RESUMEN
Which genetic alterations drive tumorigenesis and how they evolve over the course of disease and therapy are central questions in cancer biology. Here we identify 44 recurrently mutated genes and 11 recurrent somatic copy number variations through whole-exome sequencing of 538 chronic lymphocytic leukaemia (CLL) and matched germline DNA samples, 278 of which were collected in a prospective clinical trial. These include previously unrecognized putative cancer drivers (RPS15, IKZF3), and collectively identify RNA processing and export, MYC activity, and MAPK signalling as central pathways involved in CLL. Clonality analysis of this large data set further enabled reconstruction of temporal relationships between driver events. Direct comparison between matched pre-treatment and relapse samples from 59 patients demonstrated highly frequent clonal evolution. Thus, large sequencing data sets of clinically informative samples enable the discovery of novel genes associated with cancer, the network of relationships between the driver events, and their impact on disease relapse and clinical outcome.
Asunto(s)
Progresión de la Enfermedad , Evolución Molecular , Leucemia Linfocítica Crónica de Células B/genética , Mutación/genética , Recurrencia Local de Neoplasia/genética , Transformación Celular Neoplásica/genética , Células Clonales/metabolismo , Células Clonales/patología , Variaciones en el Número de Copia de ADN/genética , Exoma/genética , Genes myc/genética , Humanos , Factor de Transcripción Ikaros/genética , Leucemia Linfocítica Crónica de Células B/diagnóstico , Leucemia Linfocítica Crónica de Células B/patología , Leucemia Linfocítica Crónica de Células B/terapia , Sistema de Señalización de MAP Quinasas/genética , Pronóstico , Procesamiento Postranscripcional del ARN/genética , Transporte de ARN/genética , Proteínas Ribosómicas/genética , Resultado del TratamientoRESUMEN
Juvenile myelomonocytic leukemia (JMML) is an aggressive myeloproliferative neoplasm of childhood associated with a poor prognosis. Recently, massively parallel sequencing has identified recurrent mutations in the SKI domain of SETBP1 in a variety of myeloid disorders. These lesions were detected in nearly 10% of patients with JMML and have been characterized as secondary events. We hypothesized that rare subclones with SETBP1 mutations are present at diagnosis in a large portion of patients who relapse, but are below the limits of detection for conventional deep sequencing platforms. Using droplet digital polymerase chain reaction, we identified SETBP1 mutations in 17/56 (30%) of patients who were treated in the Children's Oncology Group sponsored clinical trial, AAML0122. Five-year event-free survival in patients with SETBP1 mutations was 18% ± 9% compared with 51% ± 8% for those without mutations (P = .006).
Asunto(s)
Proteínas Portadoras/genética , Leucemia Mielomonocítica Juvenil/genética , Mutación/genética , Proteínas Nucleares/genética , Preescolar , Femenino , Estudios de Seguimiento , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Lactante , Recién Nacido , Leucemia Mielomonocítica Juvenil/patología , Masculino , Estadificación de Neoplasias , Pronóstico , Tasa de SupervivenciaRESUMEN
Telomere length in chronic lymphocytic leukemia (CLL) has been shown to be of prognostic importance, but the analyses have largely been executed on heterogeneous patient cohorts outside of clinical trials. In the present study, we performed a comprehensive analysis of telomere length associations in the well characterized CLL8 trial (n = 620) of the German CLL study group, with validation in a representative cohort of the CLL4 trial (n = 293). Absolute telomere length was analyzed using quantitative-PCR. Apart from identifying associations of short telomere length with adverse prognostic factors and survival, the study identified cases with 17p- and 11q- associated with TP53 and ATM loss, respectively, to have the shortest telomeres, even when these aberrations were present in small subclones. Thus, telomere shortening may precede acquisition of the high-risk aberrations, contributing to disease evolution. In line with this, telomere shortening was associated with an increase in genomic complexity as well as clonal evolution, highlighting its importance as a biomarker especially in monitoring disease progression in non-high-risk CLL.
Asunto(s)
Evolución Clonal/genética , Leucemia Linfocítica Crónica de Células B/genética , Acortamiento del Telómero/genética , Telómero/genética , Estudios de Casos y Controles , Femenino , Genómica/métodos , Humanos , Masculino , Persona de Mediana Edad , Pronóstico , Estudios ProspectivosRESUMEN
Juvenile myelomonocytic leukemia (JMML) is a myeloproliferative neoplasm (MPN) of childhood with a poor prognosis. Mutations in NF1, NRAS, KRAS, PTPN11 or CBL occur in 85% of patients, yet there are currently no risk stratification algorithms capable of predicting which patients will be refractory to conventional treatment and could therefore be candidates for experimental therapies. In addition, few molecular pathways aside from the RAS-MAPK pathway have been identified that could serve as the basis for such novel therapeutic strategies. We therefore sought to genomically characterize serial samples from patients at diagnosis through relapse and transformation to acute myeloid leukemia to expand knowledge of the mutational spectrum in JMML. We identified recurrent mutations in genes involved in signal transduction, splicing, Polycomb repressive complex 2 (PRC2) and transcription. Notably, the number of somatic alterations present at diagnosis appears to be the major determinant of outcome.