title: Different spectra of recurrent gene mutations in subsets of chronic lymphocytic leukemia harboring stereotyped B-cell receptors.
abstract: We report on markedly different frequencies of genetic lesions within subsets of chronic lymphocytic leukemia patients carrying mutated or unmutated stereotyped B-cell receptor immunoglobulins in the largest cohort (n=565) studied for this purpose. By combining data on recurrent gene mutations (BIRC3, MYD88, NOTCH1, SF3B1 and TP53) and cytogenetic aberrations, we reveal a subset-biased acquisition of gene mutations. More specifically, the frequency of NOTCH1 mutations was found to be enriched in subsets expressing unmutated immunoglobulin genes, i.e. #1, #6, #8 and #59 (22-34%), often in association with trisomy 12, and was significantly different (P<0.001) to the frequency observed in subset #2 (4%, aggressive disease, variable somatic hypermutation status) and subset #4 (1%, indolent disease, mutated immunoglobulin genes). Interestingly, subsets harboring a high frequency of NOTCH1 mutations were found to carry few (if any) SF3B1 mutations. This starkly contrasts with subsets #2 and #3 where, despite their immunogenetic differences, SF3B1 mutations occurred in 45% and 46% of cases, respectively. In addition, mutations within TP53, whilst enriched in subset #1 (16%), were rare in subsets #2 and #8 (both 2%), despite all being clinically aggressive. All subsets were negative for MYD88 mutations, whereas BIRC3 mutations were infrequent. Collectively, this striking bias and skewed distribution of mutations and cytogenetic aberrations within specific chronic lymphocytic leukemia subsets implies that the mechanisms underlying clinical aggressiveness are not uniform, but rather support the existence of distinct genetic pathways of clonal evolution governed by a particular stereotyped B-cell receptor selecting a certain molecular lesion(s).
authors.affiliation: Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
authors.forename: Lesley-Ann
authors.initials: LA
authors.lastname: Sutton
authors.affiliation: Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
authors.forename: Emma
authors.initials: E
authors.lastname: Young
authors.affiliation: Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
authors.forename: Panagiotis
authors.initials: P
authors.lastname: Baliakas
authors.affiliation: Institute of Applied Biosciences, CERTH, Thessaloniki, Greece.
authors.forename: Anastasia
authors.initials: A
authors.lastname: Hadzidimitriou
authors.affiliation: Institute of Applied Biosciences, CERTH, Thessaloniki, Greece.
authors.forename: Theodoros
authors.initials: T
authors.lastname: Moysiadis
authors.affiliation: Central European Institute of Technology, Masaryk University and University Hospital Brno, Czech Republic.
authors.forename: Karla
authors.initials: K
authors.lastname: Plevova
authors.affiliation: Division of Haematology, Department of Translational Medicine, Amedeo Avogadro University of Eastern Piedmont, Novara, Italy.
authors.forename: Davide
authors.initials: D
authors.lastname: Rossi
authors.affiliation: Central European Institute of Technology, Masaryk University and University Hospital Brno, Czech Republic.
authors.forename: Jana
authors.initials: J
authors.lastname: Kminkova
authors.affiliation: Institute of Applied Biosciences, CERTH, Thessaloniki, Greece.
authors.forename: Evangelia
authors.initials: E
authors.lastname: Stalika
authors.affiliation: Department of Hematology, Rigshospitalet, Copenhagen, Denmark.
authors.forename: Lone Bredo
authors.initials: LB
authors.lastname: Pedersen
authors.affiliation: Central European Institute of Technology, Masaryk University and University Hospital Brno, Czech Republic.
authors.forename: Jitka
authors.initials: J
authors.lastname: Malcikova
authors.affiliation: Università Vita-Salute San Raffaele, Milan, Italy Division of Experimental Oncology and Department of Onco-Hematology, IRCCS, San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Andreas
authors.initials: A
authors.lastname: Agathangelidis
authors.affiliation: Department of Haematology, Royal Bournemouth Hospital, Bournemouth, UK.
authors.forename: Zadie
authors.initials: Z
authors.lastname: Davis
authors.affiliation: Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
authors.forename: Larry
authors.initials: L
authors.lastname: Mansouri
authors.affiliation: Università Vita-Salute San Raffaele, Milan, Italy Division of Experimental Oncology and Department of Onco-Hematology, IRCCS, San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Lydia
authors.initials: L
authors.lastname: Scarfò
authors.affiliation: Hematology Department and University Pierre et Marie Curie, Hopital Pitie-Salpetriere, Paris, France.
authors.forename: Myriam
authors.initials: M
authors.lastname: Boudjoghra
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: Alba
authors.initials: A
authors.lastname: Navarro
authors.affiliation: Department of Immunology, Erasmus MC, University Medical Center Rotterdam, The Netherlands.
authors.forename: Alice F
authors.initials: AF
authors.lastname: Muggen
authors.affiliation: The Feinstein Institute for Medical Research, North Shore-Long Island Jewish Health System, Manhasset, New York, NY, USA.
authors.forename: Xiao-Jie
authors.initials: XJ
authors.lastname: Yan
authors.affiliation: Hematology Department and University Pierre et Marie Curie, Hopital Pitie-Salpetriere, Paris, France.
authors.forename: Florence
authors.initials: F
authors.lastname: Nguyen-Khac
authors.affiliation: Cancer Sciences, Faculty of Medicine, University of Southampton, UK.
authors.forename: Marta
authors.initials: M
authors.lastname: Larrayoz
authors.affiliation: First Department of Propaedeutic Medicine, University of Athens, Greece.
authors.forename: Panagiotis
authors.initials: P
authors.lastname: Panagiotidis
authors.affiliation: The Feinstein Institute for Medical Research, North Shore-Long Island Jewish Health System, Manhasset, New York, NY, USA.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Chiorazzi
authors.affiliation: Department of Hematology, Rigshospitalet, Copenhagen, Denmark.
authors.forename: Carsten Utoft
authors.initials: CU
authors.lastname: Niemann
authors.affiliation: Hematology Department, Nikea General Hospital, Piraeus, Greece.
authors.forename: Chrysoula
authors.initials: C
authors.lastname: Belessi
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: Elias
authors.initials: E
authors.lastname: Campo
authors.affiliation: Cancer Sciences, Faculty of Medicine, University of Southampton, UK.
authors.forename: Jonathan C
authors.initials: JC
authors.lastname: Strefford
authors.affiliation: Department of Immunology, Erasmus MC, University Medical Center Rotterdam, The Netherlands.
authors.forename: Anton W
authors.initials: AW
authors.lastname: Langerak
authors.affiliation: Department of Haematology, Royal Bournemouth Hospital, Bournemouth, UK.
authors.forename: David
authors.initials: D
authors.lastname: Oscier
authors.affiliation: Division of Haematology, Department of Translational Medicine, Amedeo Avogadro University of Eastern Piedmont, Novara, Italy.
authors.forename: Gianluca
authors.initials: G
authors.lastname: Gaidano
authors.affiliation: Central European Institute of Technology, Masaryk University and University Hospital Brno, Czech Republic.
authors.forename: Sarka
authors.initials: S
authors.lastname: Pospisilova
authors.affiliation: Hematology Department and University Pierre et Marie Curie, Hopital Pitie-Salpetriere, Paris, France.
authors.forename: Frederic
authors.initials: F
authors.lastname: Davi
authors.affiliation: Università Vita-Salute San Raffaele, Milan, Italy Division of Experimental Oncology and Department of Onco-Hematology, IRCCS, San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Ghia
authors.affiliation: Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden Institute of Applied Biosciences, CERTH, Thessaloniki, Greece Hematology Department and HCT Unit, G. Papanicolaou Hospital, Thessaloniki, Greece.
authors.forename: Kostas
authors.initials: K
authors.lastname: Stamatopoulos
authors.affiliation: Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden richard.rosenquist@igp.uu.se.
authors.forename: Richard
authors.initials: R
authors.lastname: Rosenquist
mesh_terms: D014408:Biomarkers, Tumor; D022801:Complementarity Determining Regions / Q000235:genetics; D020732:Cytogenetic Analysis; D005260:Female; D005787:Gene Frequency; D015322:Gene Rearrangement, B-Lymphocyte; D005803:Genes, Immunoglobulin; D006801:Humans; D007143:Immunoglobulin Heavy Chains / Q000235:genetics; D007133:Immunoglobulin Joining Region / Q000235:genetics; D007135:Immunoglobulin Variable Region / Q000235:genetics; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics* / Q000378:metabolism* / Q000401:mortality; D008297:Male; D009154:Mutation; D020641:Polymorphism, Single Nucleotide; D011379:Prognosis; D011947:Receptors, Antigen, B-Cell / Q000235:genetics* / Q000378:metabolism*
chemical_list: D014408:Biomarkers, Tumor; D022801:Complementarity Determining Regions; D007143:Immunoglobulin Heavy Chains; D007133:Immunoglobulin Joining Region; D007135:Immunoglobulin Variable Region; D011947:Receptors, Antigen, B-Cell