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Leukemia. 2015 Feb;29(2):329-36. doi: 10.1038/leu.2014.196. Epub 2014 Jun 19.

Recurrent mutations refine prognosis in chronic lymphocytic leukemia.

Author information

1
1] Science for Life Laboratory, Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden [2] Hematology Department and HCT Unit, G Papanicolaou Hospital, Thessaloniki, Greece.
2
1] Science for Life Laboratory, Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden [2] Institute of Applied Biosciences, CERTH, Thessaloniki, Greece.
3
Science for Life Laboratory, Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden.
4
Division of Haematology, Department of Translational Medicine, Amedeo Avogadro University of Eastern Piedmont, Novara, Italy.
5
Institute of Applied Biosciences, CERTH, Thessaloniki, Greece.
6
Hematopathology Unit and Department of Hematology, Hospital Clinic, University of Barcelona, Institut d'Investigacions Biomèdiques August Pi iSunyer (IDIBAPS), Barcelona, Spain.
7
Cancer Sciences, Faculty of Medicine, University of Southampton, Southampton, UK.
8
Central European Institute of Technology, Masaryk University and University Hospital Brno, Brno, Czech Republic.
9
1] Università Vita-Salute San Raffaele, Milan, Italy [2] Division of Molecular Oncology and Department of Onco-Hematology, San Raffaele Scientific Institute, Milan, Italy.
10
Department of Haematology, Royal Bournemouth Hospital, Bournemouth, UK.
11
Department of Internal Medicine III, Ulm University, Ulm, Germany.
12
Hematology Department and HCT Unit, G Papanicolaou Hospital, Thessaloniki, Greece.
13
Department of Medicine, Solna, Clinical Epidemiology Unit, Karolinska Institutet, Stockholm, Sweden.
14
Lund University and Hospital Department of Hematology, Lund Stem Cell Center, Lund, Sweden.
15
Hematology Department, Nikea General Hospital, Pireaus, Greece.
16
1] Science for Life Laboratory, Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden [2] Hematology Department and HCT Unit, G Papanicolaou Hospital, Thessaloniki, Greece [3] Institute of Applied Biosciences, CERTH, Thessaloniki, Greece.

Abstract

Through the European Research Initiative on chronic lymphocytic leukemia (CLL) (ERIC), we screened 3490 patients with CLL for mutations within the NOTCH1 (n=3334), SF3B1 (n=2322), TP53 (n=2309), MYD88 (n=1080) and BIRC3 (n=919) genes, mainly at diagnosis (75%) and before treatment (>90%). BIRC3 mutations (2.5%) were associated with unmutated IGHV genes (U-CLL), del(11q) and trisomy 12, whereas MYD88 mutations (2.2%) were exclusively found among M-CLL. NOTCH1, SF3B1 and TP53 exhibited variable frequencies and were mostly enriched within clinically aggressive cases. Interestingly, as the timespan between diagnosis and mutational screening increased, so too did the incidence of SF3B1 mutations; no such increase was observed for NOTCH1 mutations. Regarding the clinical impact, NOTCH1 mutations, SF3B1 mutations and TP53 aberrations (deletion/mutation, TP53ab) correlated with shorter time-to-first-treatment (P<0.0001) in 889 treatment-naive Binet stage A cases. In multivariate analysis (n=774), SF3B1 mutations and TP53ab along with del(11q) and U-CLL, but not NOTCH1 mutations, retained independent significance. Importantly, TP53ab and SF3B1 mutations had an adverse impact even in U-CLL. In conclusion, we support the clinical relevance of novel recurrent mutations in CLL, highlighting the adverse impact of SF3B1 and TP53 mutations, even independent of IGHV mutational status, thus underscoring the need for urgent standardization/harmonization of the detection methods.

PMID:
24943832
DOI:
10.1038/leu.2014.196
[Indexed for MEDLINE]
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