title: Recurrent mutations refine prognosis in chronic lymphocytic leukemia.
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.
authors.affiliation: 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.
authors.forename: P
authors.initials: P
authors.lastname: Baliakas
authors.affiliation: 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.
authors.forename: A
authors.initials: A
authors.lastname: Hadzidimitriou
authors.affiliation: Science for Life Laboratory, Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden.
authors.forename: L-A
authors.initials: LA
authors.lastname: Sutton
authors.affiliation: Division of Haematology, Department of Translational Medicine, Amedeo Avogadro University of Eastern Piedmont, Novara, Italy.
authors.forename: D
authors.initials: D
authors.lastname: Rossi
authors.affiliation: Institute of Applied Biosciences, CERTH, Thessaloniki, Greece.
authors.forename: E
authors.initials: E
authors.lastname: Minga
authors.affiliation: Hematopathology Unit and Department of Hematology, Hospital Clinic, University of Barcelona, Institut d'Investigacions Biomèdiques August Pi iSunyer (IDIBAPS), Barcelona, Spain.
authors.forename: N
authors.initials: N
authors.lastname: Villamor
authors.affiliation: Cancer Sciences, Faculty of Medicine, University of Southampton, Southampton, UK.
authors.forename: M
authors.initials: M
authors.lastname: Larrayoz
authors.affiliation: Central European Institute of Technology, Masaryk University and University Hospital Brno, Brno, Czech Republic.
authors.forename: J
authors.initials: J
authors.lastname: Kminkova
authors.affiliation: 1] Università Vita-Salute San Raffaele, Milan, Italy [2] Division of Molecular Oncology and Department of Onco-Hematology, San Raffaele Scientific Institute, Milan, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Agathangelidis
authors.affiliation: Department of Haematology, Royal Bournemouth Hospital, Bournemouth, UK.
authors.forename: Z
authors.initials: Z
authors.lastname: Davis
authors.affiliation: Department of Internal Medicine III, Ulm University, Ulm, Germany.
authors.forename: E
authors.initials: E
authors.lastname: Tausch
authors.affiliation: Hematology Department and HCT Unit, G Papanicolaou Hospital, Thessaloniki, Greece.
authors.forename: E
authors.initials: E
authors.lastname: Stalika
authors.affiliation: Central European Institute of Technology, Masaryk University and University Hospital Brno, Brno, Czech Republic.
authors.forename: B
authors.initials: B
authors.lastname: Kantorova
authors.affiliation: Science for Life Laboratory, Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden.
authors.forename: L
authors.initials: L
authors.lastname: Mansouri
authors.affiliation: 1] Università Vita-Salute San Raffaele, Milan, Italy [2] Division of Molecular Oncology and Department of Onco-Hematology, San Raffaele Scientific Institute, Milan, Italy.
authors.forename: L
authors.initials: L
authors.lastname: Scarfò
authors.affiliation: Science for Life Laboratory, Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden.
authors.forename: D
authors.initials: D
authors.lastname: Cortese
authors.affiliation: Central European Institute of Technology, Masaryk University and University Hospital Brno, Brno, Czech Republic.
authors.forename: V
authors.initials: V
authors.lastname: Navrkalova
authors.affiliation: Cancer Sciences, Faculty of Medicine, University of Southampton, Southampton, UK.
authors.forename: M J J
authors.initials: MJ
authors.lastname: Rose-Zerilli
authors.affiliation: Department of Medicine, Solna, Clinical Epidemiology Unit, Karolinska Institutet, Stockholm, Sweden.
authors.forename: K E
authors.initials: KE
authors.lastname: Smedby
authors.affiliation: Lund University and Hospital Department of Hematology, Lund Stem Cell Center, Lund, Sweden.
authors.forename: G
authors.initials: G
authors.lastname: Juliusson
authors.affiliation: Hematology Department and HCT Unit, G Papanicolaou Hospital, Thessaloniki, Greece.
authors.forename: A
authors.initials: A
authors.lastname: Anagnostopoulos
authors.affiliation: Institute of Applied Biosciences, CERTH, Thessaloniki, Greece.
authors.forename: A M
authors.initials: AM
authors.lastname: Makris
authors.affiliation: Hematopathology Unit and Department of Hematology, Hospital Clinic, University of Barcelona, Institut d'Investigacions Biomèdiques August Pi iSunyer (IDIBAPS), Barcelona, Spain.
authors.forename: A
authors.initials: A
authors.lastname: Navarro
authors.affiliation: Hematopathology Unit and Department of Hematology, Hospital Clinic, University of Barcelona, Institut d'Investigacions Biomèdiques August Pi iSunyer (IDIBAPS), Barcelona, Spain.
authors.forename: J
authors.initials: J
authors.lastname: Delgado
authors.affiliation: Department of Haematology, Royal Bournemouth Hospital, Bournemouth, UK.
authors.forename: D
authors.initials: D
authors.lastname: Oscier
authors.affiliation: Hematology Department, Nikea General Hospital, Pireaus, Greece.
authors.forename: C
authors.initials: C
authors.lastname: Belessi
authors.affiliation: Department of Internal Medicine III, Ulm University, Ulm, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Stilgenbauer
authors.affiliation: 1] Università Vita-Salute San Raffaele, Milan, Italy [2] Division of Molecular Oncology and Department of Onco-Hematology, San Raffaele Scientific Institute, Milan, Italy.
authors.forename: P
authors.initials: P
authors.lastname: Ghia
authors.affiliation: Central European Institute of Technology, Masaryk University and University Hospital Brno, Brno, Czech Republic.
authors.forename: S
authors.initials: S
authors.lastname: Pospisilova
authors.affiliation: Division of Haematology, Department of Translational Medicine, Amedeo Avogadro University of Eastern Piedmont, Novara, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Gaidano
authors.affiliation: Hematopathology Unit and Department of Hematology, Hospital Clinic, University of Barcelona, Institut d'Investigacions Biomèdiques August Pi iSunyer (IDIBAPS), Barcelona, Spain.
authors.forename: E
authors.initials: E
authors.lastname: Campo
authors.affiliation: Cancer Sciences, Faculty of Medicine, University of Southampton, Southampton, UK.
authors.forename: J C
authors.initials: JC
authors.lastname: Strefford
authors.affiliation: 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.
authors.forename: K
authors.initials: K
authors.lastname: Stamatopoulos
authors.affiliation: Science for Life Laboratory, Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden.
authors.forename: R
authors.initials: R
authors.lastname: Rosenquist
mesh_terms: D000368:Aged; D003582:Cytogenetics; D004252:DNA Mutational Analysis; D005060:Europe; D005260:Female; D017353:Gene Deletion; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000175:diagnosis* / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D009154:Mutation; D010750:Phosphoproteins / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D011379:Prognosis; D000072260:RNA Splicing Factors; D051881:Receptor, Notch1 / Q000235:genetics; D012008:Recurrence; D017413:Ribonucleoprotein, U2 Small Nuclear / Q000235:genetics; D013997:Time Factors; D016159:Tumor Suppressor Protein p53 / Q000235:genetics
chemical_list: C497761:NOTCH1 protein, human; D010750:Phosphoproteins; D000072260:RNA Splicing Factors; D051881:Receptor, Notch1; D017413:Ribonucleoprotein, U2 Small Nuclear; C112491:SF3B1 protein, human; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53