NHL - Molecular Biology


Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

Tag cloud generated 08 August, 2015 using data from PubMed, MeSH and CancerIndex

Mutated Genes and Abnormal Protein Expression (36)

How to use this data tableClicking on the Gene or Topic will take you to a separate more detailed page. Sort this list by clicking on a column heading e.g. 'Gene' or 'Topic'.

TNFRSF8 1p36 CD30, Ki-1, D1S166E -TNFRSF8 and Non-Hodgkin Lymphoma
ALK 2p23 CD246, NBLST3 Translocation
-t(2;5)(p23;q35) NPM1-ALK translocation in Anaplastic large cell lymphoma
-ATIC-ALK Rearrangements in anaplastic large cell lymphoma
-ALK-CTCL Rearrangements in diffuse large B-cell lymphoma
NPM1 5q35.1 B23, NPM Translocation
-t(2;5)(p23;q35) NPM1-ALK translocation in Anaplastic large cell lymphoma
IGL 22q11.2 IGL@, IGLC6 -IGL and Non-Hodgkin Lymphoma
CCND2 12p13 MPPH3, KIAK0002 -CCND2 and Non-Hodgkin Lymphoma
CCND3 6p21 -CCND3 and Non-Hodgkin Lymphoma
FCGR3A 1q23 CD16, FCG3, CD16A, FCGR3, IGFR3, IMD20, FCR-10, FCRIII, FCGRIII, FCRIIIA -FCGR3A and Non-Hodgkin Lymphoma
RHOH 4p13 TTF, ARHH -RHOH and Non-Hodgkin Lymphoma
BRAF 7q34 NS7, BRAF1, RAFB1, B-RAF1 -BRAF and Non-Hodgkin's Lymphoma
CXCR5 11q23.3 BLR1, CD185, MDR15 -CXCR5 and Non-Hodgkin Lymphoma
ATIC 2q35 PURH, AICAR, AICARFT, IMPCHASE, HEL-S-70p -ATIC-ALK Rearrangements in anaplastic large cell lymphoma
-ATIC and Non-Hodgkin Lymphoma
LTA 6p21.3 LT, TNFB, TNFSF1 -LTA and Non-Hodgkin Lymphoma
IL4 5q31.1 BSF1, IL-4, BCGF1, BSF-1, BCGF-1 -IL4 and Non-Hodgkin Lymphoma
IGH 14q32.33 IGD1, IGH@, IGHJ, IGHV, IGHD@, IGHJ@, IGHV@, IGH.1@, IGHDY1 Translocation
-t(1;14)(q21;q32) BCL9/IGH
-t(1;14)(q21;q32) and MUC1 Overexpression in NHL
MUC1 1q21 EMA, MCD, PEM, PUM, KL-6, MAM6, MCKD, PEMT, CD227, H23AG, MCKD1, MUC-1, ADMCKD, ADMCKD1, CA 15-3, MUC-1/X, MUC1/ZD, MUC-1/SEC Translocation
-t(1;14)(q21;q32) and MUC1 Overexpression in NHL
SH2D1A Xq25 LYP, SAP, XLP, DSHP, EBVS, IMD5, XLPD, MTCP1, XLPD1, SAP/SH2D1A -SH2D1A and Non-Hodgkin Lymphoma
SHMT1 17p11.2 SHMT, CSHMT -SHMT1 and Non-Hodgkin Lymphoma
UCHL1 4p14 NDGOA, PARK5, PGP95, PGP9.5, Uch-L1, HEL-117, PGP 9.5 -UCHL1 and Non-Hodgkin Lymphoma
FCGR2A 1q23 CD32, FCG2, FcGR, CD32A, CDw32, FCGR2, IGFR2, FCGR2A1 -FCGR2A and Non-Hodgkin Lymphoma
IL12A 3q25.33 P35, CLMF, NFSK, NKSF1, IL-12A -IL12A and Non-Hodgkin Lymphoma
CYBA 16q24 p22-PHOX -CYBA and Non-Hodgkin Lymphoma
LEPR 1p31 OBR, OB-R, CD295, LEP-R, LEPRD -LEPR and Non-Hodgkin Lymphoma
PTPRJ 11p11.2 DEP1, SCC1, CD148, HPTPeta, R-PTP-ETA -PTPRJ and Non-Hodgkin Lymphoma
AKR1C1 10p15-p14 C9, DD1, DDH, DDH1, H-37, HBAB, MBAB, HAKRC, DD1/DD2, 2-ALPHA-HSD, 20-ALPHA-HSD -AKR1C1 and Non-Hodgkin Lymphoma
PTPRK 6q22.2-q22.3 R-PTP-kappa -PTPRK and Non-Hodgkin Lymphoma
LTB 6p21.3 p33, TNFC, TNFSF3 -LTB and Non-Hodgkin Lymphoma
PTPN1 20q13.1-q13.2 PTP1B -PTPN1 mutations in Hodgkin Lymphoma and PMBCL
BCL2L11 2q13 BAM, BIM, BOD -rs3789068 polymorphism BCL2L11 and increased risk of B-Cell NHL?
BCL6 3q27 BCL5, LAZ3, BCL6A, ZNF51, ZBTB27 Translocation
-t(3;14)(q27;q32) in B-cell non-Hodgkin's lymphoma
TSPYL2 Xp11.2 CDA1, CTCL, NP79, TSPX, CINAP, DENTT, SE204, HRIHFB2216 -ALK-CTCL Rearrangements in diffuse large B-cell lymphoma
RXRB 6p21.3 NR2B2, DAUDI6, RCoR-1, H-2RIIBP -RXRB and Non-Hodgkin Lymphoma
IDO1 8p12-p11 IDO, INDO, IDO-1 -IDO1 and Non-Hodgkin Lymphoma
PCSK7 11q23-q24 LPC, PC7, PC8, SPC7 -PCSK7 and Non-Hodgkin Lymphoma
EIF4A2 3q28 DDX2B, EIF4A, EIF4F, BM-010, eIF4A-II, eIF-4A-II -EIF4A2 and Non-Hodgkin Lymphoma
BCL9 1q21 LGS Translocation
-t(1;14)(q21;q32) BCL9/IGH
BCL2 18q21.3 Bcl-2, PPP1R50 Translocation
-t(14;18)(q32;q21) in Non-Hodgkin's Lymphoma

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications

Škunca Ž, Domimis M, Plninc-Peraica A, Jakšić B
[Clinical features in DLBCL and translocation BCL2/c-MYC "double hit" lymphoma].
Acta Med Croatica. 2014; 68(3):299-305 [PubMed] Related Publications
Diffuse large B-cell lymphoma (DLBCL) is classified as lymphoma and various entities using the gene expression of proteins are classified into three groups. The aim of this study was to clarify the clinical, biological, immunophenotypic and cytogenetic features of DLBCL with translocation t (14; 18) and 8q24/c-MYC. Eleven DLBCL patients with dual translation were monitored during the 2000-2009 period. The characteristics of these patients included morphological, immunohistochemical and cytogenetic analysis. Study results showed that all patients had aggressive characteristics, presence of B symptoms (64%), general patient condition according to ECOG scale ≥ 2 (55%), elevated serum lactate dehydrogenase activity (73%), clinical stage III and IV (82%), extranodal involvement of the disease (73%), and IPI ≥ 2 (73%). Partial remission was achieved in 73% of all patients and all patients (73%) died within a short time. Patients were treated with CHOP and similar protocols (COP, CVP, CNOP), with the addition of MabThera. Immunophenotyping was performed and determined expression of the CD20, CD3, CD10, BCL6 and MUM1 markers. The cytogenetic analysis/fluorescence in situ hybridization revealed complex karyotype changes. Thus, we analyzed the presence of BCL2, BCL6 and c-MYC genes and found eight patients to have BCL2 and c-MYC translocation genes, while three had translocation of the BCL6 and c-MYC genes. Despite appropriate therapy, the patient prognosis is poor. The median survival in these patients was 1.85 years. DLBCL with BCL2 and c-MYC rearrangement of the subgroups of lymphoma is associated with very poor survival. The presence of these two translocations has an aggressive clinical course.

Usami M, Kuroda H, Shimoyama S, et al.
[A case of primary testicular diffuse large B-cell lymphoma with a p53 gene point mutation].
Gan To Kagaku Ryoho. 2015; 42(5):613-6 [PubMed] Related Publications
A 52-year-old man with bilateral swelling in the scrotum was referred to the department of urology in our hospital in January 2013. Pathological examination of the scrotum revealed diffuse large B-cell lymphoma(DLBCL). Immunohistochemical staining revealed p53 overexpression, and polymerase chain reaction-single strand conformation polymorphism(PCRSSCP) revealed a point mutation in exon 7 of the p53 gene. Rituximab plus cyclophosphamide, doxorubicin hydrochloride, vincristine, and prednisolone(R-CHOP)therapy and intrathecal prophylaxis were initiated. After three courses of R-CHOP therapy, high-dose cytarabine was administered, followed by peripheral blood stem cell harvesting. Busulfan, etoposide, and Ara-C(BEA)therapy was then administered, followed by autologous peripheral blood stem cell transplantation(auto- PBSCT). Primary testicular lymphoma(PTL)is a rare, clinically aggressive form of extranodal lymphoma, and there is a high incidence rate of relapse in the central nervous system(CNS). The vast majority of cases are histologically DLBCL. The p53 mutation is an independent marker of poor prognosis in patients with DLBCL treated with R-CHOP therapy. Our patient has been disease free for 17 months after auto-PBSCT with high-dose chemotherapy, which results in a greater level of penetration into the CNS.

Wang G, Gao X, Zhao W, et al.
[Presence of B-cell clones in angioimmunoblastic T cell lymphoma].
Zhonghua Bing Li Xue Za Zhi. 2015; 44(2):106-10 [PubMed] Related Publications
OBJECTIVE: To study the significance of B-cell clones in angioimmunoblastic T cell lymphoma (AITL) and the correlation with Epstein-Barr virus (EBV) and prognosis.
METHOD: The histopathologic features, T cell clonality and EBV positivity in 33 cases of AITL and 10 cases of peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS) collected from May 2010 to February 2014 were analyzed by immunohistochemistry, PCR gene rearrangement and in situ hybridization. Follow-up data were also collected.
RESULTS: Of the 33 cases with AITL, seven cases (21.2%) exhibited clonal rearrangement of Ig genes; 21 cases (63.6%) were EBV positive. Seven cases had B-cell clones and all (7/7) were EBV positive; 14 of the 26 (53.8%) cases without B-cell clones were EBV positive. The difference between the two groups was statistically significant (P = 0.032). Four levels were made according to the number of EBV-labeled cells, Ig gene rearrangements, but there was no significant difference among levels 1, 2 and 3. There was no correlation between B-cell clones and prognosis (P = 0.263).
CONCLUSION: Clonal rearrangement of Ig genes is a common finding in AITL, and it is highly associated with EBV positivity, but not with the number of EBV-labeled cells. The clinical significance remains unclear; further study with more samples is warranted.

Wang T, Jia L, Liao W, et al.
[Primary cutaneous diffuse large B-cell lymphoma, leg type: a study of clinicopathology, immunophenotype and gene rearrangement].
Zhonghua Bing Li Xue Za Zhi. 2015; 44(2):100-5 [PubMed] Related Publications
OBJECTIVE: To study the clinicopathologic features, immunophenotype and gene rearrangement of primary cutaneous diffuse large B-cell lymphoma, leg type (PCLBCL).
METHODS: Seven cases of PCLBCL were enrolled into the study. Clinicopathologic analysis, immunohistochemical staining and gene rearrangement for IgH and Igκ were undertaken in the study.
RESULTS: All the seven cases were male, and the median age was 72 years. Patients usually presented with multiple purple tumors, nodules, papules and infiltrative plaques. Two patients had a history of leg injury before onset, and one had mosquito bites. Histologically, the tumor involved the dermis and subcutis with dense and diffuse infiltrative pattern composing of centroblasts and/or immunoblasts. Immunohistochemical staining showed that seven cases (7/7) expressed CD20, six (6/6) expressed bcl-2, four (4/4) expressed MUM-1, four (4/5) expressed CD79a, four (4/5) expressed PAX-5 and four (4/6) expressed bcl-6, respectively. All cases did not express CD3ε, CD45RO, CD10 and CD30. IgH gene rearranged bands were detected in three (3/6) cases and Igκ was detected in one (1/5) case. Six of the seven cases died and the remaining patient, who was 44-year-old, was alive after 22 months of follow-up.
CONCLUSIONS: PCLBCL is rare, predominantly affects elderly male patients. PCLBCL has poor prognosis and high mortality, but younger patients seem to have better prognosis. Some cases had a history of trauma or mosquito bites. The relationship between the history and the onset of PCLBCL needs further evaluation.

Ji H, Tang Y, He Y, et al.
[Correlation of immunoglobulin variable heavy chain gene mutation status with prognosis in patients with mantle cell lymphoma].
Zhonghua Bing Li Xue Za Zhi. 2015; 44(2):90-4 [PubMed] Related Publications
OBJECTIVE: To study the relationship between immunoglobulin variable heavy chain (IgVH) gene mutation status and clinical features, pathologic findings and biologic behavior of mantle cell lymphoma (MCL).
METHODS: IgVH gene was amplified in 60 cases of MCL with FR1-JH and FR2-JH primers in BIOMED-2. The sequence was determined by cloning. The IgVH somatic mutational status was analyzed using NCBI's Ig-Blast tool. The relationship between IgVH gene mutation status and clinicopathologic features was also analyzed.
RESULTS: Forty percent (24 cases, 28 functional Ig genes) of the MCL cases displayed somatically mutated VH genes (defined as > 2% mutated), whereas 60.0% (36 cases, 40 functional Ig genes) showed unmutated VH genes. The most widely used genes were VH3-21 (27.9%) and VH4-34 (19.1%). The former were mainly used by unmutated cases, while the later mainly by mutated cases.Intraclonal heterogeneity was noted in 19 cases. There was no correlation of VH mutation status and specific VH gene with survival (P > 0.05).
CONCLUSIONS: MCL comprises at least two subsets that do not correlate with morphology: one with unmutated VH genes and one with mutated VH genes. The biased use of VH3-21 and VH4-34 is noted. The nonrandom usage of IgVH segments suggests specific antigens may play a role in the pathogenesis and progression of MCL subsets. There is no correlation of IgVH mutation status and specific VH gene with survival.

Crescenzo R, Abate F, Lasorsa E, et al.
Convergent mutations and kinase fusions lead to oncogenic STAT3 activation in anaplastic large cell lymphoma.
Cancer Cell. 2015; 27(4):516-32 [PubMed] Related Publications
A systematic characterization of the genetic alterations driving ALCLs has not been performed. By integrating massive sequencing strategies, we provide a comprehensive characterization of driver genetic alterations (somatic point mutations, copy number alterations, and gene fusions) in ALK(-) ALCLs. We identified activating mutations of JAK1 and/or STAT3 genes in ∼20% of 88 [corrected] ALK(-) ALCLs and demonstrated that 38% of systemic ALK(-) ALCLs displayed double lesions. Recurrent chimeras combining a transcription factor (NFkB2 or NCOR2) with a tyrosine kinase (ROS1 or TYK2) were also discovered in WT JAK1/STAT3 ALK(-) ALCL. All these aberrations lead to the constitutive activation of the JAK/STAT3 pathway, which was proved oncogenic. Consistently, JAK/STAT3 pathway inhibition impaired cell growth in vitro and in vivo.

Cimmino L, Dawlaty MM, Ndiaye-Lobry D, et al.
TET1 is a tumor suppressor of hematopoietic malignancy.
Nat Immunol. 2015; 16(6):653-62 [PubMed] Related Publications
The methylcytosine dioxygenase TET1 ('ten-eleven translocation 1') is an important regulator of 5-hydroxymethylcytosine (5hmC) in embryonic stem cells. The diminished expression of TET proteins and loss of 5hmC in many tumors suggests a critical role for the maintenance of this epigenetic modification. Here we found that deletion of Tet1 promoted the development of B cell lymphoma in mice. TET1 was required for maintenance of the normal abundance and distribution of 5hmC, which prevented hypermethylation of DNA, and for regulation of the B cell lineage and of genes encoding molecules involved in chromosome maintenance and DNA repair. Whole-exome sequencing of TET1-deficient tumors revealed mutations frequently found in non-Hodgkin B cell lymphoma (B-NHL), in which TET1 was hypermethylated and transcriptionally silenced. Our findings provide in vivo evidence of a function for TET1 as a tumor suppressor of hematopoietic malignancy.

Nazarova EL, Shardakov VI, Dem'ianova VT, et al.
[The diagnostic of defects of inborn immunity under B-cell tumors of lymphatic system].
Klin Lab Diagn. 2014; 59(11):39-42 [PubMed] Related Publications
The genetic characteristics are key risk factors of development of many human neoplasms including B-cell tumors of lymphatic system. The relationship between polymorphic variants of genes FCGR2A (His 1 66Agr), CD14 (C-159T). IL1β (T-31C), IL2 (7:330G) and 7LR2 (Arg753Ghn) and development of various forms of B-cell tumors of lymphatic system in 80 patients was investigated. The statistically significant differences of rates of particiular genotypes of single nucleotid polymorphisms of genes FCGR2A, CD14. IL1β, IL2 and TLR2 in patients with indolent and aggressive types of course of non-Hodgkin lymphoma and also multiple myeloma. The results prove hypothesis that genetic variants of genes of inborn immune response effect the origin and character of course of different types of lymphoproliferative diseases. The markers can become additional prognostic characteristics of benign and aggressive course of tumors.

Karreth FA, Reschke M, Ruocco A, et al.
The BRAF pseudogene functions as a competitive endogenous RNA and induces lymphoma in vivo.
Cell. 2015; 161(2):319-32 [PubMed] Related Publications
Research over the past decade has suggested important roles for pseudogenes in physiology and disease. In vitro experiments demonstrated that pseudogenes contribute to cell transformation through several mechanisms. However, in vivo evidence for a causal role of pseudogenes in cancer development is lacking. Here, we report that mice engineered to overexpress either the full-length murine B-Raf pseudogene Braf-rs1 or its pseudo "CDS" or "3' UTR" develop an aggressive malignancy resembling human diffuse large B cell lymphoma. We show that Braf-rs1 and its human ortholog, BRAFP1, elicit their oncogenic activity, at least in part, as competitive endogenous RNAs (ceRNAs) that elevate BRAF expression and MAPK activation in vitro and in vivo. Notably, we find that transcriptional or genomic aberrations of BRAFP1 occur frequently in multiple human cancers, including B cell lymphomas. Our engineered mouse models demonstrate the oncogenic potential of pseudogenes and indicate that ceRNA-mediated microRNA sequestration may contribute to the development of cancer.

Voropaeva EN, Voevoda MI, Pospelova TI, Maksimov VN
[Linkage disequilibrium and haplotypes of rs1042522, rs1625895 and rs17878362 gene TP53 markers in patients with diffuse large B-cell lymphoma].
Mol Biol (Mosk). 2014 Sep-Oct; 48(5):763-70 [PubMed] Related Publications
Association of rs1042522, rs17878362 and rs1625895 markers with non-Hodgkin's lymphoma risk is not well studied. Large number of non-Hodgkin's lymphoma entities, as well as a small effect of each of the polymorphisms on the lymphomas risk, leads to the analyses of these markers in each of histological subtypes of lymphoma and to study the polymorphisms in the haplotype groups. The goal of this work was to analyze the frequency, haplotypes and linkage disequilibrium of rs1042522, rs1625895 and rs17878362 in the patients with diffuse large B-cell lymphoma and in control group. The differences in the structure of LD between rs17878362, rs1042522 and rs1625895 TP53 gene in the population of the Siberian region were shown. Haplotype approach wasmore informative in the analyses of association of the gene TP53 polymorphisms and the diffuse large B-cell lymphomas risk in case-control study than the study of each polymorphism. The association of haplotype wArgG with diffuse large B-cell lymphoma risk, and the protective effect of haplotypes wProG or dupProG were identified. The difference in the effects of the haplotype TP53 was noted depending on the homozygous or heterozygous diplotype.

Roschewski M, Dunleavy K, Pittaluga S, et al.
Circulating tumour DNA and CT monitoring in patients with untreated diffuse large B-cell lymphoma: a correlative biomarker study.
Lancet Oncol. 2015; 16(5):541-9 [PubMed] Article available free on PMC after 01/05/2016 Related Publications
BACKGROUND: Diffuse large-B-cell lymphoma is curable, but when treatment fails, outcome is poor. Although imaging can help to identify patients at risk of treatment failure, they are often imprecise, and radiation exposure is a potential health risk. We aimed to assess whether circulating tumour DNA encoding the clonal immunoglobulin gene sequence could be detected in the serum of patients with diffuse large-B-cell lymphoma and used to predict clinical disease recurrence after frontline treatment.
METHODS: We used next-generation DNA sequencing to retrospectively analyse cell-free circulating tumour DNA in patients assigned to one of three treatment protocols between May 8, 1993, and June 6, 2013. Eligible patients had diffuse large-B-cell lymphoma, no evidence of indolent lymphoma, and were previously untreated. We obtained serial serum samples and concurrent CT scans at specified times during most treatment cycles and up to 5 years of follow-up. VDJ gene segments of the rearranged immunoglobulin receptor genes were amplified and sequenced from pretreatment specimens and serum circulating tumour DNA encoding the VDJ rearrangements was quantitated.
FINDINGS: Tumour clonotypes were identified in pretreatment specimens from 126 patients who were followed up for a median of 11 years (IQR 6·8-14·2). Interim monitoring of circulating tumour DNA at the end of two treatment cycles in 108 patients showed a 5-year time to progression of 41·7% (95% CI 22·2-60·1) in patients with detectable circulating tumour DNA and 80·2% (69·6-87·3) in those without detectable circulating tumour DNA (p<0·0001). Detectable interim circulating tumour DNA had a positive predictive value of 62·5% (95% CI 40·6-81·2) and a negative predictive value of 79·8% (69·6-87·8). Surveillance monitoring of circulating tumour DNA was done in 107 patients who achieved complete remission. A Cox proportional hazards model showed that the hazard ratio for clinical disease progression was 228 (95% CI 51-1022) for patients who developed detectable circulating tumour DNA during surveillance compared with patients with undetectable circulating tumour DNA (p<0·0001). Surveillance circulating tumour DNA had a positive predictive value of 88·2% (95% CI 63·6-98·5) and a negative predictive value of 97·8% (92·2-99·7) and identified risk of recurrence at a median of 3·5 months (range 0-200) before evidence of clinical disease.
INTERPRETATION: Surveillance circulating tumour DNA identifies patients at risk of recurrence before clinical evidence of disease in most patients and results in a reduced disease burden at relapse. Interim circulating tumour DNA is a promising biomarker to identify patients at high risk of treatment failure.
FUNDING: National Cancer Institute and Adaptive Biotechnologies.

Boddicker RL, Kip NS, Xing X, et al.
The oncogenic transcription factor IRF4 is regulated by a novel CD30/NF-κB positive feedback loop in peripheral T-cell lymphoma.
Blood. 2015; 125(20):3118-27 [PubMed] Article available free on PMC after 14/05/2016 Related Publications
Peripheral T-cell lymphomas (PTCLs) are generally aggressive non-Hodgkin lymphomas with poor overall survival rates following standard therapy. One-third of PTCLs express interferon regulatory factor-4 (IRF4), a tightly regulated transcription factor involved in lymphocyte growth and differentiation. IRF4 drives tumor growth in several lymphoid malignancies and has been proposed as a candidate therapeutic target. Because direct IRF4 inhibitors are not clinically available, we sought to characterize the mechanism by which IRF4 expression is regulated in PTCLs. We demonstrated that IRF4 is constitutively expressed in PTCL cells and drives Myc expression and proliferation. Using an inhibitor screen, we identified nuclear factor κB (NF-κB) as a candidate regulator of IRF4 expression and cell proliferation. We then demonstrated that the NF-κB subunits p52 and RelB were transcriptional activators of IRF4. Further analysis showed that activation of CD30 promotes p52 and RelB activity and subsequent IRF4 expression. Finally, we showed that IRF4 transcriptionally regulates CD30 expression. Taken together, these data demonstrate a novel positive feedback loop involving CD30, NF-κB, and IRF4; further evidence for this mechanism was demonstrated in human PTCL tissue samples. Accordingly, NF-κB inhibitors may represent a clinical means to disrupt this feedback loop in IRF4-positive PTCLs.

Song A, Ye J, Zhang K, et al.
Aberrant expression of the CHFR prophase checkpoint gene in human B-cell non-Hodgkin lymphoma.
Leuk Res. 2015; 39(5):536-43 [PubMed] Related Publications
Checkpoint with FHA and Ring Finger (CHFR) is a checkpoint protein that reportedly initiates a cell cycle delay in response to microtubule stress during prophase in mitosis, which has become an interesting target for understanding cancer pathogenesis. Recently, aberrant methylation of the CHFR gene associated with gene silencing has been reported in several cancers. In the present study, we examined the expression of CHFR in B-cell non-Hodgkin lymphoma (B-NHL) in vitro and in vivo. Our results showed that the expression level of CHFR mRNA and protein was reduced in B-NHL tissue samples and B cell lines. Furthermore, CHFR methylation was detected in 39 of 122 B-NHL patients, which was not found in noncancerous reactive hyperplasia of lymph node (RH) tissues. CHFR methylation correlated with the reduced expression of CHFR, high International Prognostic Index (IPI) scores and later pathologic Ann Arbor stages of B-NHL. Treatment with demethylation reagent, 5-Aza-dC, could eliminate the hypermethylation of CHFR, enhance CHFR expression and cell apoptosis and inhibit the cell proliferation of Raji cells, which could be induced by high expression of CHFR in Raji cells. Our results indicated that aberrant methylation of CHFR may be associated with the pathogenesis, progression for B-NHL, which might be a novel molecular marker as prognosis and treatment for B-NHL.

Ansell SM
DNA methylation in lymphoma: an opportunity?
Blood. 2015; 125(12):1848-9 [PubMed] Related Publications
Epigenetic mechanisms, including DNA methylation, play an important role in not only the development and maturation of normal cells, but also the development and progression of malignant cells. In this edition of Blood, Arribas et al show that DNA methylation profiling identifies 2 subtypes of splenic marginal zone lymphoma with different clinical and genetic features. These findings provide an opportunity to better understand the biology of marginal zone lymphoma and optimize therapy by using demethylating agents to reverse the high-methylation phenotype and thereby target malignant B cells.

Lin HY, Shi H, Li CY, et al.
LEP and LEPR polymorphisms in non-Hodgkin lymphoma risk: a systematic review and pooled analysis.
J BUON. 2015 Jan-Feb; 20(1):261-8 [PubMed] Related Publications
PURPOSE: The purpose of this systematic meta-analysis was to evaluate the association between leptin (LEP) and leptin receptor (LEPR) gene polymorphisms and non-Hodgkin lymphoma (NHL) risk.
METHODS: All studies published up to July 2014 on the association between LEP and LEPR polymorphisms and NHL risk were identified by searching PubMed, Web of Science, EMBASE, and Google Scholar. Odds ratios (ORs) with 95% confidence intervals (CIs) for LEP and LEPR polymorphisms and NHL were calculated with fixed-effects and random-effects models.
RESULTS: LEP G2528A polymorphism was associated with increased, yet not statistically significant risk of NHL (homozygote comparison, OR=1.27, 95% CI=1.01-1.60, p=0.63; heterozygote comparison, OR=1.13, 95% CI=0.86-1.49, p=0.14; dominant model, OR=1.18, 95% CI=0.99-1.41, p=0.21; recessive model, OR=1.18, 95% CI=0.97-1.43, p=0.78; additive model, OR=1.14, 95% CI=1.01-1.28, p=0.52). Significant decrease of NHL risk was found in LEP A19G polymorphism, while no links were detected with the LEPR polymorphisms studied. In subgroup analysis, the pooled results showed that LEP A19G polymorphism was associated with decreased risk of follicular lymphoma (FL) (homozygote comparison, OR=0.56, 95% CI=0.37-0.85, p=0.69). However, no evidence of a significant association was observed in diffuse large B-cell lymphoma (DLBCL) for variant genotypes of all single nucleotide polymorphisms (SNPs).
CONCLUSIONS: LEP G2548A polymorphism contributes to NHL susceptibility. Also, our results provide evidence that LEP A19G polymorphism is associated with decreased risk of NHL, especially in FL. Further large-scale and well-designed studies are needed to confirm this association.

Robaina MC, Mazzoccoli L, Arruda VO, et al.
Deregulation of DNMT1, DNMT3B and miR-29s in Burkitt lymphoma suggests novel contribution for disease pathogenesis.
Exp Mol Pathol. 2015; 98(2):200-7 [PubMed] Related Publications
Methylation of CpG islands in promoter gene regions is frequently observed in lymphomas. DNA methylation is established by DNA methyltransferases (DNMTs). DNMT1 maintains methylation patterns, while DNMT3A and DNMT3B are critical for de novo DNA methylation. Little is known about the expression of DNMTs in lymphomas. DNMT3A and 3B genes can be regulated post-transcriptionally by miR-29 family. Here, we demonstrated for the first time the overexpression of DNMT1 and DNMT3B in Burkitt lymphoma (BL) tumor samples (69% and 86%, respectively). Specifically, the treatment of two BL cell lines with the DNMT inhibitor 5-aza-dC decreased DNMT1 and DNMT3B protein levels and inhibited cell growth. Additionally, miR-29a, miR-29b and miR-29c levels were significantly decreased in the BL tumor samples. Besides, the ectopic expression of miR-29a, miR-29b and miR-29c reduced the DNMT3B expression and miR-29a and miR-29b lead to increase of p16(INK4a) mRNA expression. Altogether, our data suggest that deregulation of DNMT1, DNMT3B and miR29 may be involved in BL pathogenesis.

Husby S, Ralfkiaer U, Garde C, et al.
miR-18b overexpression identifies mantle cell lymphoma patients with poor outcome and improves the MIPI-B prognosticator.
Blood. 2015; 125(17):2669-77 [PubMed] Related Publications
Recent studies show that mantle cell lymphoma (MCL) express aberrant microRNA (miRNA) profiles; however, the clinical effect of miRNA expression has not previously been examined and validated in large prospective homogenously treated cohorts. We performed genome-wide miRNA microarray profiling of 74 diagnostic MCL samples from the Nordic MCL2 trial (screening cohort). Prognostic miRNAs were validated in diagnostic MCL samples from 94 patients of the independent Nordic MCL3 trial (validation cohort). Three miRNAs (miR-18b, miR-92a, and miR-378d) were significantly differentially expressed in patients who died of MCL in both cohorts. MiR-18b was superior to miR-92a and miR-378d in predicting high risk. Thus, we generated a new biological MCL International Prognostic Index (MIPI-B)-miR prognosticator, combining expression levels of miR-18b with MIPI-B data. Compared to the MIPI-B, this prognosticator improved identification of high-risk patients with regard to cause-specific, overall, and progression-free survival. Transfection of 2 MCL cell lines with miR-18b decreased their proliferation rate without inducing apoptosis, suggesting that miR-18b may render MCL cells resistant to chemotherapy by decelerating cell proliferation. We conclude that overexpression of miR-18b identifies patients with poor prognosis in 2 large prospective MCL cohorts and adds prognostic information to the MIPI-B. MiR-18b may reduce the proliferation rate of MCL cells as a mechanism of chemoresistance.

Martinez-Lopez A, Curiel-Olmo S, Mollejo M, et al.
MYD88 (L265P) somatic mutation in marginal zone B-cell lymphoma.
Am J Surg Pathol. 2015; 39(5):644-51 [PubMed] Related Publications
MYD88 L265P is a somatic mutation that has been identified in about 90% of Waldenström macroglobulinemia/lymphoplasmacytic lymphomas (LPLs). It has also been detected in a subset of marginal zone lymphoma (MZL) cases, but the frequency and clinical and histologic features of these mutated MZL cases has only been partially characterized. We have developed a customized TaqMan allele-specific polymerase chain reaction for sensitive detection of this mutation in paraffin-embedded tissue. We analyzed samples from 19 patients with LPL, 88 patients with splenic marginal zone lymphoma (SMZL), 8 patients with nodal marginal zone lymphoma (NMZL), 21 patients with extranodal mucosa-associated lymphoid tissue (MALT), and 2 patients with B-cell lymphoma not otherwise specified. By integrating mutational, histologic, and clinical data, 5 cases were reclassified as LPL. After reclassification, MYD88 L265P was detected in 13/86 (15%) SMZL and in 19/24 LPL (79%) cases. The mutation was absent from NMZL and MALT cases. A strong correlation was found between the presence of an IgM monoclonal paraproteinemia and the MYD88 L265P mutation (P<0.0001). SMZL cases positive for MYD88 L265P were also associated with monoclonal IgM paraproteinemia (4/13 cases; P<0.0283), although with less serum paraproteinemia. They also had a higher frequency of plasmacytic differentiation (9/13) but with no correlation between the presence of mutation and of light chain-restricted plasma cells in tissue. Demonstration of the MYD88 L265 mutation is a valuable tool for the diagnosis of LPL, although some SMZL cases carrying the mutation do not fulfill the diagnostic criteria for LPL.

Jiang W, Lee BJ, Li C, et al.
Aberrant TCRδ rearrangement underlies the T-cell lymphocytopenia and t(12;14) translocation associated with ATM deficiency.
Blood. 2015; 125(17):2665-8 [PubMed] Article available free on PMC after 14/05/2016 Related Publications
Ataxia telangiectasia mutated (ATM) is a protein kinase and a master regulator of DNA-damage responses. Germline ATM inactivation causes ataxia-telangiectasia (A-T) syndrome with severe lymphocytopenia and greatly increased risk for T-cell lymphomas/leukemia. Both A-T and T-cell prolymphoblastic leukemia patients with somatic mutations of ATM frequently carry inv(14;14) between the T-cell receptor α/δ (TCRα/δ) and immunoglobulin H loci, but the molecular origin of this translocation remains elusive. ATM(-/-) mice recapitulate lymphocytopenia of A-T patients and routinely succumb to thymic lymphomas with t(12;14) translocation, syntenic to inv(14;14) in humans. Here we report that deletion of the TCRδ enhancer (Eδ), which initiates TCRδ rearrangement, significantly improves αβ T cell output and effectively prevents t(12;14) translocations in ATM(-/-) mice. These findings identify the genomic instability associated with V(D)J recombination at the TCRδ locus as the molecular origin of both lymphocytopenia and the signature t(12;14) translocations associated with ATM deficiency.

Green MR, Kihira S, Liu CL, et al.
Mutations in early follicular lymphoma progenitors are associated with suppressed antigen presentation.
Proc Natl Acad Sci U S A. 2015; 112(10):E1116-25 [PubMed] Article available free on PMC after 10/09/2015 Related Publications
Follicular lymphoma (FL) is incurable with conventional therapies and has a clinical course typified by multiple relapses after therapy. These tumors are genetically characterized by B-cell leukemia/lymphoma 2 (BCL2) translocation and mutation of genes involved in chromatin modification. By analyzing purified tumor cells, we identified additional novel recurrently mutated genes and confirmed mutations of one or more chromatin modifier genes within 96% of FL tumors and two or more in 76% of tumors. We defined the hierarchy of somatic mutations arising during tumor evolution by analyzing the phylogenetic relationship of somatic mutations across the coding genomes of 59 sequentially acquired biopsies from 22 patients. Among all somatically mutated genes, CREBBP mutations were most significantly enriched within the earliest inferable progenitor. These mutations were associated with a signature of decreased antigen presentation characterized by reduced transcript and protein abundance of MHC class II on tumor B cells, in line with the role of CREBBP in promoting class II transactivator (CIITA)-dependent transcriptional activation of these genes. CREBBP mutant B cells stimulated less proliferation of T cells in vitro compared with wild-type B cells from the same tumor. Transcriptional signatures of tumor-infiltrating T cells were indicative of reduced proliferation, and this corresponded to decreased frequencies of tumor-infiltrating CD4 helper T cells and CD8 memory cytotoxic T cells. These observations therefore implicate CREBBP mutation as an early event in FL evolution that contributes to immune evasion via decreased antigen presentation.

Wang SS, Vajdic CM, Linet MS, et al.
Associations of non-Hodgkin Lymphoma (NHL) risk with autoimmune conditions according to putative NHL loci.
Am J Epidemiol. 2015; 181(6):406-21 [PubMed] Article available free on PMC after 15/03/2016 Related Publications
Autoimmune conditions and immune system-related genetic variations are associated with risk of non-Hodgkin lymphoma (NHL). In a pooled analysis of 8,692 NHL cases and 9,260 controls from 14 studies (1988-2007) within the International Lymphoma Epidemiology Consortium, we evaluated the interaction between immune system genetic variants and autoimmune conditions in NHL risk. We evaluated the immunity-related single nucleotide polymorphisms rs1800629 (tumor necrosis factor gene (TNF) G308A), rs1800890 (interleukin-10 gene (IL10) T3575A), rs6457327 (human leukocyte antigen gene (HLA) class I), rs10484561 (HLA class II), and rs2647012 (HLA class II)) and categorized autoimmune conditions as primarily mediated by B-cell or T-cell responses. We constructed unconditional logistic regression models to measure associations between autoimmune conditions and NHL with stratification by genotype. Autoimmune conditions mediated by B-cell responses were associated with increased NHL risk, specifically diffuse large B-cell lymphoma (odds ratio (OR) = 3.11, 95% confidence interval (CI): 2.25, 4.30) and marginal zone lymphoma (OR = 5.80, 95% CI: 3.82, 8.80); those mediated by T-cell responses were associated with peripheral T-cell lymphoma (OR = 2.14, 95% CI: 1.35, 3.38). In the presence of the rs1800629 AG/AA genotype, B-cell-mediated autoimmune conditions increased NHL risk (OR = 3.27, 95% CI: 2.07, 5.16; P-interaction = 0.03) in comparison with the GG genotype (OR = 1.82, 95% CI: 1.31, 2.53). This interaction was consistent across major B-cell NHL subtypes, including marginal zone lymphoma (P-interaction = 0.02) and follicular lymphoma (P-interaction = 0.04).

Twa DD, Mottok A, Chan FC, et al.
Recurrent genomic rearrangements in primary testicular lymphoma.
J Pathol. 2015; 236(2):136-41 [PubMed] Related Publications
Primary testicular diffuse large B cell lymphoma (PTL) is an aggressive malignancy that occurs in the immune-privileged anatomical site of the testis. We have previously shown that structural genomic rearrangements involving the MHC class II transactivator CIITA and programmed death ligands (PDLs) 1 and 2 are frequent across multiple B cell lymphoma entities. Specifically in PTL, we found rearrangements in the PDL locus by fluorescence in situ hybridization (FISH). However, breakpoint anatomy and rearrangement partners were undetermined, while CIITA rearrangements had not been reported previously in PTL. Here, we performed bacterial artificial chromosome capture sequencing on three archival, formalin-fixed, paraffin-embedded tissue biopsies, interrogating 20 known rearrangement hotspots in B cell lymphomas. We report novel CIITA, FOXP1 and PDL rearrangements involving IGHG4, FLJ45248, RFX3, SMARCA2 and SNX29. Moreover, we present immunohistochemistry data supporting the association between PDL rearrangements and increased protein expression. Finally, using FISH, we show that CIITA (8/82; 10%) and FOXP1 (5/74; 7%) rearrangements are recurrent in PTL. In summary, we describe rearrangement frequencies and novel rearrangement partners of the CIITA, FOXP1 and PDL loci at base-pair resolution in a rare, aggressive lymphoma. Our data suggest immune-checkpoint inhibitor therapy as a promising intervention for PTL patients harbouring PDL rearrangements.

Pham-Ledard A, Cowppli-Bony A, Doussau A, et al.
Diagnostic and prognostic value of BCL2 rearrangement in 53 patients with follicular lymphoma presenting as primary skin lesions.
Am J Clin Pathol. 2015; 143(3):362-73 [PubMed] Related Publications
OBJECTIVES: To study the diagnostic value of BCL2 rearrangement in follicle center lymphoma (FCL) presenting as primary skin lesions, evaluate its prevalence and the prognostic value in primary cutaneous FCL (PCFCL), and assess prognostic factors in PCFCL.
METHODS: Fifty-three patients with a cutaneous presentation of FCL without a history of nodal lymphoma were selected retrospectively. Clinical and histologic data were collected together with staging and follow-up data. A fluorescence in situ hybridization (FISH) test for BCL2 split probes was performed on skin biopsy specimens.
RESULTS: Initial staging procedures identified 47 PCFCLs and six cases of secondary skin involvement of FCL (SSIFCL). FISH detected seven cases carrying a BCL2 rearrangement: four (8.5%) of 47 PCFCLs and three (50%) of six SSIFCLs. These seven cases coexpressed BCL2 and CD10. In PCFCL, cutaneous relapse rate was 42.6%. A small/medium centrocytic cell population was associated with a higher probability of skin relapse in univariate (P = .008) and multivariate (P = .028) analysis, and BCL2 rearrangement detection was associated with secondary extracutaneous spreading (P = .05).
CONCLUSIONS: We observed that BCL2 rearrangement in PCFCL is rare, associated with initial positivity of staging (diagnostic value) or with secondary extracutaneous spreading (prognostic value). In selected cases with BCL2-CD10 coexpression, FISH testing could detect patients with poor outcome and require closer monitoring.

Song JY, Yu J, Chan WC
Gene expression profiling in non-Hodgkin lymphomas.
Cancer Treat Res. 2015; 165:97-123 [PubMed] Related Publications
Although the current WHO classification (Swerdlow et al. WHO classification of tumours of haematopoietic and lymphoid tissues. International Agency for Research on Cancer, Lyon, 2008 [1]) for hematolymphoid neoplasms has delineated lymphomas based on the combined morphologic, immunophenotypic, and genotypic findings, further refinement is necessary especially in regard to therapeutics and prognostic implications. High-throughput gene expression profiling (GEP) using microarray technology (Schena et al. Science 270:467-470, 1995 [2]; Augenlicht et al. Proc Natl Acad Sci USA 88:3286-3289, 1991 [3]) was developed about 20 years ago, and further refinement of the technology and analytical approaches has enabled us to routinely evaluate practically the entire transcriptome at a time. GEP has helped to improve the classification and prognostication of non-Hodgkin lymphomas (NHL) as well as improved our understanding of their pathophysiology and response to new therapeutics. In this paper, we will briefly review how this revolutionary tool has transformed our understanding of lymphomas and given us insight into targeted therapeutics. We will also discuss the current efforts in adapting the findings to routine clinical practice, the evolution of the research technology and directions in the future.

Hartmann S, Döring C, Vucic E, et al.
Array comparative genomic hybridization reveals similarities between nodular lymphocyte predominant Hodgkin lymphoma and T cell/histiocyte rich large B cell lymphoma.
Br J Haematol. 2015; 169(3):415-22 [PubMed] Related Publications
Nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) and T cell/histiocyte rich large B cell lymphoma (THRLBCL) usually affect middle-aged men, show tumour cells with a B cell phenotype and a low tumour cell content. Whereas the clinical behaviour of NLPHL is indolent, THRLBCL presents with advanced stage disease and an aggressive behaviour. In the present study, array comparative genomic hybridization was performed in seven typical NLPHL, four THRLBCL-like NLPHL variants, six THRLBCL and four diffuse large B cell lymphomas (DLBCL) derived from NLPHL. The number of genomic aberrations was higher in THRLBCL compared with typical and THRLBCL-like variant of NLPHL. Gains of 2p16.1 and losses of 2p11.2 and 9p11.2 were commonly observed in typical and THRLBCL-like variants of NLPHL as well as THRLBCL. Gains of 2p16.1, affecting the REL locus were confirmed in an independent cohort. Expression of the REL protein was observed at similar frequencies in typical and THRLBCL-like variant of NLPHL as well as THRLBCL (33-38%). In conclusion, the present study reveals further similarities between NLPHL and THRLBCL on the genomic level, confirming that these entities are part of a pathobiological spectrum with common molecular features, but varying clinical presentations.

Tonomura N, Elvers I, Thomas R, et al.
Genome-wide association study identifies shared risk loci common to two malignancies in golden retrievers.
PLoS Genet. 2015; 11(2):e1004922 [PubMed] Article available free on PMC after 15/03/2016 Related Publications
Dogs, with their breed-determined limited genetic background, are great models of human disease including cancer. Canine B-cell lymphoma and hemangiosarcoma are both malignancies of the hematologic system that are clinically and histologically similar to human B-cell non-Hodgkin lymphoma and angiosarcoma, respectively. Golden retrievers in the US show significantly elevated lifetime risk for both B-cell lymphoma (6%) and hemangiosarcoma (20%). We conducted genome-wide association studies for hemangiosarcoma and B-cell lymphoma, identifying two shared predisposing loci. The two associated loci are located on chromosome 5, and together contribute ~20% of the risk of developing these cancers. Genome-wide p-values for the top SNP of each locus are 4.6×10-7 and 2.7×10-6, respectively. Whole genome resequencing of nine cases and controls followed by genotyping and detailed analysis identified three shared and one B-cell lymphoma specific risk haplotypes within the two loci, but no coding changes were associated with the risk haplotypes. Gene expression analysis of B-cell lymphoma tumors revealed that carrying the risk haplotypes at the first locus is associated with down-regulation of several nearby genes including the proximal gene TRPC6, a transient receptor Ca2+-channel involved in T-cell activation, among other functions. The shared risk haplotype in the second locus overlaps the vesicle transport and release gene STX8. Carrying the shared risk haplotype is associated with gene expression changes of 100 genes enriched for pathways involved in immune cell activation. Thus, the predisposing germ-line mutations in B-cell lymphoma and hemangiosarcoma appear to be regulatory, and affect pathways involved in T-cell mediated immune response in the tumor. This suggests that the interaction between the immune system and malignant cells plays a common role in the tumorigenesis of these relatively different cancers.

Battistella M, Romero M, Castro-Vega LJ, et al.
The High Expression of the microRNA 17-92 Cluster and its Paralogs, and the Downregulation of the Target Gene PTEN, Is Associated with Primary Cutaneous B-Cell Lymphoma Progression.
J Invest Dermatol. 2015; 135(6):1659-67 [PubMed] Related Publications
The oncogenic microRNA (miR) 17-92 cluster has a causative role in the lymphomagenesis of nodal B-cell lymphomas, by activating proliferation and inhibiting apoptosis. Here we analyzed primary cutaneous B-cell lymphomas for the miR-17-92 cluster and its paralogs miR-106a-363 and miR-106b-25. In 22 primary cutaneous diffuse large B-cell lymphomas, leg type (PCLBCL-LT) compared with 22 primary cutaneous follicle center lymphomas (PCFCLs), we found that miR-20a and miR-106a were overexpressed. Multivariate Cox analysis showed that higher miR-20a and miR-20b expression levels were associated with shorter disease-free and overall survival, independently from histological type. Gene expression profiling also showed a downregulation of 8 candidate target genes of miR-20a, miR-20b, and miR-106a in PCLBCL-LT compared with PCFCL. Among the candidate target genes, PTEN, NCOA3, and CAPRIN2 were confirmed to be underexpressed in PCLBCL-LT using quantitative reverse transcriptase-PCR on CD20-positive laser-microdissected tumor cells. In multivariate Cox analysis, lower PTEN mRNA expression level was associated with shorter disease-free survival (DFS), independently from the histological type. Altogether, this molecular and bioinformatic study of 44 patient skin biopsy samples showed that the oncogenic miR-17-92 cluster and its paralogs were involved in cutaneous B-cell lymphoma progression, and that the downregulation of the target gene PTEN was associated with shorter DFS.

Huang X, Zhang Y, Gao Z
Plasmablastic lymphoma of the stomach with C-MYC rearrangement in an immunocompetent young adult: a case report.
Medicine (Baltimore). 2015; 94(4):e470 [PubMed] Related Publications
Plasmablastic lymphoma (PBL) is a rare B-cell neoplasm mostly described in human immunodeficiency virus-infected patients. Herein, we described a case of PBL presenting as gastric mass in a 21-year-old young adult without known immunodeficiency. The histological examination of the specimen showed a diffuse proliferation of round- to oval-shaped large cells with scant cytoplasm, and prominent nucleoli. The neoplasm stained positively for CD45, CD38, MUM1, and Vs38C, but typical B-cell and T-cell markers (PAX5, CD20, CD79a, and CD3) were absent. The proliferative index (Ki-67) was about 95%. And the neoplastic cells diffusely expressed the c-myc protein. Epstein-Barr virus-encoded RNA in situ hybridization was negative. Molecular genetic study via interphase fluorescence in situ hybridization disclosed the rearrangement involving c-myc gene. Awareness of this distinctive lymphoma can prevent misdiagnosis by the clinicians and/or the pathologists.

Aqil B, Merritt BY, Elghetany MT, et al.
Childhood nodal marginal zone lymphoma with unusual clinicopathologic and cytogenetic features for the pediatric variant: a case report.
Pediatr Dev Pathol. 2015 Mar-Apr; 18(2):167-71 [PubMed] Related Publications
Nodal marginal zone lymphoma (NMZL) is a B-cell lymphoma that shares morphologic and immunophenotypic features with extranodal and splenic marginal zone lymphomas but lacks extranodal or splenic involvement at presentation. NMZL occurs mostly in adults with no sex predilection, at advanced stage (III or IV), with frequent relapses and a high incidence of tumoral genetic abnormalities including trisomies 3 and 18 and gain of 7q. Pediatric NMZL, however, is a rare but distinct variant of NMZL with characteristic features including male predominance, asymptomatic and localized (stage I) disease, low relapse rates with excellent outcomes, and a lower incidence of essentially similar genetic aberrations compared to adult NMZL. Here we describe a unique case of childhood NMZL with unusual clinicopathologic features for the pediatric variant including generalized lymphadenopathy, high-stage disease with persistence after therapy, unusual immunophenotype (CD5, CD23, and BCL6 positive), and unique chromosomal abnormalities including monosomy 20 and add(10)(p11.2).

Arribas AJ, Rinaldi A, Mensah AA, et al.
DNA methylation profiling identifies two splenic marginal zone lymphoma subgroups with different clinical and genetic features.
Blood. 2015; 125(12):1922-31 [PubMed] Article available free on PMC after 15/03/2016 Related Publications
Splenic marginal zone lymphoma is a rare lymphoma. Loss of 7q31 and somatic mutations affecting the NOTCH2 and KLF2 genes are the commonest genomic aberrations. Epigenetic changes can be pharmacologically reverted; therefore, identification of groups of patients with specific epigenomic alterations might have therapeutic relevance. Here we integrated genome-wide DNA-promoter methylation profiling with gene expression profiling, and clinical and biological variables. An unsupervised clustering analysis of a test series of 98 samples identified 2 clusters with different degrees of promoter methylation. The cluster comprising samples with higher-promoter methylation (High-M) had a poorer overall survival compared with the lower (Low-M) cluster. The prognostic relevance of the High-M phenotype was confirmed in an independent validation set of 36 patients. In the whole series, the High-M phenotype was associated with IGHV1-02 usage, mutations of NOTCH2 gene, 7q31-32 loss, and histologic transformation. In the High-M set, a number of tumor-suppressor genes were methylated and repressed. PRC2 subunit genes and several prosurvival lymphoma genes were unmethylated and overexpressed. A model based on the methylation of 3 genes (CACNB2, HTRA1, KLF4) identified a poorer-outcome patient subset. Exposure of splenic marginal zone lymphoma cell lines to a demethylating agent caused partial reversion of the High-M phenotype and inhibition of proliferation.

Recurrent Structural Alterations

Selected list of common recurrent structural abnormalities

This is a highly selective list aiming to capture structural abnormalies which are frequesnt and/or significant in relation to diagnosis, prognosis, and/or characterising specific cancers. For a much more extensive list see the Mitelman Database of Chromosome Aberrations and Gene Fusions in Cancer.

t(8;14;12)(q24.1;q32.3;q24.1) in a Burkitt's lymphoma

add(14q32) / dup(14p32) in Non-Hodgkin's Lymphoma

Arcaroli JJ, Dave BJ, Pickering DL, et al.
Is a duplication of 14q32 a new recurrent chromosomal alteration in B-cell non-Hodgkin lymphoma?
Cancer Genet Cytogenet. 1999; 113(1):19-24 [PubMed] Related Publications
Identification of clonal chromosomal abnormalities involving 14q32 and its association with specific histological subtypes of non-Hodgkin lymphoma (NHL) has provided substantial insight to the genetic events leading to the disease. However, in some cases with inferior morphology of tumor cell chromosomes, the additional segment on chromosome 14 remains unidentified by cytogenetic banding techniques alone. To elucidate the origin of the additional chromosomal segment and to correlate the newly determined alterations with histology, metaphases from 15 NHL patients with add(14)(q32) were examined using fluorescence in situ hybridization (FISH) techniques after cytogenetic analysis had been performed. We found the duplication of 14q involving the q32 region in 6 cases with a dup(14) (q32) in 4 cases and a dup(14)(q24q32) in 2 cases. In 8 cases, FISH unveiled known NHL associated translocations; a t(14;18)(q32;q21) in 4 cases, a t(11;14)(q13;q32) in 2 cases, a t(8;14)(q24;q32) and a t(9;14)(p13;q32) in 1 case each. We also noted a t(14;17)(q32;q21) in 1 case. The use of FISH was a valuable asset in determining the origin of the additional material on chromosome 14q32, and helped resolve a group of B-cell NHLs with involvement of a duplicated 14q32 region.

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