RESUMO
The term gray zone lymphoma has been applied to tumors that demonstrate transitional morphologic and immunophenotypic features between classical Hodgkin's lymphoma and diffuse large B-cell lymphoma, especially primary mediastinal large B-cell lymphoma. Histopathological and genetic data are limited for these unusual cases. We analyzed cases of gray zone lymphoma (n=27), mediastinal composite lymphoma (n=3) and mediastinal synchronous/metachronous lymphoma (n=3) by morphology, immunophenotyping and fluorescence in situ hybridization. Mediastinal involvement was assured in 24/33 patients (73%). The patient cohort showed a male predominance (M:F ratio; 20:13) and a median age of 32 years (range, 16-91 years). Patients with mediastinal disease were significantly younger (median age: 29.5 years) than patients presenting without evident mediastinal disease (median age: 55 years). Gains including amplifications in 2p16.1 (REL/BCL11A locus) were observed in 33% of all patients, whereas alterations affecting the JAK2/PDL2 locus in 9p24.1 were present in 55%. Further studies revealed rearrangement of the CIITA locus at 16p13.13 in 8/30 cases (27%) and 7/26 cases (27%) demonstrated gains of 8q24 (MYC). Genetic aberrations involving 2p16.1, 9p24.1 and 8q24 showed a higher incidence in cases with evident mediastinal involvement. However, this was not statistically significant when compared with cases without known mediastinal involvement. Twelve of the 27 cases of gray zone lymphoma were morphologically more reminiscent of classical Hodgkin's lymphoma, whereas the other gray zone lymphomas presented with morphological features more closely resembling large B-cell lymphoma. Both morphological groups of gray zone lymphoma were similarly positive for Cyclin E (75 and 93%) and p63 (50 and 53%, respectively) expression. These findings further support a close relationship between gray zone lymphoma, classical Hodgkin's lymphoma and primary mediastinal large B-cell lymphoma, and suggest that some cases of gray zone lymphoma without mediastinal disease may share similar genetic alterations.
Assuntos
Biomarcadores Tumorais/análise , Aberrações Cromossômicas , Doença de Hodgkin/genética , Linfoma Difuso de Grandes Células B/genética , Linfoma/genética , Neoplasias do Mediastino/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Regulação Neoplásica da Expressão Gênica , Doença de Hodgkin/classificação , Doença de Hodgkin/imunologia , Doença de Hodgkin/patologia , Humanos , Imuno-Histoquímica , Imunofenotipagem , Hibridização in Situ Fluorescente , Linfoma/classificação , Linfoma/imunologia , Linfoma/patologia , Linfoma Difuso de Grandes Células B/classificação , Linfoma Difuso de Grandes Células B/imunologia , Linfoma Difuso de Grandes Células B/patologia , Masculino , Neoplasias do Mediastino/classificação , Neoplasias do Mediastino/imunologia , Neoplasias do Mediastino/patologia , Pessoa de Meia-Idade , Prognóstico , Adulto JovemRESUMO
Chromosomal translocations are critically involved in the molecular pathogenesis of B-cell lymphomas, and highly recurrent and specific rearrangements have defined distinct molecular subtypes linked to unique clinicopathological features. In contrast, several well-characterized lymphoma entities still lack disease-defining translocation events. To identify novel fusion transcripts resulting from translocations, we investigated two Hodgkin lymphoma cell lines by whole-transcriptome paired-end sequencing (RNA-seq). Here we show a highly expressed gene fusion involving the major histocompatibility complex (MHC) class II transactivator CIITA (MHC2TA) in KM-H2 cells. In a subsequent evaluation of 263 B-cell lymphomas, we also demonstrate that genomic CIITA breaks are highly recurrent in primary mediastinal B-cell lymphoma (38%) and classical Hodgkin lymphoma (cHL) (15%). Furthermore, we find that CIITA is a promiscuous partner of various in-frame gene fusions, and we report that CIITA gene alterations impact survival in primary mediastinal B-cell lymphoma (PMBCL). As functional consequences of CIITA gene fusions, we identify downregulation of surface HLA class II expression and overexpression of ligands of the receptor molecule programmed cell death 1 (CD274/PDL1 and CD273/PDL2). These receptor-ligand interactions have been shown to impact anti-tumour immune responses in several cancers, whereas decreased MHC class II expression has been linked to reduced tumour cell immunogenicity. Thus, our findings suggest that recurrent rearrangements of CIITA may represent a novel genetic mechanism underlying tumour-microenvironment interactions across a spectrum of lymphoid cancers.
Assuntos
Linfoma de Células B/genética , Proteínas Nucleares/genética , Proteínas de Fusão Oncogênica/genética , Transativadores/genética , Translocação Genética/genética , Antígenos CD/genética , Antígenos CD/metabolismo , Antígeno B7-1/genética , Antígeno B7-1/metabolismo , Antígeno B7-H1 , Sequência de Bases , Linhagem Celular Tumoral , Pontos de Quebra do Cromossomo , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Doença de Hodgkin/genética , Humanos , Hibridização in Situ Fluorescente , Células Jurkat , Ativação Linfocitária , Dados de Sequência Molecular , Proteína 2 Ligante de Morte Celular Programada 1 , RNA Neoplásico/genética , Linfócitos T/imunologia , Linfócitos T/metabolismo , Linfócitos T/patologia , Análise Serial de Tecidos , Microambiente TumoralRESUMO
We evaluated retrospectively the cryptic t(12;21)(p13;q22) in 15 children with early B-lineage acute lymphocytic leukemia who had a normal karyotype by using the locus specific probes of TEL and AML1 genes in a dual color fluorescence in situ hybridization (FISH). The FISH analysis revealed six patients with the fusion gene TEL/AML1 on chromosome 21, three of whom possessed a double fusion gene. In addition, the AML1 probe revealed hyperdiploid clones that were not detected in the conventional cytogenetic analysis. A discrepancy between the proportion of cells with the fusion gene in interphase nuclei and metaphases was noted.