lydia, Mattsson, Mattias, Davis, Zadie, Baliakas, Panagiotis, Rapado, Inmaculada, Mirás, Fátima, Martínez-López, Joaquín, Serna, Javier de la, Hernández, Jesús M., Larráyoz, María José, Calasanz, Mª Jose, Smedby, Karin E., Espinet, Blanca, Puiggros, Anna, Bullinger, Lars, Bosch, Francesc, Tazón‐Vega, Bárbara, Baran-Marszak, Fanny, Oscier, David, Nguyen-Khac, Florence, Zenz, Thorsten, Terol, María José, Cuneo, Antonio, Hernández-Sánchez, María, Pospisilova, Sarka, Gaidano, Gianluca, Niemann, Carsten U., Campo, Elías, Strefford, Jonathan C., Ghia, Paolo, Stamatopoulos, Kostas, Rosenquist, Richard
Formato: artículo
Estado:Versión publicada
Fecha de publicación:2025
País:España
Recursos:Consejo Superior de Investigaciones Científicas (CSIC)
Repositorio:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:digital.csic.es:10261/400612
Acesso em linha:http://hdl.handle.net/10261/400612
Access Level:acceso abierto
Palavra-chave:Cancer genomics
Chronic lymphocytic leukaemia
Descrição
Resumo: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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