RESUMO
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.
Assuntos
Neoplasias do Sistema Nervoso Central/genética , Exoma , Linfoma Difuso de Grandes Células B/genética , Polimorfismo Genético , Hipermutação Somática de Imunoglobulina , Adulto , Idoso , Neoplasias do Sistema Nervoso Central/patologia , Feminino , Loci Gênicos , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Cadeias Pesadas de Imunoglobulinas/genética , Linfoma Difuso de Grandes Células B/patologia , Masculino , Glicoproteínas de Membrana/genética , Proteínas de Membrana/genética , Pessoa de Meia-Idade , Proteínas Proto-Oncogênicas c-pim-1/genética , Proteínas Tirosina Fosfatases Classe 2 Semelhantes a Receptores/genética , Receptores de Esteroides/genética , Estudos RetrospectivosAssuntos
Linfoma de Burkitt/genética , Metilação de DNA , Herpesvirus Humano 4 , Sequenciamento de Nucleotídeos em Larga Escala , Linfoma de Burkitt/virologia , Linhagem Celular Tumoral , Exoma , Regulação Neoplásica da Expressão Gênica , Herpesvirus Humano 4/genética , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Cariotipagem , Polimorfismo de Nucleotídeo ÚnicoAssuntos
Deleção Cromossômica , Cromossomos Humanos Par 14 , Leucemia Linfocítica Crônica de Células B/genética , Linfoma de Células B/genética , Fator 3 Associado a Receptor de TNF/genética , Animais , Humanos , Leucemia Linfocítica Crônica de Células B/fisiopatologia , Linfoma de Células B/fisiopatologiaRESUMO
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.