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Find video protocols related to scientific articles indexed in Pubmed.
Defining the prognosis of early stage chronic lymphocytic leukaemia patients.
Br. J. Haematol.
PUBLISHED: 12-15-2011
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Approximately 70% of chronic lymphocytic leukaemia (CLL) patients present with early stage disease, therefore defining which patients will progress and require treatment is a major clinical challenge. Here, we present the largest study of prognostic markers ever carried out in Binet stage A patients (n?=?1154) with a median follow-up of 8?years. We assessed the prognostic impact of lymphocyte doubling time (LDT), immunoglobulin gene (IGHV) mutation status, CD38 expression, ZAP-70 expression and fluorescence in situ hybridization (FISH) cytogenetics with regards to time to first treatment (TTFT) and overall survival (OS). Univariate analysis revealed LDT as the most prognostic parameter for TTFT, with IGHV mutation status most prognostic for OS. CD38 expression, ZAP-70 expression and FISH were also prognostic variables; combinations of these markers increased prognostic power in concordant cases. Multivariate analysis revealed that only LDT, IGHV mutation status, CD38 and age at diagnosis were independent prognostic variables for TTFT and OS. Therefore, IGHV mutation status and CD38 expression have independent prognostic value in early stage CLL and should be performed as part of the routine diagnostic workup. ZAP-70 expression and FISH were not independent prognostic markers in early stage disease and can be omitted at diagnosis but FISH analysis should be undertaken at disease progression to direct treatment strategy.
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A cyclin-D1 interaction with BAX underlies its oncogenic role and potential as a therapeutic target in mantle cell lymphoma.
Proc. Natl. Acad. Sci. U.S.A.
PUBLISHED: 07-11-2011
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The chromosomal translocation t(11;14)(q13;q32) leading to cyclin-D1 overexpression plays an essential role in the development of mantle cell lymphoma (MCL), an aggressive tumor that remains incurable with current treatment strategies. Cyclin-D1 has been postulated as an effective therapeutic target, but the evaluation of this target has been hampered by our incomplete understanding of its oncogenic functions and by the lack of valid MCL murine models. To address these issues, we generated a cyclin-D1-driven mouse model in which cyclin-D1 expression can be regulated externally. These mice developed cyclin-D1-expressing lymphomas capable of recapitulating features of human MCL. We found that cyclin-D1 inactivation was not sufficient to induce lymphoma regression in vivo; however, using a combination of in vitro and in vivo assays, we identified a novel prosurvival cyclin-D1 function in MCL cells. Specifically, we found that cyclin-D1, besides increasing cell proliferation through deregulation of the cell cycle at the G(1)-S transition, sequestrates the proapoptotic protein BAX in the cytoplasm, thereby favoring BCL2s antiapoptotic function. Accordingly, cyclin-D1 inhibition sensitized the lymphoma cells to apoptosis through BAX release. Thus, genetic or pharmacologic targeting of cyclin-D1 combined with a proapoptotic BH3 mimetic synergistically killed the cyclin-D1-expressing murine lymphomas, human MCL cell lines, and primary lymphoma cells. Our study identifies a role of cyclin-D1 in deregulating apoptosis in MCL cells, and highlights the potential benefit of simultaneously targeting cyclin-D1 and survival pathways in patients with MCL. This effective combination therapy also might be exploited in other cyclin-D1-expressing tumors.
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Response of ETV6-FLT3-positive myeloid/lymphoid neoplasm with eosinophilia to inhibitors of FMS-like tyrosine kinase 3.
Blood
PUBLISHED: 06-24-2011
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Imatinib-resistant tyrosine kinase (TK) fusions involving FGFR1, JAK2, or FLT3 are rare but recurrent in patients with eosinophilia-associated neoplasms. We report here 2 male patients with ETV6-FLT3(+) myeloid/lymphoid neoplasms with eosinophilia who were treated with the multitargeted TK inhibitors sunitinib and sorafenib. Patient 1 achieved rapid complete hematologic response and complete cytogenetic response after 3 months of taking sunitinib. A secondary blast phase caused by clonal evolution was diagnosed after 6 months. He achieved a second complete hematologic response after taking sorafenib but relapsed 2 months later. An N841K point mutation within the TK domain of FLT3, previously reported in acute myeloid leukemia and potentially conferring resistance to sorafenib, was subsequently identified. Patient 2 was heavily pretreated according to the initial diagnosis of T-lymphoblastic lymphoma and died in sunitinib-induced pancytopenia. This report highlights the importance of a careful diagnostic workup for eosinophilia-associated neoplasms to evaluate the possibility of TK inhibitor therapy.
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Nonsense mutation and inactivation of SMARCA4 (BRG1) in an atypical teratoid/rhabdoid tumor showing retained SMARCB1 (INI1) expression.
Am. J. Surg. Pathol.
PUBLISHED: 05-14-2011
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Atypical teratoid/rhabdoid tumors (AT/RTs) are highly aggressive brain tumors of early childhood poorly responding to therapy. The majority of cases show inactivation of SMARCB1 (INI1, hSNF5, BAF47), a core member of the adenosine triphosphate (ATP)-dependent SWI/SNF chromatin-remodeling complex. We here report the case of a supratentorial AT/RT in a 9-month-old boy, which showed retained SMARCB1 staining on immunohistochemistry and lacked genetic alterations of SMARCB1. Instead, the tumor showed loss of protein expression of another SWI/SNF chromatin-remodeling complex member, the ATPase subunit SMARCA4 (BRG1) due to a homozygous SMARCA4 mutation [c.2032C>T (p.Q678X)]. Our findings highlight the role of SMARCA4 in the pathogenesis of SMARCB1-positive AT/RT and the usefulness of antibodies directed against SMARCA4 in this diagnostic setting.
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A girl with an atypical form of ataxia telangiectasia and an additional de novo 3.14 Mb microduplication in region 19q12.
Eur J Med Genet
PUBLISHED: 04-20-2011
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A 9-year-old girl born to healthy parents showed manifestations suggestive of ataxia telangiectasia (AT), such as short stature, sudden short bouts of horizontal and rotary nystagmus, a weak and dysarthric voice, rolling gait, unstable posture, and atactic movements. She did not show several cardinal features typical of AT such as frequent, severe infections of the respiratory tract. In contrast, she showed symptoms not generally related to AT, including microcephaly, profound motor and mental retardation, small hands and feet, severely and progressively reduced muscle tone with slackly protruding abdomen and undue drooling, excess fat on her upper arms, and severe oligoarthritis. A cranial MRI showed no cerebellar hypoplasia and other abnormalities. In peripheral blood samples she carried a de novo duplication of 3.14 Mb in chromosomal region 19q12 containing six annotated genes, UQCRFS1, VSTM2B, POP4, PLEKHF1, CCNE1, and ZNF536, and a de novo mosaic inversion 14q11q32 (96% of metaphases). In a saliva-derived DNA sample only the duplication in 19q12 was detected, suggesting that the rearrangements in blood lymphocytes were acquired. These findings reinforced the suspicion that she had AT. AT was confirmed by strongly elevated serum AFP levels, cellular radiosensitivity and two inherited mutations in the ATM gene (c.510_511delGT; paternal origin and c.2922-50_2940del69; maternal origin). This case suggest that a defective ATM-dependent DNA damage response may entail additional stochastic genomic rearrangements. Screening for genomic rearrangements appears indicated in patients suspected of defective DNA damage responses.
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Translocations activating IRF4 identify a subtype of germinal center-derived B-cell lymphoma affecting predominantly children and young adults.
Blood
PUBLISHED: 04-12-2011
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The prognosis of germinal center-derived B-cell (GCB) lymphomas, including follicular lymphoma and diffuse large-B-cell lymphoma (DLBCL), strongly depends on age. Children have a more favorable outcome than adults. It is not known whether this is because of differences in host characteristics, treatment protocols, or tumor biology, including the presence of chromosomal alterations. By screening for novel IGH translocation partners in pediatric and adult lymphomas, we identified chromosomal translocations juxtaposing the IRF4 oncogene next to one of the immunoglobulin (IG) loci as a novel recurrent aberration in mature B-cell lymphoma. FISH revealed 20 of 427 lymphomas to carry an IG/IRF4-fusion. Those were predominantly GCB-type DLBCL or follicular lymphoma grade 3, shared strong expression of IRF4/MUM1 and BCL6, and lacked PRDM1/BLIMP1 expression and t(14;18)/BCL2 breaks. BCL6 aberrations were common. The gene expression profile of IG/IRF4-positive lymphomas differed from other subtypes of DLBCL. A classifier for IG/IRF4 positivity containing 27 genes allowed accurate prediction. IG/IRF4 positivity was associated with young age and a favorable outcome. Our results suggest IRF4 translocations to be primary alterations in a molecularly defined subset of GCB-derived lymphomas. The probability for this subtype of lymphoma significantly decreases with age, suggesting that diversity in tumor biology might contribute to the age-dependent differences in prognosis of lymphoma.
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Normal prenatal ultrasound findings in a case with de novo mosaic small supernumerary marker chromosome 18--how to counsel?
J. Matern. Fetal. Neonatal. Med.
PUBLISHED: 04-08-2011
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We report on a prenatally diagnosed de novo small supernumerary marker chromosome (sSMC) derived form chromosome 18. Molecular cytogenetic studies led to information about the clinical relevance of the sSMC-induced chromosomal imbalance. As prenatal ultrasound was normal, detailed information with respect to prenatal counseling of the parents was necessary. In general, detection of an sSMC requires as much information on the exact genetic content with its possible impact on the phenotype as achievable.
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Fast approach for clarification of chromosomal aberrations by using LM-PCR and FT-CGH in leukaemic sample.
Acta Haematol.
PUBLISHED: 03-10-2011
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Chromosomal abnormalities, like deletions, amplifications, inversions or translocations, are recurrent features in haematological malignancies. However, the precise molecular breakpoints are frequently not determined. Here we describe a rapid analysis of genetic imbalances combining fine tiling comparative genomic hybridization (FT-CGH) and ligation-mediated PCR (LM-PCR). We clarified an inv(14)(q11q32) in a case of T cell acute lymphoblastic leukaemia with a breakpoint in the TRA/D in 68% of cells detected by fluorescence in situ hybridization. FT-CGH showed several mono- and biallelic losses within TRA/D. LM-PCR disclosed a TRA/D rearrangement on one allele. The other allele revealed an inv(14)(q11q32), joining TRDD2 at 21,977,000 of 14q11 together with the IGH locus at 105,948,000 and 3-sequence of TRAC at 22,092,000 joined together with IGHV4-61 at 106,166,000. This sensitive approach can unravel complex chromosomal abnormalities in patient samples with a limited amount of aberrant cells and may lead to better diagnostic and therapeutic options.
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A 2 Mb deletion in 14q13 associated with severe developmental delay and hemophagocytic lymphohistiocytosis.
Eur J Med Genet
PUBLISHED: 01-09-2011
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Interstitial deletions of chromosome 14 have rarely been described. We report on a boy in whom a 2 Mb deletion in 14q13 was discovered by array CGH. The deletion was a de novo event. The boy presented with asymmetrical growth retardation at birth. There was severe developmental delay with muscular hypotonia and focal epilepsy with apneic episodes progressing to serial tonic seizures. At the age of 3 3/12 years he was diagnosed with pneumonia. In the further course he developed symptoms of hemophagocytic lymphohistiocytosis. He died due to organ failure. Herein the clinical findings are compared to patients with cytogenetic visible deletions encompassing the region deleted in the proband and the possible connection with the deleted genes.
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No significantly increased frequency of the inversion polymorphism at the WBS-critical region 7q11.23 in German parents of patients with Williams-Beuren syndrome as compared to a population control.
Mol Cytogenet
PUBLISHED: 10-27-2010
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Typical Williams-Beuren syndrome (WBS) is commonly caused by a ~1.5 Mb - ~1.8 Mb heterozygous deletion of contiguous genes at chromosome region 7q11.23. The majority of WBS cases occurs sporadically but few familial cases of autosomal dominant inheritance have been reported. Recent data demonstrated the existence of the paracentric inversion polymorphism at the WBS critical region in 7q11.23 in some of the progenitors transmitting the chromosome which shows the deletion in the affected child. In parents having a child affected by WBS the prevalence of such a structural variant has been reported to be much higher (~25- ~30%) than in the general population (~1- ~6%). However, in these previously reported studies only a limited number of randomly selected patients and non transmitting parents of WBS patients were used as controls, but without specification of any clinical data. Therefore we have undertaken a German population-based molecular cytogenetic investigation. We evaluated the incidence of the paracentric inversion polymorphism at 7q11.23 analyzing interphase nuclei of lymphocytes using a three color fluorescence in situ hybridization (FISH) probe.
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Primary bilateral Burkitt lymphoma of the lactating breast: a case report and review of the literature.
Mol Diagn Ther
PUBLISHED: 08-31-2010
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Burkitt lymphoma (BL) is a highly aggressive neoplasm, which frequently affects the ileocecal region in the sporadic form and the jaw in the endemic form; however, the breast is a rare primary site of this tumor. Here we describe a case of primary bilateral breast BL presenting during lactation in a 23-year-old woman. Excisional biopsy of breast masses demonstrated a B-cell lymphoma with a characteristic starry sky pattern highly suggestive of BL. The neoplastic cells strongly expressed CD20 and CD10, and showed proliferative activity as measured by Ki-67. An IGH-MYC gene fusion indicating the presence of a typical Burkitt translocation t(8;14)(q24;q32) in the tumor tissue was detected by fluorescent in situ hybridization. The present case, along with a comprehensive review of the literature, demonstrates that BL of the breast should be considered in the differential diagnosis of lesions of the breast during lactation. Whether hormonal or antigenic factors trigger Burkitt lymphomagenesis in the lactating breast warrants further investigation.
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Conflicting results of prenatal FISH with different probes for Downs Syndrome critical regions associated with mosaicism for a de novo del(21)(q22) characterised by molecular karyotyping: Case report.
Mol Cytogenet
PUBLISHED: 08-10-2010
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For the rapid detection of common aneuploidies either PCR or Fluorescence in situ hybridisation (FISH) on uncultured amniotic fluid cells are widely used. There are different commercial suppliers providing FISH assays for the detection of trisomies affecting the Downs syndrome critical regions (DSCR) in 21q22. We present a case in which rapid FISH screening with different commercial probes for the DSCR yielded conflicting results. Chromosome analysis revealed a deletion of one chromosome 21 in q22 which explained the findings. Prenatally an additional small supernumerary marker chromosome (sSMC) was discovered as well, which could not be characterised. Postnatal chromosome analysis in lymphocytes of the infant revealed complex mosaicism with four cell lines. By arrayCGH the sSMC was provisionally described as derivative chromosome 21 which was confirmed by targeted FISH experiments.
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Molecular characterization of a novel chromosomal translocation t(12;14)(q23;q11.2) in T-lymphoblastic lymphoma between the T-cell receptor delta-deleting elements (TRDREC and TRAJ61) and the hypothetical gene C12orf42.
Eur. J. Haematol.
PUBLISHED: 07-28-2010
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Chromosomal aberrations have diagnostic, prognostic, and therapeutic relevance in hematologic malignancies. By combining fine-tiling comparative genomic hybridization (FT-CGH) and ligation-mediated PCR (LM-PCR), we established a fast, robust approach to precisely characterize chromosomal breakpoints. Using this approach, we clarified at the molecular level novel chromosomal translocation t(12;14)(q23;q11.2) in T-lymphoblastic lymphoma. The translocation occurred during the deletional rearrangement of the T-cell receptor delta gene (TRD), which is a pivotal step in T cell differentiation toward the alpha/beta vs. the gamma/delta lineage. We found that this rearrangement disrupted the hypothetical gene C12orf42 and brought the Achaete-scute complex homolog 1 gene into proximity of the TRA enhancer, which encodes a member of the basic helix-loop-helix family of transcription factors and is overexpressed in thyroid and lung cancers.
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Gene dosage effects in chronic lymphocytic leukemia.
Cancer Genet. Cytogenet.
PUBLISHED: 07-23-2010
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To understand the influence of chromosomal alterations on gene expression in a genome-wide view, chromosomal imbalances detected by single nucleotide polymorphism (SNP) chips were compared with global gene expression in 16 cases of chronic lymphocytic leukemia (CLL). A strong concordance between chromosomal gain or loss and increased or reduced expression of genes in the affected regions was found, respectively. Regions of uniparental disomy (UPD) were rare and had usually no consistent influence on gene expression, but in one instance, a large UPD was associated with a downregulation of most genes in the affected chromosome. The frequently deleted miRNAs, MIRN15A and MIRN16-1, did not show a reduced expression in cases with monoallelic deletions. The BCL2 protein, considered to be downregulated by these miRNAs, was upregulated not only in CLL with biallelic deletion of MIRN15A and MIRN16-1, but also in cases with monoallelic deletion. This suggests a complex regulation of BCL2 levels in CLL cells. Taken together, in CLL, a global gene dosage effect exists for chromosomal gains and deletions and in some instances for UPDs. We did not confirm a consistent correlation between MIRN15A and MIRN16-1 expression levels and BCL2 protein levels, indicating a complex regulation of BCL2 expression.
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Rare occurrence of biallelic CYLD gene mutations in classical Hodgkin lymphoma.
Genes Chromosomes Cancer
PUBLISHED: 07-08-2010
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Survival of the malignant Hodgkin and Reed/Sternberg (HRS) cells in classical Hodgkin lymphoma (cHL) is dependent on constitutive activation of the nuclear factor kappaB (NF-kappaB) transcription factor. The deubiquitinating enzyme CYLD is a negative regulator of NF-kappaB and known to function as a tumor suppressor. To determine whether CYLD mutations play a role in cHL pathogenesis, we sequenced the gene in cHL cell lines and microdissected HRS cells obtained from lymph-node biopsies. A biallelic inactivation by mutations was found in the cHL cell-line KM-H2. However, the other seven cHL cell lines analyzed and HRS cells of 10 primary cHL cases did not show any mutations. By interphase cytogenetics, a (sub)clonal biallelic CYLD deletion was observed by interphase cytogenetics in 1 of 29 primary cHL, whereas signal patterns indicating decreased CYLD copy numbers were observed in a total of 10 of 29 primary cases. Our results suggest that biallelic CYLD mutations are rarely involved in cHL pathogenesis. Nevertheless, it is remarkable that KM-H2 cells, besides the CYLD mutations, also carry inactivating mutations in the genes of two other NF-kappaB inhibitors, that is, NFKBIA and TNFAIP3, exemplifying that multiple lesions in regulators of this signaling pathway can likely cooperatively contribute to the strong NF-kappaB activity of these cells.
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Mutations of CARD11 but not TNFAIP3 may activate the NF-kappaB pathway in primary CNS lymphoma.
Acta Neuropathol.
PUBLISHED: 05-31-2010
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Primary CNS lymphoma (PCNSL), the intracerebral subgroup of diffuse large B cell lymphoma (DLBCL), shows evidence for aberrant activation of the nuclear factor (NF)-kappaB pathway. In order to identify potential activators of the NF-kappaB complex, we analyzed the CARD11 and TNFAIP3 genes for the presence of somatic mutations and TNFAIP3 for aberrant promoter methylation in PCNSL. We also compared PCNSL to spinal DLBCL, because CARD11 and TNFAIP3 mutations have been described in systemic DLBCL. CARD11 mutations, located in the coiled-coil region, which may activate NF-kappaB, were detected in 16% (5/32) of PCNSL, while TNFAIP3 mutations were detected in 3% (1/32) of PCNSL. In PCNSL, all CARD11 mutations were heterozygous, in-frame, induced amino acid exchanges, and presumably led to activation of this oncogene. Spinal DLBCL harbored mutations of CARD11 and TNFAIP3 in 10% (1/10) and 20% (2/10) of cases, respectively. In both PCNSL and spinal DLBCL, mutations in CARD11 and TNFAIP3 were mutually exclusive. TNFAIP3 was unmethylated in all PCNSLs (30/30) and spinal DLBCLs (10/10). We conclude that mutations of the oncogene CARD11 may contribute to NF-kappaB activation and thereby play a role in the pathogenesis of PCNSL, while, in contrast to systemic DLBCL, inactivation of TNFAIP3 either by mutation or methylation seems to be of minor significance.
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Cytogenetic aberrations and their prognostic value in a series of 330 splenic marginal zone B-cell lymphomas: a multicenter study of the Splenic B-Cell Lymphoma Group.
Blood
PUBLISHED: 05-17-2010
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We conducted a retrospective collaborative study to cytogenetically characterize splenic marginal zone lymphoma (SMZL) and ascertain the prognostic value of chromosomal aberrations. Of 330 cases, 72% displayed an aberrant karyotype, 53% were complex, and 29% had a single aberration. The predominant aberrations were gains of 3/3q and 12q, deletions of 7q and 6q and translocations involving 8q/1q/14q. CD5 expression was detected in 39 of 158 cases (25%). The cytogenetic makeup of the CD5(+) group differed significantly from that of the CD5(-) group. Cases with unmutated IGHV were significantly associated with deletions of 7q and TP53. A strong association was noted between usage of the IGVH1-2 and deletion 7q, 14q alterations, and abnormal karyotype. On univariate analysis, patients with more than or equal to 2 aberrations, 14q alterations, and TP53 deletions had the shortest survival; 7q deletion did not affect survival. On multivariate analysis, cytogenetic aberrations did not retain prognostic significance; the parameters negatively affecting survival were hemoglobin and age. In conclusion, the cytogenetic profile of SMZL is distinct from other B-cell lymphomas. Complexity of the karyotype, 14q aberrations, and TP53 deletions are poor prognostic indicators and may be considered together with other clinicobiologic parameters to ascertain the prognosis of SMZL.
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Deregulation of the telomerase reverse transcriptase (TERT) gene by chromosomal translocations in B-cell malignancies.
Blood
PUBLISHED: 05-11-2010
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Sequence variants at the TERT-CLPTM1L locus in chromosome 5p have been recently associated with disposition for various cancers. Here we show that this locus including the gene encoding the telomerase reverse-transcriptase TERT at 5p13.33 is rarely but recurrently targeted by somatic chromosomal translocations to IGH and non-IG loci in B-cell neoplasms, including acute lymphoblastic leukemia, chronic lymphocytic leukemia, mantle cell lymphoma and splenic marginal zone lymphoma. In addition, cases with genomic amplification of TERT locus were identified. Tumors bearing chromosomal aberrations involving TERT showed higher TERT transcriptional expression and increased telomerase activity. These data suggest that deregulation of TERT gene by chromosomal abnormalities leading to increased telomerase activity might contribute to B-cell lymphomagenesis.
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Presence of the P2RY8-CRLF2 rearrangement is associated with a poor prognosis in non-high-risk precursor B-cell acute lymphoblastic leukemia in children treated according to the ALL-BFM 2000 protocol.
Blood
PUBLISHED: 04-08-2010
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High-level expression of the cytokine receptor-like factor 2 gene, CRLF2, in precursor B-cell acute lymphoblastic leukemia (pB-ALL) was shown to be caused by a translocation involving the IGH@ locus or a deletion juxtaposing CRLF2 with the P2RY8 promoter. To assess its possible prognostic value, CRLF2 expression was analyzed in 555 childhood pB-ALL patients treated according to the Acute Lymphoblastic Leukemia Berlin-Frankfurt-Münster 2000 (ALL-BFM 2000) protocol. Besides CRLF2 rearrangements, high-level CRLF2 expression was seen in cases with supernumerary copies of the CRLF2 locus. On the basis of the detection of CRLF2 rearrangements, a CRLF2 high-expression group (n = 49) was defined. This group had a 6-year relapse incidence of 31% plus or minus 8% compared with 11% plus or minus 1% in the CRLF2 low-expression group (P = .006). This difference was mainly attributable to an extremely high incidence of relapse (71% +/- 19%) in non-high-risk patients with P2RY8-CRLF2 rearrangement. The assessment of CRLF2 aberrations may therefore serve as new stratification tool in Berlin-Frankfurt-Münster-based protocols by identifying additional high-risk patients who may benefit from an intensified and/or targeted treatment.
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Germline nonsense mutation and somatic inactivation of SMARCA4/BRG1 in a family with rhabdoid tumor predisposition syndrome.
Am. J. Hum. Genet.
PUBLISHED: 01-05-2010
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Rhabdoid tumors of early infancy are highly aggressive with consequent poor prognosis. Most cases show inactivation of the SMARCB1 (also known as INI1 and hSNF5) tumor suppressor, a core member of the ATP-dependent SWI/SNF chromatin-remodeling complex. Familial cases, described as rhabdoid tumor predisposition syndrome (RTPS), have been linked to heterozygous SMARCB1 germline mutations. We identified inactivation of another member of the SWI/SNF chromatin-remodeling complex, its ATPase subunit SMARCA4 (also known as BRG1), due to a SMARCA4/BRG1 germline mutation and loss of heterozygosity by uniparental disomy in the tumor cells of two sisters with rhabdoid tumors lacking SMARCB1 mutations. SMARCA4 is thus a second member of the SWI/SNF complex involved in cancer predisposition. Its general involvement in other tumor entities remains to be established.
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Cribriform neuroepithelial tumor (CRINET): a nonrhabdoid ventricular tumor with INI1 loss and relatively favorable prognosis.
J. Neuropathol. Exp. Neurol.
PUBLISHED: 11-17-2009
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Atypical teratoid/rhabdoid tumors are malignant embryonal tumors characterized by the presence of rhabdoid cells, genetic alterations affecting the SMARCB1 gene (hSNF5/INI1), and a poor prognosis. Whether INI1 plays a role in the pathogenesis of other central nervous system tumors is uncertain. We report on cases of 2 young children with unusual intracranial nonrhabdoid neuroectodermal tumors within and around the third or fourth ventricle that are characterized by cribriform strands and trabeculae and well-defined epithelial membrane antigen-immunopositive surfaces and show INI1 protein loss. Histological and immunohistochemical features did not correspond to established tumor types, including atypical teratoid/rhabdoid tumors, medulloepithelioma, choroid plexus carcinoma, and ependymoma. Fluorescence in situ hybridization analyses failed to identify chromosomal alterations affecting the SMARCB1 locus, but sequencing revealed a homozygous 4-bp duplication in exon 4 (492duplCCTT) in one of the tumors. Both children responded well to conventional adjuvant therapy protocols and are alive and in complete remission longer than 5 years postoperatively. We suggest that cribriform neuroepithelial tumor (CRINET) is a nonrhabdoid ventricular tumor that shows loss of tumoral INI1 protein and has a relatively favorable prognosis.
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High resolution SNP array genomic profiling of peripheral T cell lymphomas, not otherwise specified, identifies a subgroup with chromosomal aberrations affecting the REL locus.
Br. J. Haematol.
PUBLISHED: 10-22-2009
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Little is known about genomic aberrations in peripheral T cell lymphoma, not otherwise specified (PTCL NOS). We studied 47 PTCL NOS by 250k GeneChip single nucleotide polymorphism arrays and detected genomic imbalances in 22 of the cases. Recurrent gains and losses were identified, including gains of chromosome regions 1q32-43, 2p15-16, 7, 8q24, 11q14-25, 17q11-21 and 21q11-21 (> or = 5 cases each) as well as losses of chromosome regions 1p35-36, 5q33, 6p22, 6q16, 6q21-22, 8p21-23, 9p21, 10p11-12, 10q11-22, 10q25-26, 13q14, 15q24, 16q22, 16q24, 17p11, 17p13 and Xp22 (> or = 4 cases each). Genomic imbalances affected several regions containing members of nuclear factor-kappaB signalling and genes involved in cell cycle control. Gains of 2p15-16 were confirmed in each of three cases analysed by fluorescence in situ hybridization (FISH) and were associated with breakpoints at the REL locus in two of these cases. Three additional cases with gains of the REL locus were detected by FISH among 18 further PTCL NOS. Five of 27 PTCL NOS investigated showed nuclear expression of the REL protein by immunohistochemistry, partly associated with genomic gains of the REL locus. Therefore, in a subgroup of PTCL NOS gains/rearrangements of REL and expression of REL protein may be of pathogenetic relevance.
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Pediatric follicular lymphoma--a clinico-pathological study of a population-based series of patients treated within the Non-Hodgkins Lymphoma--Berlin-Frankfurt-Munster (NHL-BFM) multicenter trials.
Haematologica
PUBLISHED: 08-13-2009
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Background Pediatric follicular lymphoma has recently been recognized as a novel variant of follicular lymphoma in the World Health Organization classification of lymphomas. Given the rarity of the disease, histopathological and genetic data on this type of lymphoma are still scarce.
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A comprehensive microarray-based DNA methylation study of 367 hematological neoplasms.
PLoS ONE
PUBLISHED: 07-23-2009
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Alterations in the DNA methylation pattern are a hallmark of leukemias and lymphomas. However, most epigenetic studies in hematologic neoplasms (HNs) have focused either on the analysis of few candidate genes or many genes and few HN entities, and comprehensive studies are required.
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Differential diagnosis of cyclin D2+ mantle cell lymphoma based on fluorescence in situ hybridization and quantitative real-time-PCR.
Haematologica
PUBLISHED: 07-16-2009
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Mantle cell lymphoma is characterized by the t(11;14) chromosomal translocation, resulting in the overexpression of cyclin D1 (CycD1). Recently, cases of mantle cell lymphoma negative for cycD1 but positive for cycD2 or cycD3 were identified by gene expression profiling and confirmed by immunohistochemistry. We analyzed 4 cases of cycD2(+) mantle cell lymphoma with a translocation involving the CCND2 locus, and its differential diagnosis from 35 mature B-cell non-Hodgkins lymphomas based on immunohistochemistry, quantitative RT-PCR and FISH analysis. Bona fide cycD2(+) mantle cell lymphoma carried translocations involving the CCND2 gene, and IGH and IGK loci were identified as partners. As a result of this translocation, cycD2 mRNA was highly over-expressed when compared with normal lymphoid tissue and other B-cell non-Hodgkins lymphomas, including chronic lymphocytic leukemia, making this technique ideally suited to identify cycD2(+)mantle cell lymphoma. In contrast, positive immunostaining for cycD2 was found in most B-cell non-Hodgkins lymphomas, and therefore, it is not specific for a diagnosis of cycD2(+)mantle cell lymphoma.
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Mutations of NFKBIA, encoding IkappaB alpha, are a recurrent finding in classical Hodgkin lymphoma but are not a unifying feature of non-EBV-associated cases.
Int. J. Cancer
PUBLISHED: 06-10-2009
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A consistent feature of the Hodgkin and Reed-Sternberg (HRS) cells in classical Hodgkin lymphoma (cHL) is the constitutive activation of NF-kappaB transcription factors. In Epstein-Barr virus (EBV)-associated cases of cHL, expression of viral antigens most probably leads to NF-kappaB activation but for non-EBV-associated cases, the mechanism is not clear. Previous small studies have demonstrated deleterious mutations of NFKBIA, the gene encoding IkappaB alpha, in HRS cells. In the present study, we aimed to establish the frequency of NFKBIA mutation in cHL by investigating a larger series of cases and to determine whether these mutations are a characteristic feature of non-EBV-associated cHL. Single HRS cells from 20 cases of cHL were analysed by PCRs covering all 6 exons of the gene. Clonal deleterious mutations were detected in 3 cases and in 1 case both alleles of the gene were shown to harbour mutations. NFKBIA mutations were detected only in non-EBV-associated cases but the majority of these cases had wild-type NFKBIA. It remains possible that defects in genes encoding other inhibitors of NF-kappaB, such as TNFAIP3 (A20) and CYLD, are involved in the latter cases, as described for one case in this series.
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Distribution of NPM1-ALK and X-ALK fusion transcripts in paediatric anaplastic large cell lymphoma: a molecular-histological correlation.
Br. J. Haematol.
PUBLISHED: 05-26-2009
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Anaplastic large cell lymphomas (ALCL) in children express anaplastic lymphoma kinase (ALK) fusion genes, most commonly NPM1-ALK. The distribution of X-ALK among 66 childhood ALCLs was analysed. One ALCL was ALK-negative. Reverse transcription polymerase chain reaction detected NPM1-ALK in 58 tumours, all showing nuclear and cytoplasmic ALK staining. The remaining seven ALCL stained for ALK in the cytoplasm only: two expressed TPM3-ALK, one ATIC-ALK, one MYH9-ALK; three no TPM3-, TFG-, ATIC-, CLTC- or MYH9-ALK. Almost 90% of paediatric ALK-positive ALCLs express NPM1-ALK. There was complete concordance between ALK staining pattern and the presence of a typical/variant ALK fusion partner.
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Identification of the gene encoding cyclin E1 (CCNE1) as a novel IGH translocation partner in t(14;19)(q32;q12) in diffuse large B-cell lymphoma.
Haematologica
PUBLISHED: 05-19-2009
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In a subset of B-cell malignancies, the genes encoding members of the cyclin D familiy are juxtaposed to immunoglobulin loci through recurrent chromosomal translocations. Here, we identified the gene encoding cyclin E1 as novel translocation partner of the immunoglobulin heavy chain (IGH) locus involved in a t(14;19)(q32;q12) in a case of t(8;14)(q24;q32) IGH-MYC-positive leukemic diffuse large B-cell lymphoma. The translocation breakpoints were cloned and mapped to the switch region Salpha1 of IGH in 14q32 and approximately 60kb centromeric to CCNE1 in 19q12. Immunohistochemical analysis revealed overexpression of the cyclin E1 protein in this case, which to a comparable extent was observed in 3/41 independent DLBCL. These data indicate that cyclin E1 may act as a novel oncogene in B-cell lymphomagenesis.
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TNFAIP3 (A20) is a tumor suppressor gene in Hodgkin lymphoma and primary mediastinal B cell lymphoma.
J. Exp. Med.
PUBLISHED: 04-20-2009
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Proliferation and survival of Hodgkin and Reed/Sternberg (HRS) cells, the malignant cells of classical Hodgkin lymphoma (cHL), are dependent on constitutive activation of nuclear factor kappaB (NF-kappaB). NF-kappaB activation through various stimuli is negatively regulated by the zinc finger protein A20. To determine whether A20 contributes to the pathogenesis of cHL, we sequenced TNFAIP3, encoding A20, in HL cell lines and laser-microdissected HRS cells from cHL biopsies. We detected somatic mutations in 16 out of 36 cHLs (44%), including missense mutations in 2 out of 16 Epstein-Barr virus-positive (EBV(+)) cHLs and a missense mutation, nonsense mutations, and frameshift-causing insertions or deletions in 14 out of 20 EBV(-) cHLs. In most mutated cases, both TNFAIP3 alleles were inactivated, including frequent chromosomal deletions of TNFAIP3. Reconstitution of wild-type TNFAIP3 in A20-deficient cHL cell lines revealed a significant decrease in transcripts of selected NF-kappaB target genes and caused cytotoxicity. Extending the mutation analysis to primary mediastinal B cell lymphoma (PMBL), another lymphoma with constitutive NF-kappaB activity, revealed destructive mutations in 5 out of 14 PMBLs (36%). This report identifies TNFAIP3 (A20), a key regulator of NF-kappaB activity, as a novel tumor suppressor gene in cHL and PMBL. The significantly higher frequency of TNFAIP3 mutations in EBV(-) than EBV(+) cHL suggests complementing functions of TNFAIP3 inactivation and EBV infection in cHL pathogenesis.
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GeneChip analyses point to novel pathogenetic mechanisms in mantle cell lymphoma.
Br. J. Haematol.
PUBLISHED: 02-21-2009
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The translocation t(11;14)(q13;q32) is the genetic hallmark of mantle cell lymphoma (MCL) but is not sufficient for inducing lymphomagenesis. Here we performed genome-wide 100K GeneChip Mapping in 26 t(11;14)-positive MCL and six MCL cell lines. Partial uniparental disomy (pUPD) was shown to be a recurrent chromosomal event not only in MCL cell lines but also in primary MCL. Remarkably, pUPD affected recurrent targets of deletion like 11q, 13q and 17p. Moreover, we identified 12 novel regions of recurrent gain and loss as well as 12 high-level amplifications and eight homozygously deleted regions hitherto undescribed in MCL. Interestingly, GeneChip analyses identified different genes, encoding proteins involved in microtubule dynamics, such as MAP2, MAP6 and TP53, as targets for chromosomal aberration in MCL. Further investigation, including mutation analyses, fluorescence in situ hybridisation as well as epigenetic and expression studies, revealed additional aberrations frequently affecting these genes. In total, 19 of 20 MCL cases, which were subjected to genetic and epigenetic analyses, and five of six MCL cell lines harboured at least one aberration in MAP2, MAP6 or TP53. These findings provide evidence that alterations of microtubule dynamics might be one of the critical events in MCL lymphomagenesis contributing to chromosomal instability.
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Genetic lesions of the TRAF3 and MAP3K14 genes in classical Hodgkin lymphoma.
Br. J. Haematol.
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Hodgkin and Reed/Sternberg (HRS) cells in classical Hodgkin lymphoma (cHL) show constitutive activation of nuclear factor (NF)-?B. Several genetic lesions contribute to this deregulated NF-?B activity. Here, we analysed two further NF-?B regulators for genetic lesions, the inhibitory factor TRAF3 and the key signalling component of the alternative NF-?B pathway, MAP3K14 (NIK). Single nucleotide polymorphism (SNP) array analysis of cHL cell lines revealed a uniparental disomy of the long arm of chromosome 14 associated with a biallelic deletion of TRAF3 located on this chromosome in cell line U-HO1. Cloning of the deletion breakpoint showed a 123 371 bp deletion. No inactivating mutations of TRAF3 were found in six other cHL cell lines or in microdissected HRS cells from seven cHL. However, in primary cHL samples interphase cytogenetic analyses revealed signal patterns indicating monoallelic deletion of TRAF3 in 3/20 other cases. SNP array analysis revealed a gain of copy number for MAP3K14 in three cHL cell lines. Gains of MAP3K14 were detected in 5/16 cases of primary cHL. In conclusion, in rare instances, HRS cells harbour inactivating mutations of the TRAF3 gene and recurrently show gains of MAP3K14, indicating that more components of NF-?B signalling show genetic lesions in HRS cells than previously known.
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The CBFA2T3/ACSF3 locus is recurrently involved in IGH chromosomal translocation t(14;16)(q32;q24) in pediatric B-cell lymphoma with germinal center phenotype.
Genes Chromosomes Cancer
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Translocations involving immunoglobulin (IG) loci are the hallmarks of several subtypes of B-cell lymphoma. Common to these translocations is that cellular proto-oncogenes come under the influence of IG regulatory elements leading to deregulated expression. In case of a breakpoint in the IGH switch region, oncogene activation can take place on both derivative chromosomes, which means that in principle one translocation can result in concurrent activation of two genes. By fluorescence in situ hybridization (FISH), we identified a case of leukemic B-cell lymphoma in a child with an IGH break and unknown partner. Subsequent long-distance inverse PCR revealed fusion of IGH Sl in 14q32 and the 50 region of CBFA2T3 in 16q24.3, suggesting presence of the t(14;16)(q32;q24.3). Candidate oncogenes targeted through this translocation are CBFA2T3 and ACSF3, which could be activated on der(16) and der(14), respectively. FISH screening of a population-based cohort of B-cell lymphomas from a prospective trial for the treatment of lymphoma in childhood (BFM-NHL) identified additionally a follicular lymphoma Grade 3/diffuse large B-cell lymphoma with IGH-CBFA2T3/ACSF3 juxtaposition. Both lymphomas shared expression of CD10 and CD20 in the absence of TdT, suggesting a germinal center (GC) B-cell origin. Our data indicate that the CBFA2T3/ACSF3 locus is a novel recurrent oncogenic target of IGH translocations, which might contribute to the pathogenesis of pediatric GC-derived B-cell lymphoma.
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