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Chronic Lymphocytic Leukemia

NOTCH1 mutations identify a genetic subgroup of chronic lymphocytic leukemia patients with high risk of transformation and poor outcome

Leukemia volume 27, pages 1100–1106 (2013)Cite this article

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Abstract

NOTCH1 has been found recurrently mutated in a subset of patients with chronic lymphocytic leukemia (CLL). To analyze biological features and clinical impact of NOTCH1 mutations in CLL, we sequenced this gene in 565 patients. NOTCH1 mutations, found in 63 patients (11%), were associated with unmutated IGHV, high expression of CD38 and ZAP-70, trisomy 12, advanced stage and elevated lactate dehydrogenase. Sequential analysis in 200 patients demonstrated acquisition of mutation in one case (0.5%) and disappearance after treatment in two. Binet A and B patients with NOTCH1-mutated had a shorter time to treatment. NOTCH1-mutated patients were more frequently refractory to therapy and showed shorter progression-free and overall survival after complete remission. Overall survival was shorter in NOTCH1-mutated patients, although not independently from IGHV. NOTCH1 mutation increased the risk of transformation to diffuse large B-cell lymphoma independently from IGHV, with this being validated in resampling tests of replicability. In summary, NOTCH1 mutational status, that was rarely acquired during the course of the disease, identify a genetic subgroup with high risk of transformation and poor outcome. This recently identified genetic subgroup of CLL patients deserves prospective studies to define their best management.

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Acknowledgements

We are grateful to Sara Guijarro, Silvia Martín, Cristina Capdevila, Montse Sánchez and Laura Plà for excellent technical assistance and Nathalie Villahoz and Carmen Muro for excellent work in the coordination of the CLL Spanish Consortium. We are indebted to the HCB-IDIBAPS Biobank-Tumor Bank and Hematopathology Collection for the sample procurement. We are also very grateful to all patients with CLL who have participated in this study. This study was supported by research funding from Spanish Ministry of Science and Innovation (MICINN) through the Instituto de Salud Carlos III (ISCIII) and Red Temática de Investigación del Cáncer (RTICC) (RD06-0020-0039 to E Campo and RD06-0020-0051 to AL-G), Fondo de investigaciones sanitarias (PI07/0301, MA) and Botín Foundation (CL-O).

Author information

Author notes

  1. P Abrisqueta & F Bosch

    Present address: 11Present address: Servei d’Hematologia, Hospital Vall d’Hebrón, Barcelona, Spain.,

  2. N Villamor and L Conde: These authors contributed equally to this work.

  3. E Campo and A López-Guillermo: EC and AL-G share the senior authorship of this study.

Authors and Affiliations

  1. Unitat d’Hematopatologia, Servei d'Anatomia Patològica, Hospital Clínic de Barcelona, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain

    N Villamor, L Conde, A Martínez-Trillos, M Cazorla, A Navarro, S Beà, C López, D Colomer, M Aymerich, M Rozman, P Jares & E Campo

  2. Unitat de Genòmica, IDIBAPS, Barcelona, Spain

    M Pinyol

  3. Servei d’Hematologia, Hospital Clínic de Barcelona, IDIBAPS, Barcelona, Spain

    P Abrisqueta, T Baumann, J Delgado, E Giné, F Bosch & A López-Guillermo

  4. Servicio de Hematología, Hospital Clínico Universitario, Centro de Investigación del Cancer-IBMCC (USLA-CSIC), Universidad de Salamanca, Salamanca, Spain

    M González-Díaz & J M Hernández

  5. Servicio de Hematología, Hospital Universitario Central de Asturias, Oviedo, Spain

    E Colado, A R Payer & C Rayon

  6. Servicio de Hematología, Hospital Clínico de Valencia, Valencia, Spain

    B Navarro & M José Terol

  7. Departamento de Bioquímica y Biología Molecular, Instituto Universitario de Oncología, Universidad de Oviedo, Oviedo, Spain

    V Quesada, X S Puente & C López-Otín

  8. Servei d’Hemoteràpia i Hemostàsia, Hospital Clínic de Barcelona, IDIBAPS, Barcelona, Spain

    A Pereira

  9. Universitat de Barcelona, Barcelona, Spain

    E Campo

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Correspondence to N Villamor.

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Author Contributions

LC, MC, AN, MP, VQ, XSP and CL-O performed sequencing analysis. MR, NV, MG-D, JMH, BN, E Colado and E Campo reviewed the pathological data and confirmed the diagnosis. DC, CL, SB carried out genetic and biological studies. AM-T, TB, JD, EG, PA, CR, ARP, MJT, FB and AL-G reviewed clinical data. MA prepared and supervised the bioethics requirements. AP contributed to and critically reviewed statistical analysis. E Campo and AL-G directed the research. NV, E Campo and AL-G wrote the manuscript, which all the authors approved.

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Villamor, N., Conde, L., Martínez-Trillos, A. et al. NOTCH1 mutations identify a genetic subgroup of chronic lymphocytic leukemia patients with high risk of transformation and poor outcome. Leukemia 27, 1100–1106 (2013). https://doi.org/10.1038/leu.2012.357

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