RESUMEN
To decipher the mutational pattern of primary CNS lymphoma (PCNSL), we performed whole-exome sequencing to a median coverage of 103 × followed by mutation verification in 9 PCNSL and validation using Sanger sequencing in 22 PCNSL. We identified a median of 202 (range: 139-251) potentially somatic single nucleotide variants (SNV) and 14 small indels (range: 7-22) with potentially protein-changing features per PCNSL. Mutations affected the B-cell receptor, toll-like receptor, and NF-κB and genes involved in chromatin structure and modifications, cell-cycle regulation, and immune recognition. A median of 22.2% (range: 20.0-24.7%) of somatic SNVs in 9 PCNSL overlaps with the RGYW motif targeted by somatic hypermutation (SHM); a median of 7.9% (range: 6.2-12.6%) affects its hotspot position suggesting a major impact of SHM on PCNSL pathogenesis. In addition to the well-known targets of aberrant SHM (aSHM) (PIM1), our data suggest new targets of aSHM (KLHL14, OSBPL10, and SUSD2). Among the four most frequently mutated genes was ODZ4 showing protein-changing mutations in 4/9 PCNSL. Together with mutations affecting CSMD2, CSMD3, and PTPRD, these findings may suggest that alterations in genes having a role in CNS development may facilitate diffuse large B-cell lymphoma manifestation in the CNS. This may point to intriguing mechanisms of CNS tropism in PCNSL.
Asunto(s)
Neoplasias del Sistema Nervioso Central/genética , Exoma , Linfoma de Células B Grandes Difuso/genética , Polimorfismo Genético , Hipermutación Somática de Inmunoglobulina , Adulto , Anciano , Neoplasias del Sistema Nervioso Central/patología , Femenino , Sitios Genéticos , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Cadenas Pesadas de Inmunoglobulina/genética , Linfoma de Células B Grandes Difuso/patología , Masculino , Glicoproteínas de Membrana/genética , Proteínas de la Membrana/genética , Persona de Mediana Edad , Proteínas Proto-Oncogénicas c-pim-1/genética , Proteínas Tirosina Fosfatasas Clase 2 Similares a Receptores/genética , Receptores de Esteroides/genética , Estudios RetrospectivosAsunto(s)
Linfoma de Burkitt/genética , Metilación de ADN , Herpesvirus Humano 4 , Secuenciación de Nucleótidos de Alto Rendimiento , Linfoma de Burkitt/virología , Línea Celular Tumoral , Exoma , Regulación Neoplásica de la Expresión Génica , Herpesvirus Humano 4/genética , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Humanos , Cariotipificación , Polimorfismo de Nucleótido SimpleRESUMEN
We describe a 5 2/12 years old male patient with a de novo deletion 1q43q44 of approximately 10.4 Mb in size. The boy presented with the classic features of chromosome 1q43q44 deletion syndrome including growth and psychomotor retardation, microcephaly, distinct facial features and various midline defects as agenesis of corpus callosum, cardiac and urogenital anomalies. Fronto-parietal simplified gyral pattern was an additional neuroimaging finding. The urogenital anomalies in our patient were remarkable in form of bladder exstrophy and severe hypogenitalism with a marked hypoplastic scrotum, small sized retractile testis and absent phallus. To the best of our knowledge, bladder exstrophy and absence phallus have not been previously reported in terminal deletion 1q43q44 syndrome. This report provides further evidence of phenotype-genotype correlation and expands the phenotypic spectrum of midline defects described with this syndrome.
Asunto(s)
Extrofia de la Vejiga/genética , Deleción Cromosómica , Cromosomas Humanos Par 1/genética , Enfermedades de los Genitales Masculinos/genética , Fenotipo , Anomalías Múltiples/genética , Anomalías Múltiples/patología , Agenesia del Cuerpo Calloso/genética , Agenesia del Cuerpo Calloso/patología , Extrofia de la Vejiga/patología , Preescolar , Estudios de Asociación Genética , Pruebas Genéticas , Enfermedades de los Genitales Masculinos/patología , Humanos , Masculino , Neuroimagen , Trastornos Psicomotores/genética , Trastornos Psicomotores/patologíaAsunto(s)
Amidohidrolasas/deficiencia , Emparejamiento Base/genética , Enfermedad de Canavan/genética , Cromosomas Humanos Par 17/genética , Análisis de Secuencia por Matrices de Oligonucleótidos/métodos , Polimorfismo de Nucleótido Simple/genética , Eliminación de Secuencia/genética , Alelos , Amidohidrolasas/genética , Enfermedad de Canavan/enzimología , Niño , Exones/genética , Homocigoto , Humanos , Masculino , Reacción en Cadena de la PolimerasaAsunto(s)
Deleción Cromosómica , Cromosomas Humanos Par 14 , Leucemia Linfocítica Crónica de Células B/genética , Linfoma de Células B/genética , Factor 3 Asociado a Receptor de TNF/genética , Animales , Humanos , Leucemia Linfocítica Crónica de Células B/fisiopatología , Linfoma de Células B/fisiopatologíaRESUMEN
To determine the pattern of genetic alterations in primary central nervous system lymphomas (PCNSL), 19 PCNSL were studied by high-density single-nucleotide polymorphism arrays. Recurrent losses involved 6p21.32, 6q21, 8q12-12.2, 9p21.3, 3p14.2, 4q35.2, 10q23.21 and 12p13.2, whereas gains involved 18q21-23, 19q13.31, 19q13.43 and the entire chromosomes X and 12. Partial uniparental disomies (pUPDs) were identified in 6p and 9p21.3. These genomic alterations affected the HLA locus, the CDKN2A/p16, CDKN2B/p15 and MTAP, as well as the PRDM1, FAS, MALT1, and BCL2 genes. Increased methylation values of the CDKN2A/p16 promoter region were detected in 75% (6/8) PCNSL. Gene expression profiling showed 4/21 (20%) minimal common regions of imbalances to be associated with a differential mRNA expression affecting the FAS, STAT6, CD27, ARHGEF6 and SEPT6 genes. Collectively, this study unraveled novel genomic imbalances and pUPD with a high resolution in PCNSL and identified target genes of potential relevance in the pathogenesis of this lymphoma entity.