RESUMO
The distinction between classical Hodgkin lymphoma (HL) and anaplastic large cell lymphoma (ALCL) is not problematic in most instances. In rare situations, HL may present with a sinusoidal infiltrative pattern that may mimic ALCL. It is important to use a battery of immunohistochemical stains to differentiate between these two entities as therapy and clinical behavior are different. We present a case of a young woman who presents with the very unusual intrasinusoidal infiltrative pattern.
RESUMO
In this study, we define the genetic landscape of mantle cell lymphoma (MCL) through exome sequencing of 56 cases of MCL. We identified recurrent mutations in ATM, CCND1, MLL2, and TP53. We further identified a number of novel genes recurrently mutated in patients with MCL including RB1, WHSC1, POT1, and SMARCA4. We noted that MCLs have a distinct mutational profile compared with lymphomas from other B-cell stages. The ENCODE project has defined the chromatin structure of many cell types. However, a similar characterization of primary human mature B cells has been lacking. We defined, for the first time, the chromatin structure of primary human naïve, germinal center, and memory B cells through chromatin immunoprecipitation and sequencing for H3K4me1, H3K4me3, H3Ac, H3K36me3, H3K27me3, and PolII. We found that somatic mutations that occur more frequently in either MCLs or Burkitt lymphomas were associated with open chromatin in their respective B cells of origin, naïve B cells, and germinal center B cells. Our work thus elucidates the landscape of gene-coding mutations in MCL and the critical interplay between epigenetic alterations associated with B-cell differentiation and the acquisition of somatic mutations in cancer.
Assuntos
Linfócitos B/metabolismo , Cromatina/genética , Genômica , Linfoma de Célula do Manto/genética , Mutação , Proteínas Mutadas de Ataxia Telangiectasia/genética , Linfoma de Burkitt/genética , Linfoma de Burkitt/patologia , Cromatina/metabolismo , Ciclina D1/genética , DNA Helicases/genética , Proteínas de Ligação a DNA/genética , Epigênese Genética , Exoma/genética , Redes Reguladoras de Genes , Centro Germinativo/metabolismo , Centro Germinativo/patologia , Histona-Lisina N-Metiltransferase/genética , Histonas/genética , Histonas/metabolismo , Humanos , Linfoma de Célula do Manto/patologia , Metilação , Proteínas de Neoplasias/genética , Proteínas Nucleares/genética , Proteínas Repressoras/genética , Proteína do Retinoblastoma/genética , Análise de Sequência de DNA , Complexo Shelterina , Proteínas de Ligação a Telômeros/genética , Fatores de Transcrição/genética , Proteína Supressora de Tumor p53/genéticaRESUMO
Lymphoma is a rare neoplasm in the breast. In this location, it may be primary or secondary, depending on whether there is lymphoma elsewhere in the body. The most common presentation of breast lymphoma is a painless palpable mass, indistinguishable from that of breast carcinoma, although the treatment regimens for these two neoplasms differ vastly. Knowledge of the varied mammographic and sonographic presentations of breast lymphoma should prompt more frequent recognition of this unusual malignant entity. Proper diagnosis of this neoplasm is of the utmost importance to guide appropriate treatment planning and prevent unnecessary and potentially harmful surgery. We describe secondary breast lymphoma in a woman who had been diagnosed and treated for non-Hodgkin's lymphoma several years earlier.
RESUMO
Diffuse large B-cell lymphoma (DLBCL) is the most common form of lymphoma in adults. The disease exhibits a striking heterogeneity in gene expression profiles and clinical outcomes, but its genetic causes remain to be fully defined. Through whole genome and exome sequencing, we characterized the genetic diversity of DLBCL. In all, we sequenced 73 DLBCL primary tumors (34 with matched normal DNA). Separately, we sequenced the exomes of 21 DLBCL cell lines. We identified 322 DLBCL cancer genes that were recurrently mutated in primary DLBCLs. We identified recurrent mutations implicating a number of known and not previously identified genes and pathways in DLBCL including those related to chromatin modification (ARID1A and MEF2B), NF-κB (CARD11 and TNFAIP3), PI3 kinase (PIK3CD, PIK3R1, and MTOR), B-cell lineage (IRF8, POU2F2, and GNA13), and WNT signaling (WIF1). We also experimentally validated a mutation in PIK3CD, a gene not previously implicated in lymphomas. The patterns of mutation demonstrated a classic long tail distribution with substantial variation of mutated genes from patient to patient and also between published studies. Thus, our study reveals the tremendous genetic heterogeneity that underlies lymphomas and highlights the need for personalized medicine approaches to treating these patients.
Assuntos
Heterogeneidade Genética , Linfoma Difuso de Grandes Células B/genética , Adulto , Sequência de Bases , Linhagem Celular Tumoral , Classe I de Fosfatidilinositol 3-Quinases , Análise Mutacional de DNA , DNA de Neoplasias/genética , Exoma , Expressão Gênica , Variação Genética , Humanos , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Modelos Moleculares , Dados de Sequência Molecular , Terapia de Alvo Molecular , Mutação , Oncogenes , Fosfatidilinositol 3-Quinases/química , Fosfatidilinositol 3-Quinases/genética , Conformação Proteica , Proteínas Proto-Oncogênicas c-kit/genética , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/genética , Homologia de Sequência do Ácido Nucleico , Transdução de Sinais/genéticaRESUMO
Burkitt lymphoma is characterized by deregulation of MYC, but the contribution of other genetic mutations to the disease is largely unknown. Here, we describe the first completely sequenced genome from a Burkitt lymphoma tumor and germline DNA from the same affected individual. We further sequenced the exomes of 59 Burkitt lymphoma tumors and compared them to sequenced exomes from 94 diffuse large B-cell lymphoma (DLBCL) tumors. We identified 70 genes that were recurrently mutated in Burkitt lymphomas, including ID3, GNA13, RET, PIK3R1 and the SWI/SNF genes ARID1A and SMARCA4. Our data implicate a number of genes in cancer for the first time, including CCT6B, SALL3, FTCD and PC. ID3 mutations occurred in 34% of Burkitt lymphomas and not in DLBCLs. We show experimentally that ID3 mutations promote cell cycle progression and proliferation. Our work thus elucidates commonly occurring gene-coding mutations in Burkitt lymphoma and implicates ID3 as a new tumor suppressor gene.
Assuntos
Linfoma de Burkitt/genética , Mutação , Amônia-Liases/genética , Sequência de Bases , Linhagem Celular Tumoral , Chaperonina com TCP-1/genética , DNA Helicases/genética , Proteínas de Ligação a DNA , Subunidades alfa G12-G13 de Proteínas de Ligação ao GTP/genética , Genes myc/genética , Genoma Humano , Glutamato Formimidoiltransferase/genética , Proteínas de Homeodomínio/genética , Humanos , Proteínas Inibidoras de Diferenciação/genética , Peptídeos e Proteínas de Sinalização Intracelular , Linfoma Difuso de Grandes Células B/genética , Proteínas de Membrana/genética , Dados de Sequência Molecular , Enzimas Multifuncionais , Proteínas de Neoplasias/genética , Proteínas Nucleares/genética , Proteínas Proto-Oncogênicas c-ret/genética , Análise de Sequência de DNA , Fatores de Transcrição/genética , Translocação GenéticaRESUMO
A role for microRNA (miRNA) has been recognized in nearly every biologic system examined thus far. A complete delineation of their role must be preceded by the identification of all miRNAs present in any system. We elucidated the complete small RNA transcriptome of normal and malignant B cells through deep sequencing of 31 normal and malignant human B-cell samples that comprise the spectrum of B-cell differentiation and common malignant phenotypes. We identified the expression of 333 known miRNAs, which is more than twice the number previously recognized in any tissue type. We further identified the expression of 286 candidate novel miRNAs in normal and malignant B cells. These miRNAs were validated at a high rate (92%) using quantitative polymerase chain reaction, and we demonstrated their application in the distinction of clinically relevant subgroups of lymphoma. We further demonstrated that a novel miRNA cluster, previously annotated as a hypothetical gene LOC100130622, contains 6 novel miRNAs that regulate the transforming growth factor-ß pathway. Thus, our work suggests that more than a third of the miRNAs present in most cellular types are currently unknown and that these miRNAs may regulate important cellular functions.