Background The aim of this study was to determine the impact of a gain of the MALT1 gene on gene expression and clinical parameters in diffuse large B-cell lymphoma.Design and Methods We analyzed 116 cases of diffuse large B-cell lymphoma by fluorescence in situ hybridization, array-based comparative genomic hybridization, and transcriptional profiling.Results A gain of 18q21 including MALT1 was detected in 44 cases (38%) and was accompanied by a gain of BCL2 in 43 cases. All cases with a 18q21/MALT1 gain showed BCL2 protein whereas 79% in the group without a 18q21/MALT1 gain did so (p
Bei einem 48-jahrigen Patienten wird in der Routineuntersuchung durch seinen Hausarzt eine normochrome, normozytare Anamie festgestellt. In der Osophago-Gastro-Duodenoskopie im Rahmen der Anamieabklarung findet sich im Magenantrum eine die Schleimhaut vorwolbende Raumforderung mit zentraler Einziehung.
Primary extranodal malignant lymphomas are most often localized in the stomach. In contrast to gastric carcinomas, primary gastric non-Hodgkin's lymphomas show an increasing incidence. According to their grade of malignancy they are divided into low-grade and high-grade non-Hodgkin's lymphomas and according to their immunophenotype into B-cell and T-cell non-Hodgkin's lymphomas. In most cases they show a B-cell phenotype while high-grade tumors are more frequent than those of low-grade malignancy. However, primary gastric Hodgkin's disease is still a rarity. A new entity, the so-called low-grade B-cell non-Hodgkin's lymphoma of mucosa-associated lymphoid tissue (MALT) type, is characterized by a diffuse infiltrate of centrocyte-like cells intermingled with immunoblasts of the same clone, plasma cell differentiation of the tumor cells, lymphoepithelial lesions, and reactive intratumoral lymphoid follicles. It may secondarily transform into a high-grade B-cell lymphoma but remains limited to the stomach for a considerable period of time with a favourable prognosis. The most important prognostic factors of primary gastric lymphomas are stage at initial diagnosis, classification and grading according to the histopathological concept of the MALT, and depth of infiltration. Although a considerable number of early stage gastric lymphomas achieve complete remission after surgical therapy only, primary treatment of gastric lymphoma is still controverted, thus underlining the urgency of a multicenter prospective study. Chronic Helicobacter pylori infection may play a major role in the pathogenesis of low-grade B-cell lymphoma of MALT type. Complete remission of some cases of low-grade B-cell lymphoma of MALT type with concomitant Helicobacter pylori gastritis after Helicobacter pylori eradication may lead to a new pathogenetic, therapeutic, and prognostic concept.
The epigenetic dysregulation of tumor suppressor genes is an important driver of human carcinogenesis. We have combined genome-wide DNA methylation analyses and gene expression profiling after pharmacological DNA demethylation with functional screening to identify novel tumor suppressors in diffuse large B cell lymphoma (DLBCL). We find that a CpG island in the promoter of the dual-specificity phosphatase DUSP4 is aberrantly methylated in nodal and extranodal DLBCL, irrespective of ABC or GCB subtype, resulting in loss of DUSP4 expression in 75% of >200 examined cases. The DUSP4 genomic locus is further deleted in up to 13% of aggressive B cell lymphomas, and the lack of DUSP4 is a negative prognostic factor in three independent cohorts of DLBCL patients. Ectopic expression of wild-type DUSP4, but not of a phosphatase-deficient mutant, dephosphorylates c-JUN N-terminal kinase (JNK) and induces apoptosis in DLBCL cells. Pharmacological or dominant-negative JNK inhibition restricts DLBCL survival in vitro and in vivo and synergizes strongly with the Bruton’s tyrosine kinase inhibitor ibrutinib. Our results indicate that DLBCL cells depend on JNK signaling for survival. This finding provides a mechanistic basis for the clinical development of JNK inhibitors in DLBCL, ideally in synthetic lethal combinations with inhibitors of chronic active B cell receptor signaling.
Mucosa-associated lymphoid tissue (MALT) lymphoma originates from a background of diverse chronic inflammatory disorders at various anatomic sites. The genetics underlying its development, particularly in those associated with autoimmune disorders, is poorly characterized. By whole exome sequencing of 21 cases of MALT lymphomas of the salivary gland and thyroid, we have identified recurrent somatic mutations in 2 G-protein coupled receptors (GPR34 and CCR6) not previously reported in human malignancies, 3 genes (PIK3CD, TET2, TNFRSF14) not previously implicated in MALT lymphoma, and a further 2 genes (TBL1XR1, NOTCH1) recently described in MALT lymphoma. The majority of mutations in GPR34 and CCR6 were nonsense and frameshift changes clustered in the C-terminal cytoplasmic tail, and would result in truncated proteins that lack the phosphorylation motif important for β-arrestin-mediated receptor desensitization and internalization. Screening of these newly identified mutations, together with previously defined genetic changes, revealed distinct mutation profiles in MALT lymphoma of various sites, with those of salivary gland characterized by frequent TBL1XR1 and GPR34 mutations, thyroid by frequent TET2, TNFRSF14 and PIK3CD mutations, and ocular adnexa by frequent TNFAIP3 mutation. Interestingly, in MALT lymphoma of the salivary gland, there was a significant positive association between TBL1XR1 mutation and GPR34 mutation/translocation (P=0.0002). In those of ocular adnexa, TBL1XR1 mutation was mutually exclusive from TNFAIP3 mutation (P=0.049), but significantly associated with IGHV3-23 usage (P=0.03) and PIK3CD mutation (P=0.009). These findings unravel novel insights into the molecular mechanisms of MALT lymphoma and provide further evidence for potential oncogenic co-operation between receptor signaling and genetic changes.
