RESUMO
Recurrent mutations within EGR2 were recently reported in advanced-stage chronic lymphocytic leukemia (CLL) patients and associated with a worse outcome. To study their prognostic impact, 2403 CLL patients were examined for mutations in the EGR2 hotspot region including a screening (n=1283) and two validation cohorts (UK CLL4 trial patients, n=366; CLL Research Consortium (CRC) patients, n=490). Targeted deep-sequencing of 27 known/postulated CLL driver genes was also performed in 38 EGR2-mutated patients to assess concurrent mutations. EGR2 mutations were detected in 91/2403 (3.8%) investigated cases, and associated with younger age at diagnosis, advanced clinical stage, high CD38 expression and unmutated IGHV genes. EGR2-mutated patients frequently carried ATM lesions (42%), TP53 aberrations (18%) and NOTCH1/FBXW7 mutations (16%). EGR2 mutations independently predicted shorter time-to-first-treatment (TTFT) and overall survival (OS) in the screening cohort; they were confirmed associated with reduced TTFT and OS in the CRC cohort and independently predicted short OS from randomization in the UK CLL4 cohort. A particularly dismal outcome was observed among EGR2-mutated patients who also carried TP53 aberrations. In summary, EGR2 mutations were independently associated with an unfavorable prognosis, comparable to CLL patients carrying TP53 aberrations, suggesting that EGR2-mutated patients represent a new patient subgroup with very poor outcome.
Assuntos
Proteína 2 de Resposta de Crescimento Precoce/genética , Leucemia Linfocítica Crônica de Células B/genética , Mutação , Adulto , Idoso , Feminino , Genes p53 , Humanos , Leucemia Linfocítica Crônica de Células B/classificação , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Leucemia Linfocítica Crônica de Células B/mortalidade , Masculino , Pessoa de Meia-Idade , Modelos de Riscos ProporcionaisAssuntos
2',5'-Oligoadenilato Sintetase/genética , Cromossomos Humanos Par 12/química , Íntrons , Leucemia Linfocítica Crônica de Células B/genética , Polimorfismo de Nucleotídeo Único , Alelos , Estudos de Casos e Controles , Mapeamento Cromossômico , Frequência do Gene , Loci Gênicos , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Leucemia Linfocítica Crônica de Células B/patologia , Razão de Chances , RiscoRESUMO
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.
Assuntos
Leucemia Linfocítica Crônica de Células B/diagnóstico , Leucemia Linfocítica Crônica de Células B/genética , Mutação , Idoso , Citogenética , Análise Mutacional de DNA , Europa (Continente) , Feminino , Deleção de Genes , Humanos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Fosfoproteínas/genética , Polimorfismo de Nucleotídeo Único , Prognóstico , Fatores de Processamento de RNA , Receptor Notch1/genética , Recidiva , Ribonucleoproteína Nuclear Pequena U2/genética , Fatores de Tempo , Proteína Supressora de Tumor p53/genéticaAssuntos
Leucemia Linfocítica Crônica de Células B/genética , Proteína 3 com Repetições IAP de Baculovírus , Estudos de Coortes , Humanos , Proteínas Inibidoras de Apoptose/genética , Fator 88 de Diferenciação Mieloide/genética , Fosfoproteínas/genética , Prognóstico , Fatores de Processamento de RNA , Receptor Notch1/genética , Ribonucleoproteína Nuclear Pequena U2/genética , Proteína Supressora de Tumor p53/genética , Ubiquitina-Proteína LigasesRESUMO
Recent studies have revealed recurrent mutations of the NOTCH1, SF3B1 and BIRC3 genes in chronic lymphocytic leukemia (CLL), especially among aggressive, chemorefractory cases. Nevertheless, it is currently unknown whether their presence may differ in subsets of patients carrying stereotyped B-cell receptors and also exhibiting distinct prognoses. Here, we analyzed the mutation status of NOTCH1, SF3B1 and BIRC3 in three subsets with particularly poor prognosis, that is, subset #1, #2 and #8, aiming to explore links between genetic aberrations and immune signaling. A remarkably higher frequency of SF3B1 mutations was revealed in subset #2 (44%) versus subset #1 and #8 (4.6% and 0%, respectively; P<0.001). In contrast, the frequency of NOTCH1 mutations in subset #2 was only 8%, lower than the frequency observed in either subset #1 or #8 (19% and 14%, respectively; P=0.04 for subset #1 versus #2). No associations were found for BIRC3 mutations that overall were rare. The apparent non-random association of certain mutations with stereotyped CLL subsets alludes to subset-biased acquisition of genomic aberrations, perhaps consistent with particular antigen/antibody interactions. These novel findings assist in unraveling specific mechanisms underlying clinical aggressiveness in poor-prognostic stereotyped subsets, with far-reaching implications for understanding their clonal evolution and implementing biologically oriented therapy.
Assuntos
Biomarcadores Tumorais/genética , Proteínas Inibidoras de Apoptose/genética , Leucemia Linfocítica Crônica de Células B/classificação , Leucemia Linfocítica Crônica de Células B/genética , Mutação/genética , Fosfoproteínas/genética , Receptor Notch1/genética , Ribonucleoproteína Nuclear Pequena U2/genética , Proteína 3 com Repetições IAP de Baculovírus , Estudos de Coortes , DNA de Neoplasias/genética , Seguimentos , Humanos , Leucemia Linfocítica Crônica de Células B/mortalidade , Reação em Cadeia da Polimerase , Prognóstico , Fatores de Processamento de RNA , Taxa de Sobrevida , Ubiquitina-Proteína LigasesRESUMO
In chronic lymphocytic leukemia (CLL), the microenvironment influences gene expression patterns; however, knowledge is limited regarding the extent to which methylation changes with time and exposure to specific microenvironments. Using high-resolution 450K arrays, we provide the most comprehensive DNA methylation study of CLL to date, analyzing paired diagnostic/follow-up samples from IGHV-mutated/untreated and IGHV-unmutated/treated patients (n=36) and patient-matched peripheral blood and lymph node samples (n=20). On an unprecedented scale, we revealed 2239 differentially methylated CpG sites between IGHV-mutated and unmutated patients, with the majority of sites positioned outside annotated CpG islands. Intriguingly, CLL prognostic genes (for example, CLLU1, LPL, ZAP70 and NOTCH1), epigenetic regulator (for example, HDAC9, HDAC4 and DNMT3B), B-cell signaling (for example, IBTK) and numerous TGF-ß and NF-κB/TNF pathway genes were alternatively methylated between subgroups. Contrary, DNA methylation over time was deemed rather stable with few recurrent changes noted within subgroups. Although a larger number of non-recurrent changes were identified among IGHV-unmutated relative to mutated cases over time, these equated to a low global change. Similarly, few changes were identified between compartment cases. Altogether, we reveal CLL subgroups to display unique methylation profiles and unveil methylation as relatively stable over time and similar within different CLL compartments, implying aberrant methylation as an early leukemogenic event.