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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Detalles Bibliográficos
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 recurso: artículo
Estado:Versión publicada
Fecha de publicación:2025
País:España
Institución:INCLIVA
Repositorio:r-INCLIVA. Repositorio Institucional de Producción Científica de INCLIVA
OAI Identifier:oai:incliva.fundanetsuite.com:p20011
Acceso en línea:https://incliva.portalinvestigacion.com/publicaciones/20011
Access Level:acceso abierto
Descripción
Sumario: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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