scholarly journals Whole-genome sequencing identifies recurrent somatic NOTCH2 mutations in splenic marginal zone lymphoma

2012 ◽  
Vol 209 (9) ◽  
pp. 1553-1565 ◽  
Author(s):  
Mark J. Kiel ◽  
Thirunavukkarasu Velusamy ◽  
Bryan L. Betz ◽  
Lili Zhao ◽  
Helmut G. Weigelin ◽  
...  
Keyword(s):  
B Cell ◽  
Marginal Zone ◽  
Marginal Zone Lymphoma ◽  
Lymphocytic Leukemia ◽  
Primary Lymphoma ◽  
Reactive Lymphoid Hyperplasia ◽  
Low Grade ◽  
Splenic Marginal Zone Lymphoma ◽  
Whole Genome ◽  
Histological Transformation

Splenic marginal zone lymphoma (SMZL), the most common primary lymphoma of spleen, is poorly understood at the genetic level. In this study, using whole-genome DNA sequencing (WGS) and confirmation by Sanger sequencing, we observed mutations identified in several genes not previously known to be recurrently altered in SMZL. In particular, we identified recurrent somatic gain-of-function mutations in NOTCH2, a gene encoding a protein required for marginal zone B cell development, in 25 of 99 (∼25%) cases of SMZL and in 1 of 19 (∼5%) cases of nonsplenic MZLs. These mutations clustered near the C-terminal proline/glutamate/serine/threonine (PEST)-rich domain, resulting in protein truncation or, rarely, were nonsynonymous substitutions affecting the extracellular heterodimerization domain (HD). NOTCH2 mutations were not present in other B cell lymphomas and leukemias, such as chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL; n = 15), mantle cell lymphoma (MCL; n = 15), low-grade follicular lymphoma (FL; n = 44), hairy cell leukemia (HCL; n = 15), and reactive lymphoid hyperplasia (n = 14). NOTCH2 mutations were associated with adverse clinical outcomes (relapse, histological transformation, and/or death) among SMZL patients (P = 0.002). These results suggest that NOTCH2 mutations play a role in the pathogenesis and progression of SMZL and are associated with a poor prognosis.

Absence of Mutations of the Histone Methyltransferase Gene EZH2 In Splenic B-Cell Marginal Zone Lymphoma

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 5086-5086
Author(s):  
Luz Martínez-Avilés ◽  
Marta Salido ◽  
Beatriz Bellosillo ◽  
Vera Adema ◽  
Ana Ferrer ◽  
...  
Keyword(s):  
B Cell ◽  
Marginal Zone ◽  
Mutational Analysis ◽  
Conflicts Of Interest ◽  
Direct Sequencing ◽  
Normal Karyotype ◽  
Marginal Zone Lymphoma ◽  
Low Grade ◽  
Splenic Marginal Zone Lymphoma ◽  
7Q Deletion

Abstract Abstract 5086 Background Splenic marginal zone lymphoma (SMZL) is a rare low-grade B-cell lymphoproliferative disorder with characteristic clinical, cytological, histological and immunophenotypical features. The most common cytogenetic abnormality, present in 30–40% of the patients is the 7q deletion, that extends from 7q21 to 7q36. This aberration may represent a primary pathogenic event in SMZL. Recently, mutations in the EZH2 gene, located at 7q36.1, have been described in different hematological malignancies including B-cell lymphomas. However, the role of the EZH2 gene in SMZL has to be elucidated. Aim To determine the prevalence of EZH2 mutations in a cohort of SMZL patients. Patients and Methods Twenty-nine patients with SMZL were screened for mutations in the EZH2 gene. From the whole cohort, 11 patients presented 7q deletion (three of them as a single anomaly), 11 had a normal karyotype and 7 had other cytogenetic aberrations. The mutational analysis of the EZH2 gene was performed by direct sequencing using primers covering the whole exome of the gene. DNA was extracted from CD19 isolated B-cells from peripheral blood or from total lymphocytes if the percentage of pathologic B-cell was higher than 50%. Results From the whole cohort of 29 SMZL patients, no pathogenic mutations (frameshift or nonsense mutations) were detected in the EZH2 gene in any of the patients analyzed. Five patients harboured the missense mutation D185H in exon 6, that has been previously described as a single nucleotide polymorphism (SNP). Conclusions In conclusion, the EZH2 gene is not mutated in our series of SMZL patients suggesting that this gene is not involved in the pathogeny of this entity. Acknowledgments: Fellowship FI2008 (AGAUR) to LMA, This work was supported (in part) by grants from Instituto de Salud Carlos III FEDER; Red Temática de Investigación Cooperativa en Cáncer (RTICC, FEDER): RD06/0020/0031 and RD07/0020/2004; Ministerio de Sanidad y Consumo (Spain): PI07/0586. Disclosures: No relevant conflicts of interest to declare.

The chemokine receptor CXCR3 is expressed in a subset of B-cell lymphomas and is a marker of B-cell chronic lymphocytic leukemia

Blood ◽  
2000 ◽  
Vol 95 (2) ◽  
pp. 627-632 ◽  
Author(s):  
Dan Jones ◽  
Richard J. Benjamin ◽  
Aliakbar Shahsafaei ◽  
David M. Dorfman
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Chemokine Receptor ◽  
Marginal Zone ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Marginal Zone Lymphoma ◽  
Lymphocytic Leukemia ◽  
Splenic Marginal Zone Lymphoma ◽  
Flow Cytometric

Chemotaxis in leukocytes is mediated through binding of soluble chemokines to transmembrane G-protein coupled receptors. The chemokine receptor CXCR3 has been previously shown to be widely expressed on activated T cells and to mediate T-cell chemotaxis on binding to various ligands, including Mig, IP-10, and ITAC. By using immunohistochemical and flow cytometric analysis, we report that CXCR3 is also expressed on a subset of peripheral blood B cells and in distinct subtypes of B-cell lymphoma. CXCR3 immunohistochemical or flow cytometric expression was seen in 37 of 39 cases of chronic lymphocytic leukemia/small lymphocytic lymphoma (diffusely positive in 33 cases), whereas mantle cell lymphoma (30 cases), follicular lymphoma (27 cases), and small noncleaved cell lymphoma (8 cases) were negative in all but 2 cases. Strong CXCR3 expression was also seen in splenic marginal zone lymphoma (14 of 14 cases) and in the monocytoid and plasmacytic cells in extranodal marginal zone lymphoma (15 of 16 cases). This differential expression of CXCR3 in B-cell tumors contrasts with that of another B-cell–associated chemokine receptor, BLR1/CXCR5, which we show here is expressed on all types of B-cell lymphoma tested. We also report that the CXCR3 ligand, Mig, is coexpressed on tumor cells in many cases of CLL/SLL (10 of 13 cases examined) with Mig expression less frequently seen in other B-cell lymphoma subtypes. Coexpression of CXCR3 and its ligand, Mig, may be an important functional interaction in B-CLL, as well as a useful diagnostic marker for the differential diagnosis of small cell lymphomas.

A Phase 2 Study of Fludarabine and Rituximab for the Treatment of Marginal Zone Lymphomas.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1358-1358 ◽  
Author(s):  
Jennifer R. Brown ◽  
Jonathan Friedberg ◽  
Yang Feng ◽  
Kimberly Phillips ◽  
Jennifer C. Clark ◽  
...  
Keyword(s):  
B Cell ◽  
Marginal Zone ◽  
Marginal Zone Lymphoma ◽  
Chromosome 1 ◽  
Hematologic Toxicity ◽  
Low Grade ◽  
Splenic Marginal Zone Lymphoma ◽  
Phase 2 ◽  
Phase 2 Study ◽  
Grade 3

Abstract The marginal zone lymphomas are a recently defined group of related diseases likely arising from a common cell of origin, the marginal zone B cell. The clinical presentation varies; data on therapy for subtypes other than gastric MALT has been largely limited to retrospective case series. We therefore undertook this prospective phase 2 study of fludarabine 25 mg/m2 for 5 days with rituximab 375 mg/m2 on day 1 for the treatment of marginal zone lymphomas. To be eligible, patients were required to have newly diagnosed or relapsed, histologically confirmed MALT, marginal zone lymphoma, or a CD5/CD10 negative low-grade B cell lymphoproliferative disorder. They could not be candidates for curative local therapy. From 2004 to 2007, 26 patients were enrolled with a median age of 64 (31–84) and a median time from diagnosis to treatment of 1.6 months. This was the initial therapy for 21 of 26 patients (81%). Seven were diagnosed with MALT lymphomas (27%), 12 with nodal marginal zone lymphomas (46%), 3 with splenic marginal zone lymphoma (12%) and 4 with CD5/10 negative low-grade lymphoproliferative disorders (15%). FISH for BCL-6, trisomy 3, MALT1 and chromosome 1 rearrangements was attempted on 18 available tissue biopsies. Of these, four were normal, three showed BCL-6 rearrangement with other abnormalities, four had chromosome 3 abnormalities, two MALT1 rearrangements and one chromosome 1 abnormality. The majority of patients had stage IV disease (18; 69%), with 5 stage 3, 2 stage 2 and 1 stage 1E disease. Of the 23 patients who have completed therapy, 18 completed at least 4 cycles (78%), with 12 patients completing the planned 6 cycles (52%). Nine patients discontinued therapy due to unacceptable toxicity (39%), six for hematologic toxicity, two for grade 3 rash and one for a delayed grade 3 reaction to rituximab. Of 26 patients evaluable for toxicity, 46% developed grade 4 toxicity (solely hematologic), and 35% grade 3 toxicity. Grade 3–4 toxicities included: neutropenia 14 (54%), thrombocytopenia 5 (19%), febrile neutropenia 2 (8%), rash 3 (11%), myositis 1 (4%), allergic reaction 1 (4%). Two delayed opportunistic pneumonias were observed, one Nocardia and one P. jiroveci. The ORR in the 23 patients who have completed therapy and are evaluable for response is 83% (95% CI 61–95%), with 12 patients achieving CR/CRu (52%). Three patients have relapsed. Two patients have died, one due to small cell lung cancer diagnosed after study enrollment, and the other due to urosepsis with bone marrow aplasia. At the median follow-up of 1.8 years, the PFS is 84% (95% CI 68–99%), and OS 94% (95% CI 82–99%). Concurrent fludarabine and rituximab is therefore a highly effective regimen in the treatment of marginal zone lymphoma but one which is complicated by significant hematologic toxicity and allergic hypersensitivity. These toxicities prevented half the patients from completing the planned therapy and were more severe than usually seen in other low-grade lymphomas, emphasizing the need to study marginal zone lymphomas as a separate entity.

Splenic Marginal Zone Lymphoma (SMZL): Clinical Course after Splenectomy. A Single Institution Experience

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3993-3993
Author(s):  
Susanna S Gaykazyan ◽  
Nalini Janakiraman ◽  
Philip Kuriakose ◽  
Koichi Maeda ◽  
Tareq Hammour
Keyword(s):  
Bone Marrow ◽  
B Cell ◽  
Systemic Therapy ◽  
Marginal Zone ◽  
Clinical Course ◽  
Bone Marrow Involvement ◽  
Marginal Zone Lymphoma ◽  
Low Grade ◽  
Splenic Marginal Zone Lymphoma ◽  
Symptomatic Disease

Abstract SMZL is an indolent B-cell malignancy accounting for 1–2% of chronic lymphoid leukemia found on bone marrow examination and up to 25% of low-grade B-cell neoplasms in splenectomy patients. Aggressive transformation of SMZL rarely occurs. It usually presents as an incidental finding or with symptoms of splenomegaly and anemia. There is still no reliable clinical or biological scoring system for prognostic stratification. We reviewed pathology reports of 41 splenectomized patients at HFHS from 1994 to 2007 and identified 14 patients with splenic marginal zone lymphoma (SMZL). The reasons for splenectomy were symptoms of splenomegaly in all 14 patients, anemia in 13 patients, thrombocytopenia in 12 patients, AIHA in 4 patients, splenic laceration in one patient. We report here the demographics, clinical course and pathology review of these patients. The median age of patients was 77.8 years. There were 7 male and 7 female patients. ECOG performance status was 0–1 in 12(86%), and 2 in 2(14%). Of the 14 patients, 8(57%) were at Ann Arbor stage IV, 1(7%) was at stage III, 4(29%) were at stage II, and 1(7%) at stage I. LDH was above normal in 9(64%) patients B-symptoms were observed in 1(7%). Bone marrow involvement was documented in 8(57%) of the patients. Anemia in 13(93%), thrombocytopenia in 12(86%), AIHA in 4(29%). IPI score was 1–2 in 5(36%), and score 3–4 in 9(64%) of the patients. Median weight of the spleen was 1235 gm. Bone marrow cytogenetics were abnormal in 4(29%) cases. Following splenectomy, cytopenias resolved completely or partially (CR/PR) in 13(93%) patients. Bacterial infections were observed in 4(29%) patients and 2(14%) died of infectious complications. Progressive disease requiring additional systemic therapy was documented in 5(36%) patients. Total of 5(36%) patients died. One secondary to NSLC, 1(7%) of urothelial carcinoma, 1(7%) secondary to hypercalcemia, 2(14%) due to bacterial sepsis. Patients were followed up to 139 months (with median follow-up time of 42 months). The estimated median overall survival (OS) for this group was 116.5 months (9.7 years), the median progression-free survival (PFS) was 91 months (7.6 years). The Kaplan Meier method was used to calculate these estimates. A simple median was calculated for the sample median. In summary, we report the course of 14 patients with SMZL who underwent splenectomy for symptomatic disease. Only 5(36%) required systemic therapy following splenectomy. No death was attributed to progressive SMZL. Overall course was indolent even after splenectomy. Estimated OS was 116.5 months (9.7 years), PFS - 91 month (7.6 years).

CD11b Is Useful in the Diagnosis of Chronic Lymphocytic Leukemia/Prolymphocytic Leukemia, Mixed Chronic Lymphocytic Leukemia, and Prolymphocytic Leukemia.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 4806-4806
Author(s):  
William Fricke
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Marginal Zone ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Lymphoproliferative Disorders ◽  
Marginal Zone Lymphoma ◽  
Lymphocytic Leukemia ◽  
Splenic Marginal Zone Lymphoma ◽  
Prolymphocytic Leukemia

Abstract CD11b is well known as an integrin, Mac-1, is often complexed with CD18, and is found on monocytes, granulocytes, and natural killer cells. It also serves as a receptor for iC3b. However, its occurrence in B cell chronic lymphoproliferative disorders is not generally recognized and has not been fully evaluated. To address this issue, a series of B cell leukemias and lymphomas referred for primary diagnosis was evaluated for the presence of CD11b. The purpose was to determine the frequency of its expression on these tumors and to evaluate its diagnostic value. Consecutive cases referred for flow cytometry as possible lymphoproliferative disease were analyzed. Included were bone marrow, peripheral blood, and lymph nodes. All cases were diagnosed according to the WHO classification based on immunophenotypic, morphologic, and clinical findings. The morphologic criteria of Melo (1986) and Bennett (1989) were used for classification of chronic lymphocytic leukemia (CLL), CLL/prolymphocytic leukemia (CLL/PLL), mixed CLL, and PLL. Cases identified as not related to chronic lymphocytic leukemia or prolymphocytic leukemia were recorded but not further analyzed. Similarly, lymph node and spleen-based tumors were excluded from the final analysis. CD11b was present on cells from 32 of 123 cases, including occasional follicular lymphoma, (5/35); mantle cell lymphoma, (1/8); diffuse large B cell lymphoma, (3/9); hairy cell leukemia, (3/5); multiple myeloma, (1/2); lymphoplasmacytic lymphoma, (2/2); nodal marginal zone lymphoma, 0/1); and splenic marginal zone lymphoma, (1/1). However, it was most consistently expressed on CLL that contained increased numbers of prolymphocytes or large cells and on PLL. A total of 16 such cases were found. Morphologic assessment showed them to include 8 CLL/PLL, 3 mixed CLL, 4 PLL, and 1 typical CLL. The typical CLL case included both large cells and prolymphocytes but did not have more than 10% PLs. Five of the 16 cases (31%) were negative for CD5, CD23, and CD38 but were positive for FMC-7. In contrast, the other 11 cases were all CD5(+) and CD23(+); 3/11 were positive for CD38; and 5/11 were positive for FMC-7. Forty-five CLLs also were identified during the study, of which 27 had sufficient data for comparison. Twenty-six of the 27 CLLs were morphologically typical. The remaining case was mixed CLL. All of the CLLs were CD11b(−), CD5(+) and CD23(+); 15/43 were CD38(+), and 6/43 were FMC-7(+). The findings show that CD11b is expressed on chronic B cell lymphoproliferative disorders. In particular, it is expressed on almost all CLL cases that contain large cells or prolymphocytes and on PLL. Inclusion of CD11b in routine screening panels of possible chronic B cell leukemiaa will improve diagnosis of these disorders.

Blastic Transformation of Splenic Marginal Zone B-Cell Lymphoma

2000 ◽  
Vol 124 (5) ◽  
pp. 748-752
Author(s):  
Hernani Cualing ◽  
Paul Steele ◽  
David Zellner
Keyword(s):  
Bone Marrow ◽  
B Cell ◽  
Marginal Zone ◽  
B Cell Lymphoma ◽  
Marginal Zone Lymphoma ◽  
Low Grade ◽  
Splenic Marginal Zone Lymphoma ◽  
Moderate Amount ◽  
Blastic Transformation ◽  
One Year

Abstract To our knowledge, blastic transformation of splenic marginal zone lymphoma, a recently characterized low-grade lymphoproliferative disorder, has not been reported previously. In this regard, we report the unique case of a 70-year-old woman whose untreated splenic marginal zone lymphoma underwent blastic transformation 3 years after diagnosis. Her hematologic medical history started in 1988 as thrombocytopenia refractory to steroids associated with atypical lymphoid infiltrate in the bone marrow. She underwent splenectomy in 1989, which revealed splenic marginal zone lymphoma. One year later, the patient developed lymphadenopathy noted in the chest, axillary, abdominal, and retroperitoneal lymph nodes. Because she was asymptomatic, treatment was limited to a conservative supportive regimen. The nodal lymphoma cells had features associated with marginal zone lymphoma and expressed B-cell monotypic κ light chain. She was readmitted for the last time 2 years later with findings of 16% blasts in the peripheral blood and massive infiltration of the bone marrow by large blastoid cells. The blasts showed dispersed chromatin and prominent nucleoli, and possessed a moderate amount of clear cytoplasm. The blasts, like the previous nodal and splenic lymphomas, had a CD20-, CD19-, IgM-positive phenotype, but lacked reactivity for CD5, CD10, and CD23. The patient displayed clinical remission after treatment with vincristine and prednisone, but died of aspiration pneumonia 1 month later. These observations suggest that, similar to the other low-grade lymphoproliferative disorders, an untreated splenic marginal zone lymphoma may undergo high-grade blastic transformation.

scholarly journals Lymphomas in Patients With Sjögren's Syndrome Are Marginal Zone B-Cell Neoplasms, Arise in Diverse Extranodal and Nodal Sites, and Are Not Associated With Viruses

Blood ◽  
1997 ◽  
Vol 90 (2) ◽  
pp. 766-775 ◽  
Author(s):  
Bruno Royer ◽  
Dominique Cazals-Hatem ◽  
Jean Sibilia ◽  
Felix Agbalika ◽  
Jean-Michel Cayuela ◽  
...  
Keyword(s):  
B Cell ◽  
Marginal Zone ◽  
P53 Protein ◽  
B Cell Lymphoma ◽  
Lymphoid Tissues ◽  
Low Grade ◽  
Human Herpes Virus 8 ◽  
Barr Virus ◽  
P53 Antibodies ◽  
Histological Transformation

Abstract The occurrence of non-Hodgkin's lymphoma (NHL) is the most serious complication of Sjögren's syndrome (SS). We performed a study of 16 NHLs occurring in patients with an underlying SS. These lymphomas arose not only in salivary glands (7 cases) but also in other mucosal extranodal sites (the stomach [4 cases], the lung [3 cases], the skin [3 cases], the buccal mucosa [1 case], the thymus [1 case]) and in nodal sites (8 cases). Low-grade marginal zone lymphomas (MZL) were diagnosed in 12 of the 16 patients, 9 of mucosa-associated lymphoid tissues (MALT) type in mucosal sites and 3 exclusively nodal. The 4 other patients presented with a high-grade B-cell lymphoma that was probably a histological transformation of an underlying low-grade MZL at least in 3 of the cases involving skin, stomach, and parotid, respectively. A t(14; 18) translocation was detected in 1 of 8 lymphomas tested. We detected serum anti-p53 antibodies in 2 of the 14 studied patients. p53 protein was detected in 1 of 11 lymphomas tested. LMP protein and Eber RNAs of Epstein-Barr virus (EBV) were not detected in the 16 NHL biopsies. Using polymerase chain reaction, EBV was never detected except in 1 of 4 parotid lymphomas. No human T-lymphotropic virus 1 or human herpes virus 8 DNAs were detected in NHL biopsies. None of the patients had hepatitis C virus infection found using serological methods. Chemotherapy was usually efficient. In conclusion, lymphomas occurring in patients with an underlying SS are in most cases MZL. These lymphomas are not associated with viruses known to be present in other types of lymphomas. Some of the translocations or mutations of oncogenes or antioncogenes described in other lymphomas are detected in SS-associated lymphomas.

scholarly journals Improved biological insight and influence on management in indolent lymphoma. Talk 3: update on nodal and splenic marginal zone lymphoma

Hematology ◽  
2017 ◽  
Vol 2017 (1) ◽  
pp. 371-378 ◽  
Author(s):  
Catherine Thieblemont
Keyword(s):  
B Cell ◽  
Signaling Pathways ◽  
Marginal Zone ◽  
Cell Receptor ◽  
Nuclear Factor Κb ◽  
Therapeutic Strategies ◽  
Tumor Burden ◽  
Marginal Zone Lymphoma ◽  
Splenic Marginal Zone Lymphoma ◽  
B Cell Signaling

Abstract Splenic marginal zone lymphoma (SMZL) and nodal marginal zone lymphoma (NMZL) are rare indolent chronic B-cell lymphomas. Prognosis is typically good with median survival around 10-15 years. Management is generally based on the presence of symptoms or high tumor burden. There are no standard treatments for these 2 entities, and therapeutic strategies are rapidly evolving. Clinical developments for these 2 entities are oriented by genomic studies, with largely overlapping mutational profiles involving the NOTCH, B-cell receptor (BcR) and nuclear factor κB (NF-κB) signaling, chromatin remodeling, and the cytoskeleton. Although new therapeutic options based on targeting signaling pathways and overcoming resistance are increasingly available, few specific prospective studies are performed for these rare subtypes, limiting the conclusions that can be drawn. Novel drugs targeting B-cell signaling have shown promise, including ibrutinib and copanlisib. The second-generation oral immunomodalator (IMiD) lenalidomide showed impressive results when combined with rituximab. Other potential solutions include targeting the NF-κB, JAK/STAT, BCL2, NOTCH, and Toll-like receptor signaling pathways; however, studies in these 2 MZL entities are yet to prove a definitive benefit. Molecular profiling is now a cornerstone of diagnostic, prognostic, and therapeutic strategies to offer patient- and disease-specific solutions. The development of a wider range of effective targeted therapies and prognostic biomarkers is keenly awaited and is expected to strongly affect the natural history of SMZL and NMZL.

Splenic Marginal Zone Lymphoma Shows a Distinct Pattern of DNA Copy Number Aberrations That Correlates with Tumor Characteristics and Predicts Disease Outcome.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2422-2422
Author(s):  
Jose A. Martinez-Climent ◽  
Cristina Robledo ◽  
Manuela Mollejo ◽  
Anton Parker ◽  
Juan L. Garcia ◽  
...  
Keyword(s):  
B Cell ◽  
Copy Number ◽  
Marginal Zone ◽  
Array Cgh ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Marginal Zone Lymphoma ◽  
Splenic Marginal Zone Lymphoma ◽  
Genomic Aberrations ◽  
7Q Deletion

Abstract Splenic marginal zone lymphoma (SMZL) is an indolent B cell malignancy whose diagnosis is based on lymphocyte morphology, immunophenotype and marrow and/or splenic histology. Unlike other lymphomas, there is not a common chromosomal translocation specific for SMZL, and genetic prognostic factors are poorly defined. To investigate the pattern of genomic aberrations in SMZL, we applied comparative genomic hybridization to BAC microarrays (array CGH) to a well characterized series of 75 SMZL specimens. We applied two different 1 Mb-resolution BAC arrays: UCSF HumArray 3.2 and a novel array CGH platform developed at Univ. of Salamanca. These arrays allowed us to detect DNA copy number changes across the genome with high accuracy in 67 of 75 patient samples. Data were compared with our previous array CGH studies of 170 samples from different B-cell lymphoma subgroups. FISH studies for IGH, IGK and IGL translocations and 7q deletion were performed on tissue microarrays in 24 cases. Of the 67 samples, 19 (28%) showed a normal genomic profile. The median number of genomic aberrations per tumor was 2.2 (1.3 gains and 0.9 losses), which was lower than the rates detected in other lymphoma subgroups (diffuse large cell lymphoma, 6.4; mantle cell lymphoma, 6; follicular lymphoma, 4.5) and comparable to MALT lymphomas (2 abnormalities per tumor). SMZL cells showed a genomic pattern characterized by gain of chromosomes 3q24-q29 (18%), 6p (9%), 12q (9%), and 18q (4%) and loss of 7q32 (34%), 8p21-p23 (13%), 17p13 (10%) at P53 locus and 6q21-q27 (9%). Notably, no alterations of the P16/ARF (9p21) or MYC loci (8q24) were detected. Correlation of array CGH data with conventional cytogenetics, FISH and LOH studies revealed a high concordance. Detailed mapping of 7q deletions delineated a consensus region of loss of 3 Mb in 7q32. This 7q deletion was almost exclusive to SMZL, being observed in only 5 of 170 non-SMZL B-cell lymphomas (p=0.0000001). Four cases presented IG-translocation. Mutation of IGH was observed in 62% and correlated with a complex karyotype (61 vs. 13%; p=0,0008) whereas unmutated IGH correlated with the deletion of 7q (56 vs. 23%; p=0,01). Among the various genomic abnormalities, only the deletion of 8p or the presence of a complex karyotype correlated with inferior overall survival (OS) (median OS, 58 vs. 110 months, p=0,004; and 60 vs. 105 months, p=0,01; respectively). In summary, array CGH has defined a pattern of genomic aberrations in SMZL that differs from other B-cell lymphoma subgroups and that may predict overall survival. Because the deletion of 7q32 is the most distinctive genetic marker in SMZL, the identification of a putative tumor suppressor gene inactivated within the region of deletion seems mandatory.

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