Translocations involving the immunoglobulin heavy chain locus (IGH@) at chromosome band 14q32 are common in mature B-cell neoplasms, but are rare in B-cell precursor acute lymphoblastic leukemia ...(BCP-ALL). Here, we report the translocation, t(6;14)(p22;q32), involving IGH@ as a novel recurrent translocation in 13 BCP-ALL patients. Fluorescence in situ hybridization and long-distance inverse polymerase chain reaction (PCR) identified ID4 as the partner gene. Breakpoints were scattered over a 19kb region centromeric of ID4. Quantitative real-time PCR showed up-regulation of ID4 mRNA. All patients had deletions of CDKN2A and PAX5 located on the short arm of chromosome 9, frequently as a result of an isochromosome, i(9)(q10) (9/13, 69%). This study defines a new subgroup of BCP-ALL characterized by ID4 over-expression and CDKN2A and PAX5 deletions. Preliminary survival data suggest that this subgroup may be associated with a good response to therapy.
Recent studies suggest that mutations in the
LGI1/Epitempin gene cause autosomal dominant lateral temporal epilepsy. This gene encodes a protein of unknown function, which we postulate is secreted. ...The LGI1 protein has leucine-rich repeats in the N-terminal sequence and a tandem repeat (which we named EPTP) in its C-terminal region. A redefinition of the C-terminal repeat and the application of sensitive sequence analysis methods enabled us to define a new superfamily of proteins carrying varying numbers of the novel EPTP repeats in combination with various extracellular domains. Genes encoding proteins of this family are located in genomic regions associated with epilepsy and other neurological disorders.
The EPTP repeat, a novel type of repeat that is present in vertebrate proteins involved in neurological disorders.
Burkitt lymphoma (BL) has a characteristic clinical presentation, morphology, immunophenotype and primary chromosomal aberration, i.e. the translocation t(8;14) (q24;q32) or its variants. However, ...diagnostic dilemmas may arise in daily practice due to overlap of BL with subsets of other aggressive, mature B cell lymphomas such as a small subset of diffuse large B cell lymphomas (DLBCL). Recently, two gene expression studies have described a distinct molecular profile for BL, but also showed the persistence of some cases intermediate between BL and DLBCL. An alternative approach to define BL is to consider (cyto)genetic data, in particular chromosomal abnormalities other than the t(8;14) or its variants. In this study the “Mitelman Database of Chromosome Aberrations in Cancer”, harboring the majority of all published neoplasia related karyotypes, was explored to define a cytogenetic profile of “true” BL. To that end a core subset of BL was defined by
a histologic diagnosis of BL,the presence of a t(8;14), t(2;8) or t(8;22) indicating a MYC/IG breakpoint, andthe absence of a 3q27/BCL6, 18q21/BCL2 or 11q13/CCND1 breakpoint additional to the 8q24/MYC breakpoint.
These core BL (N=481) showed a very low complexity of chromosomal changes, with 40% of the cases having the IG-MYC fusion as the sole abnormality; in the remaining cases additional recurrent and partially exclusive abnormalities included gains at chromosomes 1q, 7 and 12, and losses of 6q, 13q32-34 and 17p. No differences were found between pediatric (N=205) and adult patients (N=215). Moreover, no differences were found between such core BL cases published before (N= 280) and after 1994 (N=201) indicating that historical changes in classification systems had no major impact on this profile.
The genetic profiles and age distribution of the core subset were significantly different from BL with an 8q24 breakpoint not affecting one of the three IG loci (N=13), lymphomas that were diagnosed as BL but had a translocation involving 18q21/BCL2, 3q27/BCL6 or 11q13/BCL1 additional to a breakpoint at 8q24/MYC (“double hit BL”; N=44), and from other morphological types of lymphomas with an 8q24/MYC breakpoint (N=327; 256/327 cases had an IG-MYC breakpoint). These groups showed an other age distribution and a higher cytogenetic complexity than the core subset of BL. BL without a detectable 8q24/MYC breakpoint (N=108) might have been heterogeneous and deserves further studies. We suggest that, concordant with the WHO classification to be published in 2008, the diagnosis of BL should be restricted to cases with expression of CD10 and BCL6, absence or very weak expression of BCL2 protein, a homogeneously very high proliferation index, and a proven IG-MYC translocation without evidence of a chromosomal translocation typical for other lymphoma entities. Additionally, a high number of non-specific cytogenetic abnormalities should suggest need for a critical review of the diagnosis of BL. Finally, the steady increase in age of lymphomas that mimic BL strongly emphasizes that there is no distinct age at which a pathologist can safely make a diagnosis of BL without any ancillary cytogenetic or molecular studies.
The translocation t(2;7)(p11;q21) has repeatedly been documented in association with indolent B-cell lymphoproliferative disorders (BLPDs). However, the chromosomal breakpoints associated with this ...recurrent translocation have rarely been characterized. Using an approach based on long-range PCR, we mapped the t(2;7) breakpoints in five patients presenting with indolent B-cell neoplasia. The sequencing of these rearrangements revealed several striking parallels across the t(2;7) breakpoints. The junction sites on 2p11 consistently mapped to the heptamer recombination signal sequence (RSS) of an immunoglobulin kappa variable gene ( IGK ) within the Vκ3 family, while the breakpoints on 7q21 each localized to within 4 bp of an RSS-like element located approximately 0.5 kb upstream of the transcription start site of the cyclin-dependent kinase 6 gene ( CDK6 ). These findings confirm the significant genetic overlap arising in BLPD-associated t(2;7) translocations, and implicate the deregulated expression of CDK6 as a common molecular mechanism involved in the emergence of clonal B-cell proliferations presenting with this recurrent abnormality. In addition, the successful mapping of the t(2;7) translocations in each of five patients using a simple PCR-based protocol highlights the potential diagnostic utility of this approach during characterization of cases harboring analogous rearrangements.
Wilms tumor 1 (WT1) is over-expressed in numerous cancers with respect to normal cells, and has either a tumor suppressor or oncogenic role depending on cellular context. This gene is associated with ...numerous alternatively spliced transcripts, which initiate from two different unique first exons within the WT1 and the alternative (A)WT1 promoter intervals. Within the hematological system, WT1 expression is restricted to CD34+/CD38- cells and is undetectable after differentiation. Detectable expression of this gene is an excellent marker for minimal residual disease in acute myeloid leukemia (AML), but the underlying epigenetic alterations are unknown.
To determine the changes in the underlying epigenetic landscape responsible for this expression, we characterized expression, DNA methylation and histone modification profiles in 28 hematological cancer cell lines and confirmed the methylation signature in 356 cytogenetically well-characterized primary hematological malignancies.
Despite high expression of WT1 and AWT1 transcripts in AML-derived cell lines, we observe robust hypermethylation of the AWT1 promoter and an epigenetic switch from a permissive to repressive chromatin structure between normal cells and AML cell lines. Subsequent methylation analysis in our primary leukemia and lymphoma cohort revealed that the epigenetic signature identified in cell lines is specific to myeloid-lineage malignancies, irrespective of underlying mutational status or translocation. In addition to being a highly specific marker for AML diagnosis (positive predictive value 100%; sensitivity 86.1%; negative predictive value 89.4%), we show that AWT1 hypermethylation also discriminates patients that relapse from those achieving complete remission after hematopoietic stem cell transplantation, with similar efficiency to WT1 expression profiling.
We describe a methylation signature of the AWT1 promoter CpG island that is a promising marker for classifying myeloid-derived leukemias. In addition AWT1 hypermethylation is ideally suited to monitor the recurrence of disease during remission in patients undergoing allogeneic stem cell transfer.
High-level BCL2 expression is seen in most patients with chronic lymphocytic leukemia (CLL) in the absence of BCL2 chromosomal translocation. A single nucleotide polymorphism (SNP; −938C>A) within an ...inhibitory region of the BCL2 promoter has been reported to regulate BCL2 protein expression and to be associated with adverse prognostic features in CLL. We screened 276 patients with CLL for this SNP and 100 patients by quantitative Western blot for BCL2 expression. In contrast to the previous report, we found no association with BCL2 protein levels or with any clinical or laboratory parameters. BCL2 protein levels remained constant in 10 individual patients at different time points. A total of 19 patients with the lowest levels of BCL2 protein expression were biologically and clinically heterogeneous; 5 patients exhibited high-level BCL2 RNA expression and 4 were fludarabine resistant. BCL2 protein levels in CLL reflect a complex interplay of transcriptional and posttranscriptional controls, but do not appear to be associated with the −938C>A promoter SNP.
Zusammenfassung
In Analogie zu den bekannten Imprintingstörungen der elterlich geprägten Regionen auf Chromosom 15 (Prader-Willi-/Angelman-Syndrom) und Chromosom 11 ...(Beckwith-Wiedemann-/Silver-Russell-Syndrom) existieren auch für die Imprintingregion 14q32 zwei molekular gegensätzliche syndromale Störungen. Aufgrund der ersten klinischen Beschreibungen und des häufigsten molekularen Basismechanismus dieser Störungen erfolgte die Namensgebung zunächst als upd(14)mat- bzw. upd(14)pat-Syndrom (upd, uniparentale Disomie). Da das klinische Bild aber auch durch chromosomale Imbalancen und Epimutationen der Region 14q32 hervorgerufen wird, wurden die Bezeichnungen Temple-Syndrom (TS14, upd(14)mat) und Kagami-Ogata-Syndrom (KOS14, upd(14)pat) vorgeschlagen.
Das KOS14 zeichnet sich durch ein charakteristisches klinisches Bild aus, welches bereits intrauterin durch das Auftreten eines Polyhydramnions, eines glockenförmigen Thorax (bell-shaped thorax) mit „Kleiderbügel ähnlichen“ Rippen (coathanger rips) und einer kritischen Perinatalperiode gekennzeichnet ist. Der faziale Phänotyp mit vollen Wangen, eingesunkener Nasenwurzel, vorstehendem Philtrum, Mikrognathie und einem kurzen, breiten Nacken ist wiedererkennbar. Es liegen erste Hinweise auf ein erhöhtes Risiko für das Auftreten eines Hepatoblastoms vor. Hingegen handelt es sich beim TS14 um eine weniger spezifische und variablere Störung, die vor allem durch einen prä- und postnatalen Kleinwuchs und eine vorzeitige Pubertätsentwicklung gekennzeichnet ist. Es bestehen sowohl Übereinstimmungen mit dem PWS als auch Parallelen zu Patienten mit SRS. Nach neueren Erkenntnissen ist die mentale Retardierung kein konstantes Merkmal des TS14.
In den meisten Fällen ist das Wiederholungsrisiko für das Auftreten eines TS14 oder eines KOS14 bei Geschwistern eines betroffenen Kindes klein. Es kann aber in Abhängigkeit des zugrunde liegenden molekularen Defektes bis zu 50 % betragen, sodass eine entsprechende Diagnostik im Rahmen einer genetischen Beratung erfolgen sollte.
Zusammenfassung
Die Katalogisierung genomischer, epigenetischer und transkriptioneller Veränderungen in Tumorzellen sowie die Integration disponierender oder klinisch relevanter Keimbahnvarianten ist ...die Voraussetzung für die zukünftige Anwendung präzisionsmedizinischer Ansätze in der Onkologie. Das Internationale Krebsgenomkonsortium (International Cancer Genome Consortium, ICGC) hat sich deshalb zum Ziel gesetzt, auf verschiedenen OMICs-Ebenen die wesentlichen Aberrationen in den 50 häufigsten und sozioökonomisch relevanten Tumorentitäten zu beschreiben. Dazu werden die Tumoren nach standardisierten Protokollen mittels sequenzierungsbasierter Verfahren analysiert. Die erhobenen Daten sind unter bestimmten Bedingungen auch Wissenschaftlern außerhalb des ICGC zugänglich. Auch wenn die Datensammlung noch nicht abgeschlossen ist, konnten entitätenspezifische und -übergreifende Analysen u. a. bereits Mutationssignaturen oder neue Driververänderungen und pathogene Signalwege identifizieren.
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