269 results on '"Weisenburger, Dennis D"'
Search Results
2. DNMT3A mutations define a unique biological and prognostic subgroup associated with cytotoxic T cells in PTCL-NOS
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Herek, Tyler A., Bouska, Alyssa, Lone, Waseem, Sharma, Sunandini, Amador, Catalina, Heavican, Tayla B., Li, Yuping, Wei, Qi, Jochum, Dylan, Greiner, Timothy C., Smith, Lynette, Pileri, Stefano, Feldman, Andrew L., Rosenwald, Andreas, Ott, German, Lim, Soon Thye, Ong, Choon Kiat, Song, Joo, Jaffe, Elaine S., Wang, Gang Greg, Staudt, Louis, Rimsza, Lisa M., Vose, Julie, d’Amore, Francesco, Weisenburger, Dennis D., Chan, Wing C., and Iqbal, Javeed
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Peripheral T-cell lymphomas (PTCLs) are heterogenous T-cell neoplasms often associated with epigenetic dysregulation. We investigated de novo DNA methyltransferase 3A (DNMT3A) mutations in common PTCL entities, including angioimmunoblastic T-cell lymphoma and novel molecular subtypes identified within PTCL–not otherwise specified (PTCL-NOS) designated as PTCL-GATA3 and PTCL-TBX21. DNMT3A-mutated PTCL-TBX21 cases showed inferior overall survival (OS), with DNMT3A-mutated residues skewed toward the methyltransferase domain and dimerization motif (S881–R887). Transcriptional profiling demonstrated significant enrichment of activated CD8+ T-cell cytotoxic gene signatures in the DNMT3A-mutant PTCL-TBX21 cases, which was further validated using immunohistochemistry. Genomewide methylation analysis of DNMT3A-mutant vs wild-type (WT) PTCL-TBX21 cases demonstrated hypomethylation in target genes regulating interferon-γ (IFN-γ), T-cell receptor signaling, and EOMES (eomesodermin), a master transcriptional regulator of cytotoxic effector cells. Similar findings were observed in a murine model of PTCL with Dnmt3a loss (in vivo) and further validated in vitro by ectopic expression of DNMT3A mutants (DNMT3A-R882, -Q886, and -V716, vs WT) in CD8+ T-cell line, resulting in T-cell activation and EOMES upregulation. Furthermore, stable, ectopic expression of the DNMT3A mutants in primary CD3+ T-cell cultures resulted in the preferential outgrowth of CD8+ T cells with DNMT3AR882H mutation. Single-cell RNA sequencing(RNA-seq) analysis of CD3+ T cells revealed differential CD8+ T-cell subset polarization, mirroring findings in DNMT3A-mutated PTCL-TBX21 and validating the cytotoxic and T-cell memory transcriptional programs associated with the DNMT3AR882H mutation. Our findings indicate that DNMT3A mutations define a cytotoxic subset in PTCL-TBX21 with prognostic significance and thus may further refine pathological heterogeneity in PTCL-NOS and suggest alternative treatment strategies for this subset.
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- 2022
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3. Drinking water and dietary sources of nitrate and nitrite and risk of glioma
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Ward, Mary H., Heineman, Ellen F., McComb, Rodney D., and Weisenburger, Dennis D.
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Environmental issues ,Health - Published
- 2005
4. Occupation and risk of non-Hodgkin's lymphoma and chronic lymphocytic leukemia
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Zheng, Tongzhang, Blair, Aaron, Zhang, Yawei, Weisenburger, Dennis D., and Zahm, Shelia H.
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Chronic lymphocytic leukemia -- Risk factors ,Chronic lymphocytic leukemia -- Environmental aspects ,Non-Hodgkin's lymphomas -- Risk factors ,Non-Hodgkin's lymphomas -- Environmental aspects ,Occupational diseases ,Environmental issues ,Health - Published
- 2002
5. Dietary patterns and adenocarcinoma of the esophagus and distal stomach
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Chen, Honglei, Ward, Mary H, Graubard, Barry I, Heineman, Ellen F, Markin, Rodney M, Potischman, Nancy A, Russell, Robert M, Weisenburger, Dennis D, and Tucker, Katherine L
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Adenocarcinoma -- Health aspects ,Esophageal cancer -- Health aspects ,Stomach cancer -- Health aspects ,Disease susceptibility -- Health aspects ,Food/cooking/nutrition ,Health - Abstract
Background: Dietary pattern analysis is a unique approach to studying relations between diet and disease. Objective: Our objective was to describe the dietary patterns of an eastern Nebraska population and investigate the associations between those dietary patterns and risks of adenocarcinoma of the esophagus and distal stomach. Design: We recruited 124 subjects with esophageal adenocarcinoma, 124 subjects with distal stomach adenocarcinoma, and 449 control subjects in a population-based, case-control study. Results: Six dietary patterns were identified with the use of cluster analysis. The first dietary pattern represented healthy food choices and had higher energy contributions from fruit and vegetables and grain products and lower energy contributions from red meats, processed meats, and gravy than did the other dietary patterns. In contrast, a second dietary pattern was high in meats and low in fruit and cereals. The other 4 dietary patterns were each characterized by a concentrated energy source: salty snacks, desserts, milk, and white bread, respectively. The test of overall difference in cancer risk across dietary patterns was significant for distal stomach adenocarcinoma (P = 0.04) but not for esophageal adenocarcinoma. Risk of esophageal adenocarcinoma was inversely associated with intakes of dairy products, fish, all vegetables, citrus fruit and juices, and dark bread and was positively associated with gravy intake. Risk of distal stomach adenocarcinoma was positively associated with red meat intake. Conclusions: Our study suggests that a diet high in fruit and vegetables may decrease the risk of esophageal adenocarcinoma and that a diet high in meats may increase the risk of distal stomach adenocarcinoma. Am J Clin Nutr 2002;75:137-44. KEY WORDS Esophagus, stomach, neoplasm, dietary pattern, cluster analysis, cancer
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- 2002
6. Primary Cutaneous Gamma-Delta T-Cell Lymphoma Mimicking anaplastic lymphoma kinase-1-Negative Anaplastic Large Cell Lymphoma: A Case Report
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Meawad, Hany, Song, Joo Y., Ulrickson, Matthew L., and Weisenburger, Dennis D.
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Primary cutaneous gamma-delta T-cell lymphoma is a rare and aggressive neoplasm, representing less than 1% of all cutaneous T-cell lymphomas. In this article, we report the case of a 49-year-old woman who presented with a history of generalized skin rash and a recent mass on the left upper extremity, as well as right inguinal soft tissue swelling and splenomegaly. Histologic examination of the mass revealed a diffuse subcutaneous infiltrate of large anaplastic and CD30-positive lymphoid cells with rimming of the adipocytes. This case demonstrates unusual cytologic features in primary cutaneous gamma-delta T-cell lymphoma that mimic the features of anaplastic lymphoma kinase-1-negative anaplastic large-cell lymphoma.
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- 2022
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7. Clonality analysis of B-lymphoid proliferations using the polymerase chain reaction
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Lozano, Maria D., Tierens, Anne, Greiner, Timothy C., Wickert, Robert S., Weisenburger, Dennis D., and Chan, Wing C.
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Polymerase chain reaction ,Non-Hodgkin's lymphomas -- Diagnosis ,Health - Published
- 1996
8. The role of agricultural pesticide use in the development of non-Hodgkin's lymphoma in women
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Zahm, Shelia Hoar, Weisenburger, Dennis D., Saal, Robert C., Vaught, Jimmie B., Babbitt, Paula A., and Blair, Aaron
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Non-Hodgkin's lymphomas -- Risk factors ,Pesticides -- Health aspects ,Women -- Health aspects ,Environmental issues ,Health - Published
- 1993
9. Prognostic significance of clinical and pathologic features in diffuse large B-cell lymphoma
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Nakamine, Hirokazu, Bagin, Robert G., Vose, Julie M., Bast, Martin A., Bierman, Philip J., Armitage, James O., and Weisenburger, Dennis D.
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Non-Hodgkin's lymphomas -- Prognosis ,B cells -- Physiological aspects ,Health - Abstract
Background and Methods. The diffuse large cell non-Hodgkin lymphomas are a heterogeneous group of neoplasms that are potentially curable. To identify important predictors of clinical outcome, the authors evaluated the clinical and pathologic features of 114 patients with newly diagnosed diffuse large B-cell lymphoma who were uniformly staged and treated with curative intent. The authors were particularly interested in determining whether any pathologic features added to the ability of the clinical features to predict patient survival. Results. Several clinical and pathologic features were found to be associated with survival by univariate analysis. However, multivariate analysis disclosed that only the stage of disease and the symptom status were significantly associated with survival. Low stage and lack of B symptoms were favorable indicators of overall survival and failure-free survival. Conclusions. The authors suggest that the evaluation of pathologic features in diffuse large B-cell lymphoma has little prognostic utility and recommend that the pathology evaluation be limited to features that are useful for diagnostic purposes. Cancer 1993; 71:3130-7.
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- 1993
10. Peripheral T-cell lymphoma in childhood and adolescence: a clinicopathologic study of 22 patients
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Gordon, Bruce G., Weisenburger, Dennis D., Warkentin, Phyllis I., Anderson, James, Sanger, Warren G., Bast, Martin, Gnarra, David, Vose, Julie M., Bierman, Phillip J., Armitage, James O., and Coccia, Peter F.
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Lymphocytic leukemia in children -- Diagnosis ,Lymphomas -- Physiological aspects ,Tumors in children -- Care and treatment ,Bone marrow -- Transplantation ,Health - Abstract
Background. Peripheral T-cell lymphoma (PTCL), although the most common T-cell lymphoma in adults, is relatively rare in childhood, and only small series have been reported. Methods/Results. Twenty-two cases of PTCL were studied that occurred in patients 18 months to 20 years of age. Nine were seen when the condition was diagnosed, and the other 13 were referred after they had relapses. The stage at diagnosis was I or II (45%), III (41%), and IV (14%). Patients with Stage IV disease were younger than those with Stage I or II disease (2.5 versus 14.8 years, P = 0.04). Twelve patients had extranodal disease when the diagnosis was made; the skin was the most common site. Ten tumors were classified as diffuse large cell type; five, as diffuse anaplastic large cell type; and s*even, as diffuse mixed cell type. Twenty of the 21 tumors tested were CD30 (Ki-1 or Ber-H2) antigen positive. Of the nine patients seen when the diagnosis was made and treated by the authors, three had a relapse (median, 12 months), a 2-year relapse-free survival (RFS) rate of 61%. For the total group, the RFS was longer for patients older than 12 years of age compared with those who were younger (20 versus 12 months, P = 0.05). Overall, six patients remained in their first complete remission. Sixteen patients had a relapse, and 13 of these underwent bone marrow transplantation (BMT). Six of these remained in complete remission (median, 18 months after BMT). Overall, only 6 of 22 patients died (median survival, > 60 months). Conclusion. It was concluded that aggressive therapy, including BMT for relapses, can provide prolonged disease control in most children with PTCL. Cancer 1993; 71:257-63.
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- 1993
11. Autologous bone marrow transplantation for patients with relapsed Hodgkin's disease
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Armitage, James O., Bierman, PHilip J., Vose, Julie M., Anderson, James R., Weisenburger, Dennis D., Kessinger, Anne, Reed, Elizabeth C., Vaughan, William P., Coccia, Peter F., and Purtilo, David T.
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Bone marrow -- Transplantation ,Hodgkin's disease ,Health ,Health care industry - Abstract
Hodgkin's disease is often curable with radiotherapy and chemotherapy, and cure may even be possible after the failure of an initial chemotherapy regimen. However, a poor prognosis awaits patients with early relapse after complete remission; those who do not achieve remission with chemotherapy; and those who do not achieve remission even after more than one chemotherapy regimen. Autologous bone marrow transplantation (ABMT), a procedure in which previously removed and stored bone marrow is reinfused into a patient after extremely high doses of chemotherapy are given, is successful for treating many malignancies, but is often withheld until late in the course of Hodgkin's disease. To determine the optimal time for ABMT in relapsed Hodgkin's disease, 70 patients were studied who underwent this procedure after chemotherapy treatment with high-dose cyclophosphamide, carmustine, and etoposide. All patients had been treated with at least one previous chemotherapy regimen, and 29 had been treated with 3 or more. Forty percent of the patients had received radiotherapy as part of their initial treatment. Results showed that 59 percent of the patients who underwent ABMT achieved a complete remission; 11 percent responded partially; 19 percent did not respond; and 11 percent died. The 4-year disease-free survival was approximately 27 percent, and 4-year survival was approximately 47 percent. Patients treated earlier in the course of the disease fared significantly better than those in whom several chemotherapy regimens failed. High-dose chemotherapy plus ABMT appears more effective than salvage chemotherapy (another regimen begun after failure) for patients with relapsed Hodgkin's disease. This treatment should be carried out as soon as possible after relapse. (Consumer Summary produced by Reliance Medical Information, Inc.)
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- 1991
12. Validation of the Double-Hit Gene Expression Signature (DLBCL90) in an Independent Cohort of Patients with Diffuse Large B-Cell Lymphoma of Germinal Center Origin
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Nguyen, Ha, Perry, Anamarija, Skrabek, Pamela, Nasr, Michel, Herrera, Alex F., Bedell, Victoria, Murata-Collins, Joyce, Pillai, Raju, Xu, Minlin, Chen, Lu, Chan, Wing C., Weisenburger, Dennis D., Scott, David W., and Song, Joo Y.
- Abstract
The prognosis of diffuse large B-cell lymphoma (DLBCL) has been associated with clinical parameters, cell of origin, and various genetic aberrations. Recently, a NanoString gene expression assay (DLBCL90) was developed, which identifies DLBCL cases with an outcome similar to those with double- or triple-hit DLBCL with both MYCand BCL2rearrangements. This study validates the predictive ability of the DLBCL90 assay in an independent cohort of patients with the germinal center B-cell subtype DLBCL. A customized targeted sequencing panel was used to analyze the mutational profile in these patients. Cases with a double or triple hit by conventional fluorescence in situhybridization cytogenetic analysis are known to have a poor prognosis, and the DLBCL90 gene expression signature identified these cases, as well as additional cases that would have otherwise been missed by fluorescence in situhybridization analysis. Our findings validate use of the DLBCL90 assay for identifying high-risk patients for new and innovative therapies.
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- 2021
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13. Mantle zone lymphoma: a clinicopathologic study of 22 cases
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Duggan, Michael J., Weisenburger, Dennis D., Ye, Yuling L., Bast, Martin A., Pierson, Jene L., Linder, James, and Armitage, James O.
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Lymphomas -- Identification and classification ,Lymphomas -- Prognosis ,Health - Abstract
Mantle zone lymphoma is a cancer of the lymphatic system, characterized by the overgrowth of cancerous lymphoid cells in wide layers, or mantles. These mantles develop around benign germinal centers, regions of tissue located in the center of lymphatic nodules of the spleen, tonsils, and lymph nodes. Among 22 cases of mantle zone lymphoma, 18 were of the intermediate lymphocytic type, and four cases were of the small lymphocytic type. The immunological features of the tumors were characterized, and were similar to normal lymphoid tissue in some respects. Most patients were about 63 years old, and more men than women were affected. Symptoms of weight loss, night sweats, and fever developed in 55 percent of the patients. Other symptoms included enlargement of the spleen (81 percent); lymphocytosis, an excess of lymph cells (13 percent); and bone marrow disorders (67 percent). Patients were assessed according to the progression of the disease, which was classified into stages. Sixty-four percent of the patients were in the most advanced stage of the disease. All patients were given some form of treatment, with 73 percent receiving treatment with multiple anticancer agents. Complete remission was achieved in 11 patients, and overall survival was 88 months. Survival was adversely affected by increased numbers of lymphocytes, a type of white blood cell; decreased numbers of platelets, cells involved in blood clotting; male sex; a high rate of cell division and multiplication; and the presence of large lymphoid cells. Survival was favorably affected by the development of complete remission. Based on these findings, it was suggested that mantle zone lymphoma is a type of non-Hodgkin's lymphoma. (Consumer Summary produced by Reliance Medical Information, Inc.)
- Published
- 1990
14. Genomic characterization of diffuse large B-cell lymphoma transformation of nodular lymphocyte-predominant Hodgkin lymphoma
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Song, Joo Y., Egan, Caoimhe, Bouska, Alyssa C., Zhang, Weiwei, Gong, Qiang, Venkataraman, Girish, Herrera, Alex F., Chen, Lu, Ottesen, Rebecca, Niland, Joyce C., Bedell, Victoria, Valle-Catuna, Maria, Murata-Collins, Joyce, Weisenburger, Dennis D., Iqbal, Javeed, Jaffe, Elaine S., and Chan, Wing C.
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- 2020
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15. Reproducing the molecular subclassification of peripheral T-cell lymphoma–NOS by immunohistochemistry
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Amador, Catalina, Greiner, Timothy C., Heavican, Tayla B., Smith, Lynette M., Galvis, Karen Tatiana, Lone, Waseem, Bouska, Alyssa, D’Amore, Francesco, Pedersen, Martin Bjerregaard, Pileri, Stefano, Agostinelli, Claudio, Feldman, Andrew L., Rosenwald, Andreas, Ott, German, Mottok, Anja, Savage, Kerry J., de Leval, Laurence, Gaulard, Philippe, Lim, Soon Thye, Ong, Choon Kiat, Ondrejka, Sarah L., Song, Joo, Campo, Elias, Jaffe, Elaine S., Staudt, Louis M., Rimsza, Lisa M., Vose, Julie, Weisenburger, Dennis D., Chan, Wing C., and Iqbal, Javeed
- Abstract
Peripheral T-cell lymphoma (PTCL) is a heterogeneous group of mature T-cell malignancies; approximately one-third of cases are designated as PTCL–not otherwise specified (PTCL-NOS). Using gene-expression profiling (GEP), we have previously defined 2 major molecular subtypes of PTCL-NOS, PTCL-GATA3 and PTCL-TBX21, which have distinct biological differences in oncogenic pathways and prognosis. In the current study, we generated an immunohistochemistry (IHC) algorithm to identify the 2 subtypes in paraffin tissue using antibodies to key transcriptional factors (GATA3 and TBX21) and their target proteins (CCR4 and CXCR3). In a training cohort of 49 cases of PTCL-NOS with corresponding GEP data, the 2 subtypes identified by the IHC algorithm matched the GEP results with high sensitivity (85%) and showed a significant difference in overall survival (OS) (P = .03). The IHC algorithm classification showed high interobserver reproducibility among pathologists and was validated in a second PTCL-NOS cohort (n = 124), where a significant difference in OS between the PTCL-GATA3 and PTCL-TBX21 subtypes was confirmed (P = .003). In multivariate analysis, a high International Prognostic Index score (3-5) and the PTCL-GATA3 subtype identified by IHC were independent adverse predictors of OS (P = .0015). Additionally, the 2 IHC-defined subtypes were significantly associated with distinct morphological features (P < .001), and there was a significant enrichment of an activated CD8+ cytotoxic phenotype in the PTCL-TBX21 subtype (P = .03). The IHC algorithm will aid in identifying the 2 subtypes in clinical practice, which will aid the future clinical management of patients and facilitate risk stratification in clinical trials.
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- 2019
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16. Mechanistic Elucidation of the Tumor-Promoting Role of Carcinoembryonic Antigen-Related Cell Adhesion Molecule 1 in B-Cell Receptor Signaling in Mantle Cell Lymphoma
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Xavier, Serene, Nguyen, Vivian, Khairnar, Vishal, Phan, An, Yang, Lu, Nelson, Michael, Tseng, Elizabeth, Li, Aimin, Song, Joo Y, Weisenburger, Dennis D., Chan, Wing C., Müschen, Markus, and Ngo, Vu N.
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Mantle cell lymphoma (MCL) is a highly aggressive and incurable type of B-cell non-Hodgkin's lymphoma. B cell receptor (BCR) signaling plays an important role in the pathogenesis of MCL; however, the underlying mechanisms are unknown. Our genome-wide screens identified that carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1/CC1) is a central component of BCR signaling and is essential for MCL survival in vitro and in vivo. Among the twelve alternatively spliced human CC1 isoforms, we found that CC1-4L, the longest CC1 isoform is overexpressed in MCL. Structurally, it has the N-terminal domain and three type 2 constant ectodomains, a transmembrane sequence and a signaling cytoplasmic domain with two immunoreceptor tyrosine-based inhibitory motifs (ITIMs or Y493/520). These ITIMs of CC1 can inhibit signals in T cells, NK cells, neutrophils and granulocytes. However, its role in B cells and BCR signaling is not clear.
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- 2023
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17. Integrative Genomic and Transcriptomic Analysis Reveals Targetable Vulnerabilities in Angioimmunoblastic T-Cell Lymphoma
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Bouska, Alyssa, Zhang, Weiwei, Sharma, Sunandini, Holte, Harald, Shah, Ab Rauf, Lone, Waseem Gul, Cappelli, Luca Vincenzo, Fiore, Danilo, Gong, Qiang, Heavican-Foral, Tayla, Cannatella, Jeffrey, Amador, Catalina, Arif, Aiza, Smith, Lynette, Lim, Soon Thye, Ong, Choon Kiat, Feldman, Andrew L., Du, Ming-Qing, de Leval, Laurence, Greiner, Timothy C., Fu, Kai, Trøen, Gunhild, Vodak, Daniel, Nakken, Sigve, Delabie, Jan, Weinstock, David M., Pileri, Stefano A., Laginestra, Antonella, Kim, Kyeongjin, Pajvani, Utpal, Vose, Julie M., Weisenburger, Dennis D, Dave, Sandeep, Inghirami, Giorgio, Chan, Wing C., and Iqbal, Javeed
- Abstract
Follicular helper T-cell lymphoma of the angioimmunoblastic type (AITL) is associated with dismal prognosis. We performed functional genomic approaches including whole-exome sequencing (WES; n=119), transcriptomic (n=78) and methylation (n=40) analysis. We identified recurrent mutations in known epigenetic drivers ( TET2, DNMT3A, IDH2 R172), and also identified novel ones (TET3, KMT2D). Somatic mutation of all three epigenetic drivers ( TET2, IDH2, and DNMT3A) was associated with poor prognosis (p<.001). Mutations in genes regulating T-cell receptor (TCR) signaling ( CD28 VAV1, FYN, PLCG1) or activation ( RHOA G17V), and regulators of the PI3K pathway (PIK(3)C members, PTEN,PHLPP-1/-2) were also found. Genome-wide DNA-methylation analysis integrated with mRNA expression profiling also revealed epigenetic alterations in genes regulating TCR-RHOA/B/C or PI3K-signaling. TET2 loss was noted in 85% AITLs and was significantly associated with RHOA G17V, CD28and IDH2 R172mutations. AITLs lacking RHOA G17Vtended to have mutations regulating the JAK-STAT pathway ( JAK2, JAK3, STAT1, STAT3, SOCS1). RNA-seq analysis identified fusion transcripts in genes regulating TCR activation (8%), revealed a restricted TCR repertoire in the majority of cases (a=87%, b=72%), and showed the presence of Epstein-Barr virus transcriptome (73%). GEP demonstrated association of B-cells in the tumor-milieu with better prognosis (p=.006), while dendritic cells were associated with worse prognosis (p=.001), which was further validated by immunohistochemistry using CD20, CD68, and CD163 antibodies. RNA-seq and corresponding WES analysis of 12 AITL patient-derived-xenografts (PDX) showed that bi-allelic TET2mutations, DNMT3Amutations or sub-clonal mutations ( PLCG1 PHLPP2) werepropagated in sequential passages. Gene signatures related to T FH(follicular helper) and T CM(central memory) were also well-maintained in secondary passages in PDX models. Gene signatures of late PDX passages (3 rd-5 th) were enriched with genes related to proliferation and metabolic reprogramming, and in an independent cohort of AITLs, high expression of T3/T5 related signatures was associated with worse outcome (p=0.02/p=0.009). Low mRNA expression of PHLPP2 predicted poor prognosis (p=.03) and engineered PHLPP2 loss showed enhanced PI(3)K activation and FOXO1 inactivation in CD4+ T-cells in-vitro. Thus, we defined the genomic landscape for AITL, which is largely characterized by epigenetic alterations, TCR signaling and PI3K/AKT dysregulation, which may be amenable for therapeutic targeting.
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- 2023
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18. Refining Diagnostic Subtypes of Peripheral T-Cell Lymphoma Using a Multiparameter Approach
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Amador, Catalina, Weisenburger, Dennis D, Gomez, Ana, Bouska, Alyssa, Vega, Francisco, Cook, James R., Greiner, Timothy C., Feldman, Andrew L., Jaffe, Elaine S., Ondrejka, Sarah L., Ott, German, Ozkaya, Neval, Raess, Phil, Rosenwald, Andreas, Savage, Kerry J., Slack, Graham, Song, Joo Y., Rimsza, Lisa M., Chan, Wing C., and Iqbal, Javeed
- Abstract
Peripheral T-cell lymphoma (PTCL) encompasses a diverse group of post-thymic lymphomas, with ~40% of cases not further classifiable and designated as PTCL-not otherwise specified (PTCL-NOS). Two molecular prognostic subtypes of PTCL-NOS, PTCL-TBX21 and PTCL-GATA3, were identified through gene expression profiling (GEP). A subset of PTCL-NOS with T-follicular helper (TFH) differentiation was subsequently categorized as nodal PTCL with TFH phenotype (PTCL-TFH), also known in current classifications as nodal PTCL-TFH, NOS, or TFH lymphoma, NOS. However, the boundary between PTCL-NOS and PTCL-TFH remains poorly defined. To refine these subtypes, 101 PTCL-NOS with centralized pathology review and extensive immunophenotyping by immunohistochemistry (IHC) using 22 antibodies, digital GEP (nCounter, NanoString Inc) (n= 70), and RNA sequencing (n= 73) were included in this study. IHC was used to identify PTCL-TFH cases (those with strong expression of more than two TFH markers); the remaining patients were classified as PTCL-GATA3 and PTCL-TBX21 using pre-defined GEP signatures.
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- 2023
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19. Adult Burkitt lymphoma: advances in diagnosis and treatment
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Aldoss, Ibrahim T., Weisenburger, Dennis D., Fu, Kai, Chan, Wing C., Vose, Julie M., Bierman, Philip J., Bociek, R. Gregory, and Armitage, James O.
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Burkitt's lymphoma -- Care and treatment ,Burkitt's lymphoma -- Diagnosis ,Burkitt's lymphoma -- Prognosis ,Cancer -- Diagnosis ,Cancer -- Methods ,Cancer -- Health aspects ,Cancer -- Care and treatment - Abstract
ABSTRACT Burkitt lymphoma is a unique B-cell malignancy with a high proliferation rate and characteristic genetic changes involving the c-myc oncogene. Burkitt lymphoma is common in children but also occurs [...]
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- 2008
20. Genetic drivers of oncogenic pathways in molecular subgroups of peripheral T-cell lymphoma
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Heavican, Tayla B., Bouska, Alyssa, Yu, Jiayu, Lone, Waseem, Amador, Catalina, Gong, Qiang, Zhang, Weiwei, Li, Yuping, Dave, Bhavana J., Nairismägi, Maarja-Liisa, Greiner, Timothy C., Vose, Julie, Weisenburger, Dennis D., Lachel, Cynthia, Wang, Chao, Fu, Kai, Stevens, Jadd M., Lim, Soon Thye, Ong, Choon Kiat, Gascoyne, Randy D., Missiaglia, Edoardo, Lemonnier, Francois, Haioun, Corinne, Hartmann, Sylvia, Pedersen, Martin Bjerregård, Laginestra, Maria Antonella, Wilcox, Ryan A., Teh, Bin Tean, Yoshida, Noriaki, Ohshima, Koichi, Seto, Masao, Rosenwald, Andreas, Ott, German, Campo, Elias, Rimsza, Lisa M., Jaffe, Elaine S., Braziel, Rita M., d'Amore, Francesco, Inghirami, Giorgio, Bertoni, Francesco, de Leval, Laurence, Gaulard, Philippe, Staudt, Louis M., McKeithan, Timothy W., Pileri, Stefano, Chan, Wing C., and Iqbal, Javeed
- Abstract
Peripheral T-cell lymphoma (PTCL) is a group of complex clinicopathological entities, often associated with an aggressive clinical course. Angioimmunoblastic T-cell lymphoma (AITL) and PTCL-not otherwise specified (PTCL-NOS) are the 2 most frequent categories, accounting for >50% of PTCLs. Gene expression profiling (GEP) defined molecular signatures for AITL and delineated biological and prognostic subgroups within PTCL-NOS (PTCL-GATA3 and PTCL-TBX21). Genomic copy number (CN) analysis and targeted sequencing of these molecular subgroups revealed unique CN abnormalities (CNAs) and oncogenic pathways, indicating distinct oncogenic evolution. PTCL-GATA3 exhibited greater genomic complexity that was characterized by frequent loss or mutation of tumor suppressor genes targeting the CDKN2A/B-TP53axis and PTEN-PI3K pathways. Co-occurring gains/amplifications of STAT3and MYCoccurred in PTCL-GATA3. Several CNAs, in particular loss of CDKN2A,exhibited prognostic significance in PTCL-NOS as a single entity and in the PTCL-GATA3 subgroup. The PTCL-TBX21 subgroup had fewer CNAs, primarily targeting cytotoxic effector genes, and was enriched in mutations of genes regulating DNA methylation. CNAs affecting metabolic processes regulating RNA/protein degradation and T-cell receptor signaling were common in both subgroups. AITL showed lower genomic complexity compared with other PTCL entities, with frequent co-occurring gains of chromosome 5 (chr5) and chr21 that were significantly associated with IDH2R172mutation. CN losses were enriched in genes regulating PI3K–AKT–mTOR signaling in cases without IDH2mutation. Overall, we demonstrated that novel GEP-defined PTCL subgroups likely evolve by distinct genetic pathways and provided biological rationale for therapies that may be investigated in future clinical trials.
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- 2019
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21. Regulation of SOX11 expression through CCND1 and STAT3 in mantle cell lymphoma
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Mohanty, Atish, Sandoval, Natalie, Phan, An, Nguyen, Thang V., Chen, Robert W., Budde, Elizabeth, Mei, Matthew, Popplewell, Leslie, Pham, Lan V., Kwak, Larry W., Weisenburger, Dennis D., Rosen, Steven T., Chan, Wing C., Müschen, Markus, and Ngo, Vu N.
- Abstract
The neural transcription factor SOX11 is usually highly expressed in typical mantle cell lymphoma (MCL), but it is absent in the more indolent form of MCL. Despite being an important diagnostic marker for this hard-to-treat malignancy, the mechanisms of aberrant SOX11 expression are largely unknown. Herein, we describe 2 modes of SOX11 regulation by the cell-cycle regulator cyclin D1 (CCND1) and the signal transducer and activator of transcription 3 (STAT3). We found that ectopic expression of CCND1 in multiple human MCL cell lines resulted in increased SOX11 transcription, which correlated with increased acetylated histones H3K9 and H3K14 (H3K9/14Ac). Increased H3K9/14Ac and SOX11 expression was also observed after histone deacetylase 1 (HDAC1) or HDAC2 was depleted by RNA interference or inhibited by the HDAC inhibitor vorinostat. Mechanistically, we showed that CCND1 interacted with and sequestered HDAC1 and HDAC2 from the SOX11 locus, leading to SOX11 upregulation. Interestingly, our data revealed a potential inverse relationship between phosphorylated Y705 STAT3 and SOX11 expression in MCL cell lines, primary tumors, and patient-derived xenografts. Functionally, inactivation of STAT3 by inhibiting the upstream Janus kinase (JAK) 1 or JAK2 or by STAT3 knockdown was found to increase SOX11 expression, whereas interleukin-21 (IL-21)–induced STAT3 activation or overexpression of the constitutively active form of STAT3 decreased SOX11 expression. In addition, targeting SOX11 directly by RNA interference or indirectly by IL-21 treatment induced toxicity in SOX11+ MCL cells. Collectively, we demonstrate the involvement of CCND1 and STAT3 in the regulation of SOX11 expression, providing new insights and therapeutic implications in MCL.
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- 2019
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22. Molecular classification of primary mediastinal large B-cell lymphoma using routinely available tissue specimens
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Mottok, Anja, Wright, George, Rosenwald, Andreas, Ott, German, Ramsower, Colleen, Campo, Elias, Braziel, Rita M., Delabie, Jan, Weisenburger, Dennis D., Song, Joo Y., Chan, Wing C., Cook, James R., Fu, Kai, Greiner, Tim, Smeland, Erlend, Holte, Harald, Savage, Kerry J., Glinsmann-Gibson, Betty J., Gascoyne, Randy D., Staudt, Louis M., Jaffe, Elaine S., Connors, Joseph M., Scott, David W., Steidl, Christian, and Rimsza, Lisa M.
- Abstract
Primary mediastinal large B-cell lymphoma (PMBCL) is recognized as a distinct entity in the World Health Organization classification. Currently, the diagnosis relies on consensus of histopathology, clinical variables, and presentation, giving rise to diagnostic inaccuracy in routine practice. Previous studies have demonstrated that PMBCL can be distinguished from subtypes of diffuse large B-cell lymphoma (DLBCL) based on gene expression signatures. However, requirement of fresh-frozen biopsy material has precluded the transfer of gene expression–based assays to the clinic. Here, we developed a robust and accurate molecular classification assay (Lymph3Cx) for the distinction of PMBCL from DLBCL subtypes based on gene expression measurements in formalin-fixed, paraffin-embedded tissue. A probabilistic model accounting for classification error, comprising 58 gene features, was trained on 68 cases of PMBCL and DLBCL. Performance of the model was subsequently evaluated in an independent validation cohort of 158 cases and showed high agreement of the Lymph3Cx molecular classification with the clinicopathological diagnosis of an expert panel (frank misclassification rate, 3.8%). Furthermore, we demonstrate reproducibility of the assay with 100% concordance of subtype assignments at 2 independent laboratories. Future studies will determine Lymph3Cx’s utility for routine diagnostic purposes and therapeutic decision making.
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- 2018
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23. Familial Multiple Myeloma: a Family Study and Review of the Literature
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Lynch, Henry T., Sanger, Warren G., Pirruccello, Samuel, Quinn-Laquer, Brigid, and Weisenburger, Dennis D.
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Multiple myeloma -- Case studies ,Health - Abstract
Background: The etiology of multiple myeloma (MM) remains obscure, although reports of familial clustering have implicated both a host susceptibility factor and environmental effects. Here we describe the medical histories of members of a family prone to MM. Methods: We developed a pedigree for an MM-prone family by using information obtained from a questionnaire. Protein immunoelectrophoresis of serum and urine from the proband and from 19 family members was performed to detect monoclonal immunoproteins. Peripheral blood obtained from the proband and from five relatives was subjected to standard cytogenetic studies to detect constitutional chromosomal abnormalities. Multifluor-fluorescence in situ hybridization (M-FISH) and standard FISH studies were performed on peripheral blood from the proband and from two other affected living relatives to determine their karyotypes and to detect clonal chromosomal abnormalities frequently seen in patients with MM. Results: Within this family, a sibship of seven included three individuals (including the proband) with histologically verified MM and two individuals with a monoclonal gammopathy of unknown significance (MGUS), as determined by immunoelectrophoresis of serum and urine. This family also had members with acute lymphocytic leukemia, malignant melanoma, and prostate cancer. In the family members tested, we detected no constitutional chromosomal abnormality. None of the three individuals analyzed by FISH had a deletion of the retinoblastoma (Rb-1) locus, which is frequently deleted in patients with MM, and only one (the proband) had a translocation involving chromosomes 11 and 14, a clonal abnormality commonly seen in MM. Conclusion: The study of familial MM may provide insights into the pathogenesis and, ultimately, the control and prevention of MM and related disorders. [J Natl Cancer Inst 2001;93:1479-83]
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- 2001
24. Agricultural Exposure to Carbamate Pesticides and Risk of Non-Hodgkin Lymphoma
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Zheng, Tongzhang, Zahm, Shelia Hoar, Cantor, Kenneth P, Weisenburger, Dennis D, Zhang, Yawei, and Blair, Aaron
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Carbamates -- Health aspects ,Non-Hodgkin's lymphomas -- Risk factors ,Pesticide residues -- Health aspects ,Environmental issues ,Health - Published
- 2001
25. Adult high-grade B-cell lymphoma with Burkitt lymphoma signature: genomic features and potential therapeutic targets
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Bouska, Alyssa, Bi, Chengfeng, Lone, Waseem, Zhang, Weiwei, Kedwaii, Ambreen, Heavican, Tayla, Lachel, Cynthia M., Yu, Jiayu, Ferro, Roberto, Eldorghamy, Nanees, Greiner, Timothy C., Vose, Julie, Weisenburger, Dennis D., Gascoyne, Randy D., Rosenwald, Andreas, Ott, German, Campo, Elias, Rimsza, Lisa M., Jaffe, Elaine S., Braziel, Rita M., Siebert, Reiner, Miles, Rodney R., Dave, Sandeep, Reddy, Anupama, Delabie, Jan, Staudt, Louis M., Song, Joo Y., McKeithan, Timothy W., Fu, Kai, Green, Michael, Chan, Wing C., and Iqbal, Javeed
- Abstract
The adult high-grade B-cell lymphomas sharing molecular features with Burkitt lymphoma (BL) are highly aggressive lymphomas with poor clinical outcome. High-resolution structural and functional genomic analysis of adult Burkitt lymphoma (BL) and high-grade B-cell lymphoma with BL gene signature (adult-molecularly defined BL [mBL]) revealed the MYC-ARF-p53 axis as the primary deregulated pathway. Adult-mBL had either unique or more frequent genomic aberrations (del13q14, del17p, gain8q24, and gain18q21) compared with pediatric-mBL, but shared commonly mutated genes. Mutations in genes promoting the tonic B-cell receptor (BCR)→PI3K pathway (TCF3and ID3) did not differ by age, whereas effectors of chronic BCR→NF-κB signaling were associated with adult-mBL. A subset of adult-mBL had BCL2translocation and mutation and elevated BCL2mRNA and protein expression, but had a mutation profile similar to mBL. These double-hit lymphomas may have arisen from a tumor precursor that acquired both BCL2and MYCtranslocations and/or KMT2D(MLL2) mutation. Gain/amplification of MIR17HGand its paralogue loci was observed in 50% of adult-mBL. In vitro studies suggested miR-17∼92's role in constitutive activation of BCR signaling and sensitivity to ibrutinib. Overall integrative analysis identified an interrelated gene network affected by copy number and mutation, leading to disruption of the p53 pathway and the BCR→PI3K or NF-κB activation, which can be further exploited in vivo by small-molecule inhibitors for effective therapy in adult-mBL.
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- 2017
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26. Cyclin D1 expression in peripheral T-cell lymphomas
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Song, Joo Y, Song, Liping, Herrera, Alex F, Venkataraman, Girish, Murata-Collins, Joyce L, Bedell, Victoria H, Chen, Yuan Yuan, Kim, Young S, Tadros, Reda, Nathwani, Bharat N, Weisenburger, Dennis D, and Feldman, Andrew L
- Abstract
Cyclin D1 is an important regulator of the cell cycle and overexpression of this protein by immunohistochemistry is characteristically seen in mantle cell lymphoma and other B-cell neoplasms. However, little is known about the expression of this protein in T-cell lymphomas. Cyclin-dependent kinase pathway inhibitors are in development, therefore identifying cyclin D1-positive T-cell lymphomas may provide a therapeutic target in a disease where novel treatments are urgently needed. We collected 200 peripheral T-cell lymphomas from three institutions including the following types of cases: 34 anaplastic large cell lymphoma, ALK+, 44 anaplastic large cell lymphoma, ALK negative, 68 peripheral T-cell lymphomas, not otherwise specified, 24 angioimmunoblastic T-cell lymphomas, 7 extranodal NK/T-cell lymphomas, 4 enteropathy associated T-cell lymphomas, 3 hepatosplenic T-cell lymphomas, 12 cutaneous T-cell lymphomas, and 4 large granular lymphocytic leukemias. Immunohistochemical stains for cyclin D1 protein (SP4 clone) were performed on paraffin-embedded tissue. In a subset of cases, IGH/CCND1 fluorescence in situ hybridization analysis was also performed. Cyclin D1 staining was predominantly seen in anaplastic large cell lymphoma, including 8 of 34 cases with ALK+ anaplastic large cell lymphoma (24%), and 3 of 44 cases of ALK-negative (7%) anaplastic large cell lymphoma. Three cases of peripheral T-cell lymphoma, not otherwise specified, were also positive (3/68, 4%). All other T-cell lymphomas were negative for cyclin D1. In four of the cyclin D1-positive T-cell lymphomas by immunohistochemistry, fluorescence in situ hybridization analysis was negative for IGH/CCND1 translocation or extra copies of the CCND1 gene. Cyclin D1 overexpression by immunohistochemistry is not limited to B-cell lymphomas and is also observed in some peripheral T-cell lymphomas, particularly in anaplastic large cell lymphoma, ALK+. Cyclin D1 expression was not associated with extra copies or translocation of the CCND1 gene. Cyclin D1 overexpression may be the result of a post-translational phenomenon and may represent a potential therapeutic target using agents that target the cyclin-dependent kinase pathway.
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- 2016
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27. Salvage therapy for relapsed or refractory non-Hodgkin's lymphoma utilizing autologous bone marrow transplantation
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Vose, Julie M., Armitage, James O., Bierman, Philip J., Weisenburger, Dennis D., Hutchins, Mark, Dowling, Monroe D., Moravec, Daniel F., Sorensen, Scot, Okerbloom, John, Bascom, George, Johnson, P. Steven, Langdon, Robert M., Jr., Mailliard, James, Pevnick, Warren, Westberg, Mark, and Kessinger, Anne
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Bone marrow -- Transplantation ,Transplantation of organs, tissues, etc. -- Health aspects ,Non-Hodgkin's lymphomas -- Care and treatment ,Cancer -- Relapse ,Health ,Health care industry - Published
- 1989
28. IDH2R172mutations define a unique subgroup of patients with angioimmunoblastic T-cell lymphoma
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Wang, Chao, McKeithan, Timothy W., Gong, Qiang, Zhang, Weiwei, Bouska, Alyssa, Rosenwald, Andreas, Gascoyne, Randy D., Wu, Xiwei, Wang, Jinhui, Muhammad, Zahid, Jiang, Bei, Rohr, Joseph, Cannon, Andrew, Steidl, Christian, Fu, Kai, Li, Yuping, Hung, Stacy, Weisenburger, Dennis D., Greiner, Timothy C., Smith, Lynette, Ott, German, Rogan, Eleanor G., Staudt, Louis M., Vose, Julie, Iqbal, Javeed, and Chan, Wing C.
- Abstract
Angioimmunoblastic T-cell lymphoma (AITL) is a common subtype of peripheral T-cell lymphoma (PTCL) with a poor prognosis. We performed targeted resequencing on 92 cases of PTCL and identified frequent mutations affecting RHOA, TET2, DNMT3A,and isocitrate dehydrogenase 2 (IDH2). Although IDH2mutations are largely confined to AITL, mutations of the other 3 can be found in other types of PTCL, although at lower frequencies. These findings indicate a key role of epigenetic regulation in the pathogenesis of AITL. However, the epigenetic alterations induced by these mutations and their role in AITL pathogenesis are still largely unknown. We correlated mutational status with gene expression and global DNA methylation changes in AITL. Strikingly, AITL cases with IDH2R172mutations demonstrated a distinct gene expression signature characterized by downregulation of genes associated with TH1differentiation (eg, STAT1and IFNG) and a striking enrichment of an interleukin 12-induced gene signature. Ectopic expression of IDH2R172Kin the Jurkat cell line and CD4+T cells led to markedly increased levels of 2-hydroxyglutarate, histone-3 lysine methylation, and 5-methylcytosine and a decrease of 5-hydroxymethylcytosine. Correspondingly, clinical samples with IDH2mutations displayed a prominent increase in H3K27me3 and DNA hypermethylation of gene promoters. Integrative analysis of gene expression and promoter methylation revealed recurrently hypermethylated genes involved in T-cell receptor signaling and T-cell differentiation that likely contribute to lymphomagenesis in AITL.
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- 2015
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29. IDH2 R172 mutations define a unique subgroup of patients with angioimmunoblastic T-cell lymphoma
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Wang, Chao, McKeithan, Timothy W., Gong, Qiang, Zhang, Weiwei, Bouska, Alyssa, Rosenwald, Andreas, Gascoyne, Randy D., Wu, Xiwei, Wang, Jinhui, Muhammad, Zahid, Jiang, Bei, Rohr, Joseph, Cannon, Andrew, Steidl, Christian, Fu, Kai, Li, Yuping, Hung, Stacy, Weisenburger, Dennis D., Greiner, Timothy C., Smith, Lynette, Ott, German, Rogan, Eleanor G., Staudt, Louis M., Vose, Julie, Iqbal, Javeed, and Chan, Wing C.
- Abstract
Angioimmunoblastic T-cell lymphoma (AITL) is a common subtype of peripheral T-cell lymphoma (PTCL) with a poor prognosis. We performed targeted resequencing on 92 cases of PTCL and identified frequent mutations affecting RHOA, TET2, DNMT3A, and isocitrate dehydrogenase 2 (IDH2). Although IDH2 mutations are largely confined to AITL, mutations of the other 3 can be found in other types of PTCL, although at lower frequencies. These findings indicate a key role of epigenetic regulation in the pathogenesis of AITL. However, the epigenetic alterations induced by these mutations and their role in AITL pathogenesis are still largely unknown. We correlated mutational status with gene expression and global DNA methylation changes in AITL. Strikingly, AITL cases with IDH2R172 mutations demonstrated a distinct gene expression signature characterized by downregulation of genes associated with TH1 differentiation (eg, STAT1 and IFNG) and a striking enrichment of an interleukin 12-induced gene signature. Ectopic expression of IDH2R172K in the Jurkat cell line and CD4+ T cells led to markedly increased levels of 2-hydroxyglutarate, histone-3 lysine methylation, and 5-methylcytosine and a decrease of 5-hydroxymethylcytosine. Correspondingly, clinical samples with IDH2 mutations displayed a prominent increase in H3K27me3 and DNA hypermethylation of gene promoters. Integrative analysis of gene expression and promoter methylation revealed recurrently hypermethylated genes involved in T-cell receptor signaling and T-cell differentiation that likely contribute to lymphomagenesis in AITL.
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- 2015
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30. Identification of Primary Mediastinal Large B-cell Lymphoma at Nonmediastinal Sites by Gene Expression Profiling
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Yuan, Ji, Wright, George, Rosenwald, Andreas, Steidl, Christian, Gascoyne, Randy D., Connors, Joseph M., Mottok, Anja, Weisenburger, Dennis D., Greiner, Timothy C., Fu, Kai, Smith, Lynette, Rimsza, Lisa M., Jaffe, Elaine S., Campo, Elias, Martinez, Antonio, Delabie, Jan, Braziel, Rita M., Cook, James R., Ott, German, Vose, Julie M., Staudt, Louis M., and Chan, Wing C.
- Abstract
Mediastinal involvement is considered essential for the diagnosis of primary mediastinal large B-cell lymphoma (PMBL). However, we have observed cases of diffuse large B-cell lymphoma (DLBCL) with features of PMBL but without detectable mediastinal involvement. The goal was to assess our previously established gene expression profiling (GEP) signature for PMBL in classifying these cases. In a large series of DLBCL cases, we identified 24 cases with a GEP signature of PMBL, including 9 cases with a submission diagnosis of DLBCL consistent with PMBL (G-PMBL-P) and 15 cases with a submission diagnosis of DLBCL. The pathology reviewers agreed with the diagnosis in the 9 G-PMBL-P cases. Among the other 15 DLBCL cases, 11 were considered to be PMBL or DLBCL consistent with PMBL, 3 were considered to be DLBCL, and 1 case was a gray-zone lymphoma with features intermediate between DLBCL and classical Hodgkin lymphoma. All 9 G-PMBL-P and 9 of the 15 DLBCL cases (G-PMBL-M) had demonstrated mediastinal involvement at presentation. Interestingly, 6 of the 15 DLBCL cases (G-PMBL-NM) had no clinical or radiologic evidence of mediastinal involvement. The 3 subgroups of PMBL had otherwise similar clinical characteristics, and there were no significant differences in overall survival. Genetic alterations of CIITAand PDL1/2 were detected in 26% and 40% of cases, respectively, including 1 G-PMBL-NM case with gain of PDL1/2. In conclusion, PMBL can present as a nonmediastinal tumor without evidence of mediastinal involvement, and GEP offers a more precise diagnosis of PMBL.
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- 2015
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31. Global microRNA expression profiling uncovers molecular markers for classification and prognosis in aggressive B-cell lymphoma
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Iqbal, Javeed, Shen, Yulei, Huang, Xin, Liu, Yanyan, Wake, Laura, Liu, Cuiling, Deffenbacher, Karen, Lachel, Cynthia M., Wang, Chao, Rohr, Joseph, Guo, Shuangping, Smith, Lynette M., Wright, George, Bhagavathi, Sharathkumar, Dybkaer, Karen, Fu, Kai, Greiner, Timothy C., Vose, Julie M., Jaffe, Elaine, Rimsza, Lisa, Rosenwald, Andreas, Ott, German, Delabie, Jan, Campo, Elias, Braziel, Rita M., Cook, James R., Tubbs, Raymond R., Armitage, James O., Weisenburger, Dennis D., Staudt, Louis M., Gascoyne, Randy D., McKeithan, Timothy W., and Chan, Wing C.
- Abstract
We studied the global microRNA (miRNA) expression in diffuse large B-cell lymphoma (DLBCL; n = 79), Burkitt lymphoma (BL; n = 36), primary mediastinal B-cell lymphoma (PMBL; n = 12), B-cell lines (n = 11), and normal subsets of naïve B cells, centroblasts (CBs), and peripheral blood B cells along with their corresponding gene expression profiles (GEPs). The normal B-cell subsets have well-defined miRNA signatures. The CB miRNA signature was significantly associated with germinal center B-cell (GCB)–DLBCL compared with activated B-cell (ABC)–DLBCL (P = .002). We identified a 27-miRNA signature that included v-myc avian myelomatosis viral oncogene homolog (MYC) targets and enabled the differentiation of BL from DLBCL, a distinction comparable with the “gold standard” GEP-defined diagnosis. Distinct miRNA signatures were identified for DLBCL subgroups, including GCB-DLBCL, activated B-cell (ABC)-DLBCL, and PMBL. Interestingly, most of the unclassifiable-DLBCL by GEP showed a strong similarity to the ABC-DLBCL by miRNA expression profiling. Consistent results for BL and DLBCL subgroup classification were observed in formalin-fixed, paraffin-embedded tissue, making such tests practical for clinical use. We also identified predictive miRNA biomarker signatures in DLBCL, including high expression of miR-155, which is significantly associated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) treatment failure. This finding was further supported by the observation that high expression of miR-155 sensitizes cells to v-akt murine thymoma viral oncogene homolog-1 inhibitors in vitro, suggesting a novel treatment option for resistant DLBCL.
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- 2015
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32. Gene expression signatures delineate biological and prognostic subgroups in peripheral T-cell lymphoma
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Iqbal, Javeed, Wright, George, Wang, Chao, Rosenwald, Andreas, Gascoyne, Randy D., Weisenburger, Dennis D., Greiner, Timothy C., Smith, Lynette, Guo, Shuangping, Wilcox, Ryan A., Teh, Bin Tean, Lim, Soon Thye, Tan, Soon Yong, Rimsza, Lisa M., Jaffe, Elaine S., Campo, Elias, Martinez, Antonio, Delabie, Jan, Braziel, Rita M., Cook, James R., Tubbs, Raymond R., Ott, German, Geissinger, Eva, Gaulard, Philippe, Piccaluga, Pier Paolo, Pileri, Stefano A., Au, Wing Y., Nakamura, Shigeo, Seto, Masao, Berger, Francoise, de Leval, Laurence, Connors, Joseph M., Armitage, James, Vose, Julie, Chan, Wing C., and Staudt, Louis M.
- Abstract
Peripheral T-cell lymphoma (PTCL) encompasses a heterogeneous group of neoplasms with generally poor clinical outcome. Currently 50% of PTCL cases are not classifiable: PTCL-not otherwise specified (NOS). Gene-expression profiles on 372 PTCL cases were analyzed and robust molecular classifiers and oncogenic pathways that reflect the pathobiology of tumor cells and their microenvironment were identified for major PTCL-entities, including 114 angioimmunoblastic T-cell lymphoma (AITL), 31 anaplastic lymphoma kinase (ALK)-positive and 48 ALK-negative anaplastic large cell lymphoma, 14 adult T-cell leukemia/lymphoma and 44 extranodal NK/T-cell lymphoma that were further separated into NK-cell and gdT-cell lymphomas. Thirty-seven percent of morphologically diagnosed PTCL-NOS cases were reclassified into other specific subtypes by molecular signatures. Reexamination, immunohistochemistry, and IDH2mutation analysis in reclassified cases supported the validity of the reclassification. Two major molecular subgroups can be identified in the remaining PTCL-NOS cases characterized by high expression of either GATA3 (33%; 40/121) or TBX21 (49%; 59/121). The GATA3 subgroup was significantly associated with poor overall survival (P= .01). High expression of cytotoxic gene-signature within the TBX21 subgroup also showed poor clinical outcome (P= .05). In AITL, high expression of several signatures associated with the tumor microenvironment was significantly associated with outcome. A combined prognostic score was predictive of survival in an independent cohort (P= .004).
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- 2014
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33. Genome-wide copy-number analyses reveal genomic abnormalities involved in transformation of follicular lymphoma
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Bouska, Alyssa, McKeithan, Timothy W., Deffenbacher, Karen E., Lachel, Cynthia, Wright, George W., Iqbal, Javeed, Smith, Lynette M., Zhang, Weiwei, Kucuk, Can, Rinaldi, Andrea, Bertoni, Francesco, Fitzgibbon, Jude, Fu, Kai, Weisenburger, Dennis D., Greiner, Timothy C., Dave, Bhavana J., Gascoyne, Randy D., Rosenwald, Andreas, Ott, German, Campo, Elias, Rimsza, Lisa M., Delabie, Jan, Jaffe, Elaine S., Braziel, Rita M., Connors, Joseph M., Staudt, Louis M., and Chan, Wing-Chung
- Abstract
Follicular lymphoma (FL), the second most common type of non-Hodgkin lymphoma in the western world, is characterized by the t(14;18) translocation, which is present in up to 90% of cases. We studied 277 lymphoma samples (198 FL and 79 transformed FL [tFL]) using a single-nucleotide polymorphism array to identify the secondary chromosomal abnormalities that drive the development of FL and its transformation to diffuse large B-cell lymphoma. Common recurrent chromosomal abnormalities in FL included gains of 2, 5, 7, 6p, 8, 12, 17q, 18, 21, and X and losses on 6q and 17p. We also observed many frequent small abnormalities, including losses of 1p36.33-p36.31, 6q23.3-q24.1, and 10q23.1-q25.1 and gains of 2p16.1-p15, 8q24.13-q24.3, and 12q12-q13.13, and identified candidate genes that may be driving this selection. Recurrent abnormalities more frequent in tFL samples included gains of 3q27.3-q28 and chromosome 11 and losses of 9p21.3 and 15q. Four abnormalities, gain of X or Xp and losses of 6q23.2-24.1 or 6q13-15, predicted overall survival. Abnormalities associated with transformation of the disease likely impair immune surveillance, activate the nuclear factor–κB pathway, and deregulate p53 and B-cell transcription factors.
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- 2014
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34. Determining cell-of-origin subtypes of diffuse large B-cell lymphoma using gene expression in formalin-fixed paraffin-embedded tissue
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Scott, David W., Wright, George W., Williams, P. Mickey, Lih, Chih-Jian, Walsh, William, Jaffe, Elaine S., Rosenwald, Andreas, Campo, Elias, Chan, Wing C., Connors, Joseph M., Smeland, Erlend B., Mottok, Anja, Braziel, Rita M., Ott, German, Delabie, Jan, Tubbs, Raymond R., Cook, James R., Weisenburger, Dennis D., Greiner, Timothy C., Glinsmann-Gibson, Betty J., Fu, Kai, Staudt, Louis M., Gascoyne, Randy D., and Rimsza, Lisa M.
- Abstract
The assignment of diffuse large B-cell lymphoma into cell-of-origin (COO) groups is becoming increasingly important with the emergence of novel therapies that have selective biological activity in germinal center B cell–like or activated B cell–like groups. The Lymphoma/Leukemia Molecular Profiling Project's Lymph2Cx assay is a parsimonious digital gene expression (NanoString)–based test for COO assignment in formalin-fixed paraffin-embedded tissue (FFPET). The 20-gene assay was trained using 51 FFPET biopsies; the locked assay was then validated using an independent cohort of 68 FFPET biopsies. Comparisons were made with COO assignment using the original COO model on matched frozen tissue. In the validation cohort, the assay was accurate, with only 1 case with definitive COO being incorrectly assigned, and robust, with >95% concordance of COO assignment between 2 independent laboratories. These qualities, along with the rapid turnaround time, make Lymph2Cx attractive for implementation in clinical trials and, ultimately, patient management.
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- 2014
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35. Indolent T-cell lymphoproliferative disease of the gastrointestinal tract
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Perry, Anamarija M., Warnke, Roger A., Hu, Qinglong, Gaulard, Philippe, Copie-Bergman, Christiane, Alkan, Serhan, Wang, Huan-You, Cheng, Jason X., Bacon, Chris M., Delabie, Jan, Ranheim, Erik, Kucuk, Can, Hu, XiaoZhou, Weisenburger, Dennis D., Jaffe, Elaine S., and Chan, Wing C.
- Abstract
Primary gastrointestinal (GI) T-cell lymphoma is an infrequent and aggressive disease. However, rare indolent clonal T-cell proliferations in the GI tract have been described. We report 10 cases of GI involvement by an indolent T-cell lymphoproliferative disease, including 6 men and 4 women with a median age of 48 years (range, 15-77 years). Presenting symptoms included abdominal pain, diarrhea, vomiting, food intolerance, and dyspepsia. The lesions involved oral cavity, esophagus, stomach, small intestine, and colon. The infiltrates were dense, but nondestructive, and composed of small, mature-appearing lymphoid cells. Eight cases were CD4−/CD8+, 1 was CD4+/CD8−, and another was CD4−/CD8−. T-cell receptor-γ chain gene rearrangement identified a clonal population in all 10 cases. There was no evidence of STAT3 SH2 domain mutation or activation. Six patients received chemotherapy because of an initial diagnosis of peripheral T-cell lymphoma, with little or no response, whereas the other 4 were followed without therapy. After a median follow-up of 38 months (range, 9-175 months), 9 patients were alive with persistent disease and 1 was free of disease. We propose the name “indolent T-LPD of the GI tract” for these lesions that can easily be mistaken for intestinal peripheral T-cell lymphoma, and lead to aggressive therapy.
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- 2013
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36. Double-Hit Signature with TP53Abnormalities Predicts Poor Survival in Patients with Germinal Center Type Diffuse Large B-Cell Lymphoma Treated with R-CHOP
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Song, Joo Y, Perry, Anamarija M., Herrera, Alex F., Chen, Lu, Skrabek, Pam, Nasr, Michel, Ottesen, Rebecca, Nikowitz, Janet, Bedell, Victoria, Murata-Collins, Joyce, Li, Yuping, McCarthy, Christine, Pillai, Raju, Wang, Jinhui, Wu, Xiwei, Zain, Jasmine M., Popplewell, Leslie L., Kwak, Larry W, Nademanee, Auayporn P., Niland, Joyce, Scott, David W., Gong, Qiang, Chan, Wing (John) C., and Weisenburger, Dennis D.
- Abstract
Background:In diffuse large B-cell lymphoma (DLBCL), the presence of MYCand BCL2and/or BCL6translocations, so-called double-hit lymphoma (DH), has been associated with an aggressive clinical course. Recently, it was reported that gene expression profiling (GEP) could also identify cases with the biological and clinical characteristics of DH lymphoma, including some without the requisite translocations (DHITsig-positive cases)1. The purpose of this study was to develop a molecular subtyping schema for germinal center B-cell type (GCB) DLBCL using genomic studies such as fluorescence in situhybridization (FISH) cytogenetic analysis, GEP, and mutation analysis to risk-stratify patients with GCB DLBCL.
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- 2020
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37. microRNA expression profiling identifies molecular signatures associated with anaplastic large cell lymphoma
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Liu, Cuiling, Iqbal, Javeed, Teruya-Feldstein, Julie, Shen, Yulei, Dabrowska, Magdalena Julia, Dybkaer, Karen, Lim, Megan S., Piva, Roberto, Barreca, Antonella, Pellegrino, Elisa, Spaccarotella, Elisa, Lachel, Cynthia M., Kucuk, Can, Jiang, Chun-Sun, Hu, Xiaozhou, Bhagavathi, Sharathkumar, Greiner, Timothy C., Weisenburger, Dennis D., Aoun, Patricia, Perkins, Sherrie L., McKeithan, Timothy W., Inghirami, Giorgio, and Chan, Wing C.
- Abstract
Anaplastic large-cell lymphomas (ALCLs) encompass at least 2 systemic diseases distinguished by the presence or absence of anaplastic lymphoma kinase (ALK) expression. We performed genome-wide microRNA (miRNA) profiling on 33 ALK-positive (ALK[+]) ALCLs, 25 ALK-negative (ALK[−]) ALCLs, 9 angioimmunoblastic T-cell lymphomas, 11 peripheral T-cell lymphomas not otherwise specified (PTCLNOS), and normal T cells, and demonstrated that ALCLs express many of the miRNAs that are highly expressed in normal T cells with the prominent exception of miR-146a. Unsupervised hierarchical clustering demonstrated distinct clustering of ALCL, PTCL-NOS, and the AITL subtype of PTCL. Cases of ALK(+) ALCL and ALK(–) ALCL were interspersed in unsupervised analysis, suggesting a close relationship at the molecular level. We identified an miRNA signature of 7 miRNAs (5 upregulated: miR-512-3p, miR-886-5p, miR-886-3p, miR-708, miR-135b; 2 downregulated: miR-146a, miR-155) significantly associated with ALK(+) ALCL cases. In addition, we derived an 11-miRNA signature (4 upregulated: miR-210, miR-197, miR-191, miR-512-3p; 7 downregulated: miR-451, miR-146a, miR-22, miR-455-3p, miR-455-5p, miR-143, miR-494) that differentiates ALK(–) ALCL from other PTCLs. Our in vitro studies identified a set of 32 miRNAs associated with ALK expression. Of these, the miR-17∼92 cluster and its paralogues were also highly expressed in ALK(+) ALCL and may represent important downstream effectors of the ALK oncogenic pathway.
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- 2013
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38. Classification of non-Hodgkin lymphoma in Central and South America: a review of 1028 cases
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Laurini, Javier A., Perry, Anamarija M., Boilesen, Eugene, Diebold, Jacques, MacLennan, Kenneth A., Müller-Hermelink, H. Konrad, Nathwani, Bharat N., Armitage, James O., and Weisenburger, Dennis D.
- Abstract
The distribution of non-Hodgkin lymphoma (NHL) subtypes differs around the world but a systematic study of Latin America has not been done. Therefore, we evaluated the relative frequencies of NHL subtypes in Central and South America (CSA). Five expert hematopathologists classified consecutive cases of NHL from 5 CSA countries using the WHO classification and compared them to 400 cases from North America (NA). Among the 1028 CSA cases, the proportions of B- and T-cell NHL and the sex distribution were similar to NA. However, the median age of B-cell NHL in CSA (59 years) was significantly lower than in NA (66 years; P< .0001). The distribution of high-grade (52.9%) and low-grade (47.1%) mature B-cell NHL in CSA was also significantly different from NA (37.5% and 62.5%; P< .0001). Diffuse large B-cell lymphoma was more common in CSA (40%) than in NA (29.2%; P< .0001), whereas the frequency of follicular lymphoma was similar in Argentina (34.1%) and NA (33.8%), and higher than the rest of CSA (17%; P< .001). Extranodal NK/T-cell NHL was also more common in CSA (P< .0001). Our study provides new objective evidence that the distribution of NHL subtypes varies significantly by geographic region and should prompt epidemiologic studies to explain these differences.
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- 2012
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39. Cutaneous T-cell Lymphomas
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Guitart, Joan, Weisenburger, Dennis D., Subtil, Antonio, Kim, Ellen, Wood, Gary, Duvic, Madeleine, Olsen, Elise, Junkins-Hopkins, Jacqueline, Rosen, Steve, Sundram, Uma, Ivan, Doina, Selim, M. Angelica, Pincus, Laura, Deonizio, Janyana M.D., Kwasny, Mary, and Kim, Youn H.
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We reviewed our multicenter experience with gamma-delta () T-cell lymphomas first presenting in the skin. Fifty-three subjects with a median age of 61 years (range, 25 to 91 y) were diagnosed with this disorder. The median duration of the skin lesions at presentation was 1.25 years (range, 1 mo to 20 y). The most common presentation was deep plaques (38 cases) often resembling a panniculitis, followed by patches resembling psoriasis or mycosis fungoides (10 cases). These lesions tended to ulcerate overtime (27 cases). Single lesions or localized areas of involvement resembling cellulitis or pyoderma were reported in 8 cases. The most common anatomic site of involvement was the legs (40 cases), followed by the torso (30 cases) and arms (28 cases). Constitutional symptoms were reported in 54 (2546) of the patients, including some with limited skin involvement. Significant comorbidities included autoimmunity (12 cases), other lymphoproliferative disorders (5 cases), internal carcinomas (4 cases), and viral hepatitis (2 cases). Lymphadenopathy (342 cases) and bone marrow involvement (528 cases) were uncommon, but serum lactose dehydrogenase (LDH) was elevated in 55 (2239) of the patients. Abnormal positron emission tomography andor computed tomography scans in 2037 subjects mostly highlighted soft tissue or lymph nodes. Disease progression was associated with extensive ulcerated lesions resulting in 27 deaths including complications of hemophagocytic syndrome (4) and cerebral nervous system involvement (3). Median survival time from diagnosis was 31 months. Skin biopsies varied from a pagetoid pattern to purely dermal or panniculitic infiltrates composed of intermediate-sized lymphocytes with tissue evidence of cytotoxicity. The most common immunophenotype was CD3CD4−CD5−CD8−BF1−-M1TIA-1granzyme-BCD45RA−CD7−, and 4 cases were Epstein-Barr virus positive. This is the largest study to date of cutaneous T-cell lymphomas and demonstrates a variety of clinical and pathologic presentations with a predictable poor outcome.
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- 2012
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40. A new biologic prognostic model based on immunohistochemistry predicts survival in patients with diffuse large B-cell lymphoma
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Perry, Anamarija M., Cardesa-Salzmann, Teresa M., Meyer, Paul N., Colomo, Luis, Smith, Lynette M., Fu, Kai, Greiner, Timothy C., Delabie, Jan, Gascoyne, Randy D., Rimsza, Lisa, Jaffe, Elaine S., Ott, German, Rosenwald, Andreas, Braziel, Rita M., Tubbs, Raymond, Cook, James R., Staudt, Louis M., Connors, Joseph M., Sehn, Laurie H., Vose, Julie M., López-Guillermo, Armando, Campo, Elias, Chan, Wing C., and Weisenburger, Dennis D.
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Biologic factors that predict the survival of patients with a diffuse large B-cell lymphoma, such as cell of origin and stromal signatures, have been discovered by gene expression profiling. We attempted to simulate these gene expression profiling findings and create a new biologic prognostic model based on immunohistochemistry. We studied 199 patients (125 in the training set, 74 in the validation set) with de novo diffuse large B-cell lymphoma treated with rituximab and CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) or CHOP-like therapies, and immunohistochemical stains were performed on paraffin-embedded tissue microarrays. In the model, 1 point was awarded for each adverse prognostic factor: nongerminal center B cell–like subtype, SPARC (secreted protein, acidic, and rich in cysteine) < 5%, and microvascular density quartile 4. The model using these 3 biologic markers was highly predictive of overall survival and event-free survival in multivariate analysis after adjusting for the International Prognostic Index in both the training and validation sets. This new model delineates 2 groups of patients, 1 with a low biologic score (0-1) and good survival and the other with a high score (2-3) and poor survival. This new biologic prognostic model could be used with the International Prognostic Index to stratify patients for novel or risk-adapted therapies.
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- 2012
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41. Genome-wide miRNA profiling of mantle cell lymphoma reveals a distinct subgroup with poor prognosis
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Iqbal, Javeed, Shen, Yulei, Liu, Yanyan, Fu, Kai, Jaffe, Elaine S., Liu, Cuiling, Liu, Zhongfeng, Lachel, Cynthia M., Deffenbacher, Karen, Greiner, Timothy C., Vose, Julie M., Bhagavathi, Sharathkumar, Staudt, Louis M., Rimsza, Lisa, Rosenwald, Andreas, Ott, German, Delabie, Jan, Campo, Elias, Braziel, Rita M., Cook, James R., Tubbs, Raymond R., Gascoyne, Randy D., Armitage, James O., Weisenburger, Dennis D., McKeithan, Timothy W., and Chan, Wing C.
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miRNA deregulation has been implicated in the pathogenesis of mantle cell lymphoma (MCL). Using a high-throughput quantitative real-time PCR platform, we performed miRNA profiling on cyclin D1–positive MCL (n = 30) and cyclin D1–negative MCL (n = 7) and compared them with small lymphocytic leukemia/lymphoma (n = 12), aggressive B-cell lymphomas (n = 138), normal B-cell subsets, and stromal cells. We identified a 19-miRNA classifier that included 6 up-regulated miRNAs and 13 down regulated miRNA that was able to distinguish MCL from other aggressive lymphomas. Some of the up-regulated miRNAs are highly expressed in naive B cells. This miRNA classifier showed consistent results in formalin-fixed paraffin-embedded tissues and was able to distinguish cyclin D1–negative MCL from other lymphomas. A 26-miRNA classifier could distinguish MCL from small lymphocytic leukemia/lymphoma, dominated by 23 up-regulated miRNAs in MCL. Unsupervised hierarchical clustering of MCL patients demonstrated a cluster characterized by high expression of miRNAs from the polycistronic miR17-92 cluster and its paralogs, miR-106a-363 and miR-106b-25, and associated with high proliferation gene signature. The other clusters showed enrichment of stroma-associated miRNAs, and also had higher expression of stroma-associated genes. Our clinical outcome analysis in the present study suggested that miRNAs can serve as prognosticators.
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- 2012
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42. Molecular distinctions between pediatric and adult mature B-cell non-Hodgkin lymphomas identified through genomic profiling
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Deffenbacher, Karen E., Iqbal, Javeed, Sanger, Warren, Shen, Yulei, Lachel, Cynthia, Liu, Zhongfeng, Liu, Yanyan, Lim, Megan S., Perkins, Sherrie L., Fu, Kai, Smith, Lynette, Lynch, James, Staudt, Louis M., Rimsza, Lisa M., Jaffe, Elaine, Rosenwald, Andreas, Ott, German K., Delabie, Jan, Campo, Elias, Gascoyne, Randy D., Cairo, Mitchell S., Weisenburger, Dennis D., Greiner, Timothy C., Gross, Thomas G., and Chan, Wing C.
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Burkitt lymphoma (BL) predominates in pediatric patients, whereas diffuse large B-cell lymphoma (DLBCL) is uncommon. In contrast to adults, BL and DLBCL are treated similarly in children and both entities have superior outcomes in children compared with adults. Gene expression profiling (GEP) and miRNA expression profiling clearly differentiated pediatric DLBCL from BL, forming distinct clusters regardless of patient age. However, pathway analysis of GEP data identified minor differences between corresponding pediatric and adult tumors. Predominance (6:1) of the germinal center B-cell subtype to activated B-cell subtype was found among pediatric DLBCL. Two cases were molecularly classified as primary mediastinal B-cell lymphoma. We observed frequent abnormalities in 8q24 in pediatric DLBCL, including MYCrearrangement in 31% (5 of 16) and gain or amplification in 50% (6 of 12) nonrearranged cases. MYCrearrangement was present in 96% (23 of 24) BL cases. Array-based CGH analysis identified abnormalities that are shared between adult and pediatric DLBCL (+12q15, +19q13, −6q), and abnormalities unique to the pediatric cases (−4p14, −19q13.32, +16p11.2), suggesting distinct pathogenetic mechanisms relative to age. Elucidation of the underlying target genes may provide insight into factors that modulate outcome and could provide potential novel therapeutic targets with less toxicity for pediatric patients with B-cell non-Hodgkin lymphoma.
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- 2012
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43. MicroRNA profiles of t(14;18)–negative follicular lymphoma support a late germinal center B-cell phenotype
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Leich, Ellen, Zamo, Alberto, Horn, Heike, Haralambieva, Eugenia, Puppe, Bernhard, Gascoyne, Randy D., Chan, Wing-Chung, Braziel, Rita M., Rimsza, Lisa M., Weisenburger, Dennis D., Delabie, Jan, Jaffe, Elaine S., Fitzgibbon, Jude, Staudt, Louis M., Mueller-Hermelink, Hans-Konrad, Calaminici, Mariarita, Campo, Elias, Ott, German, Hernández, Luis, and Rosenwald, Andreas
- Abstract
A total of 90% of follicular lymphomas (FLs) harbor the translocation t(14;18) leading to deregulated BCL2 expression. Conversely, 10% of FLs lack the t(14;18), and the majority of these FLs do not express BCL2. The molecular features of t(14;18)–negative FLs remain largely unknown. We performed microRNA expression analysis in 32 FL grades 1 to 3A, including 17 t(14;18)–positive FLs, 9 t(14;18)–negative FLs without BCL2 expression, and 6 t(14;18)–negative FLs with BCL2 expression. MicroRNA profiles were correlated with corresponding mRNA expression patterns, and potential targets were investigated by quantitative PCR and immunohistochemistry in an independent validation series of 83 FLs. Statistical analysis identified 17 microRNAs that were differentially expressed between t(14;18)–positive FLs and t(14;18)–negative FLs. The down-regulation of miR-16, miR-26a, miR-101, miR-29c, and miR138 in the t(14;18)-negative FL subset was associated with profound mRNA expression changes of potential target genes involving cell cycle control, apoptosis, and B-cell differentiation. miR-16 target CHEK1 showed increased expression in t(14;18)-negative FLs, whereas TCL1A expression was reduced, in line with a partial loss of the germinal center B-cell phenotype in this FL subset. In conclusion, t(14;18)–negative FL have distinct microRNA profiles that are associated with an increased proliferative capacity and a “late” germinal center B-cell phenotype.
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- 2011
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44. Enteropathy-associated T-cell lymphoma: clinical and histological findings from the International Peripheral T-Cell Lymphoma Project
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Delabie, Jan, Holte, Harald, Vose, Julie M., Ullrich, Fred, Jaffe, Elaine S., Savage, Kerry J., Connors, Joseph M., Rimsza, Lisa, Harris, Nancy L., Müller-Hermelink, Konrad, Rüdiger, Thomas, Coiffier, Bertrand, Gascoyne, Randy D., Berger, Françoise, Tobinai, Kensei, Au, Wing Y., Liang, Raymond, Montserrat, Emili, Hochberg, Ephraim P., Pileri, Stefano, Federico, Massimo, Nathwani, Bharat, Armitage, James O., and Weisenburger, Dennis D.
- Abstract
Few large, international series of enteropathy-associated T-cell lymphoma (EATL) have been reported. We studied a cohort of 62 patients with EATL among 1153 patients with peripheral T-cell or natural killer (NK)–cell lymphoma from 22 centers worldwide. The diagnosis was made by a consensus panel of 4 expert hematopathologists using World Health Organization (WHO) criteria. Clinical correlations and survival analyses were performed. EATL comprised 5.4% of all lymphomas in the study and was most common in Europe (9.1%), followed by North America (5.8%) and Asia (1.9%). EATL type 1 was more common (66%) than type 2 (34%), and was especially frequent in Europe (79%). A clinical diagnosis of celiac sprue was made in 32.2% of the patients and was associated with both EATL type 1 and type 2. The median overall survival was only 10 months, and the median failure-free survival was only 6 months. The International Prognostic Index (IPI) was not as good a predictor of survival as the Prognostic Index for Peripheral T-Cell Lymphoma (PIT). Clinical sprue predicted for adverse survival independently of the PIT. Neither EATL subtype nor other biologic parameters accurately predicted survival. Our study confirms the poor prognosis of patients with EATL and the need for improved treatment options.
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- 2011
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45. Peripheral T-cell lymphoma, not otherwise specified: a report of 340 cases from the International Peripheral T-cell Lymphoma Project
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Weisenburger, Dennis D., Savage, Kerry J., Harris, Nancy Lee, Gascoyne, Randy D., Jaffe, Elaine S., MacLennan, Kenneth A., Rüdiger, Thomas, Pileri, Stefano, Nakamura, Shigeo, Nathwani, Bharat, Campo, Elias, Berger, Francoise, Coiffier, Bertrand, Kim, Won-Seog, Holte, Harald, Federico, Massimo, Au, Wing Y., Tobinai, Kensei, Armitage, James O., and Vose, Julie M.
- Abstract
The International Peripheral T-cell Lymphoma Project is a collaborative effort to better understand peripheral T-cell lymphoma (PTCL). A total of 22 institutions submitted clinical and pathologic material on 1314 cases. One objective was to analyze the clinical and pathologic features of 340 cases of PTCL, not otherwise specified. The median age of the patients was 60 years, and the majority (69%) presented with advanced stage disease. Most patients (87%) presented with nodal disease, but extranodal disease was present in 62%. The 5-year overall survival was 32%, and the 5-year failure-free survival was only 20%. The majority of patients (80%) were treated with combination chemotherapy that included an anthracycline, but there was no survival advantage. The International Prognostic Index (IPI) was predictive of both overall survival and failure-free survival (P< .001). Multivariate analysis of clinical and pathologic prognostic factors, respectively, when controlling for the IPI, identified bulky disease (≥ 10 cm), thrombocytopenia (< 150 × 109/L), and a high number of transformed tumor cells (> 70%) as adverse predictors of survival, but only the latter was significant in final analysis. Thus, the IPI and a single pathologic feature could be used to stratify patients with PTCL-not otherwise specified for novel and risk-adapted therapies.
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- 2011
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46. InterLymph hierarchical classification of lymphoid neoplasms for epidemiologic research based on the WHO classification (2008): update and future directions
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Turner, Jennifer J., Morton, Lindsay M., Linet, Martha S., Clarke, Christina A., Kadin, Marshall E., Vajdic, Claire M., Monnereau, Alain, Maynadié, Marc, Chiu, Brian C.-H., Marcos-Gragera, Rafael, Costantini, Adele Seniori, Cerhan, James R., and Weisenburger, Dennis D.
- Abstract
After publication of the updated World Health Organization (WHO) classification of tumors of hematopoietic and lymphoid tissues in 2008, the Pathology Working Group of the International Lymphoma Epidemiology Consortium (InterLymph) now presents an update of the hierarchical classification of lymphoid neoplasms for epidemiologic research based on the 2001 WHO classification, which we published in 2007. The updated hierarchical classification incorporates all of the major and provisional entities in the 2008 WHO classification, including newly defined entities based on age, site, certain infections, and molecular characteristics, as well as borderline categories, early and “in situ” lesions, disorders with limited capacity for clinical progression, lesions without current International Classification of Diseases for Oncology, 3rd Edition codes, and immunodeficiency-associated lymphoproliferative disorders. WHO subtypes are defined in hierarchical groupings, with newly defined groups for small B-cell lymphomas with plasmacytic differentiation and for primary cutaneous T-cell lymphomas. We suggest approaches for applying the hierarchical classification in various epidemiologic settings, including strategies for dealing with multiple coexisting lymphoma subtypes in one patient, and cases with incomplete pathologic information. The pathology materials useful for state-of-the-art epidemiology studies are also discussed. We encourage epidemiologists to adopt the updated InterLymph hierarchical classification, which incorporates the most recent WHO entities while demonstrating their relationship to older classifications.
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- 2010
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47. Pathway discovery in mantle cell lymphoma by integrated analysis of high-resolution gene expression and copy number profiling
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Hartmann, Elena M., Campo, Elias, Wright, George, Lenz, Georg, Salaverria, Itziar, Jares, Pedro, Xiao, Wenming, Braziel, Rita M., Rimsza, Lisa M., Chan, Wing-Chung, Weisenburger, Dennis D., Delabie, Jan, Jaffe, Elaine S., Gascoyne, Randy D., Dave, Sandeep S., Mueller-Hermelink, Hans-Konrad, Staudt, Louis M., Ott, German, Beà, Sílvia, and Rosenwald, Andreas
- Abstract
The genome of mantle cell lymphoma (MCL) is, in addition to the translocation t(11;14), characterized by a high number of secondary chromosomal gains and losses that probably account for the various survival times of MCL patients. We investigated 77 primary MCL tumors with available clinical information using high-resolution RNA expression and genomic profiling and applied our recently developed gene expression and dosage integrator algorithm to identify novel genes and pathways that may be of relevance for the pathobiology of MCL. We show that copy number neutral loss of heterozygosity is common in MCL and targets regions that are frequently affected by deletions. The molecular consequences of genomic copy number changes appear complex, even in genomic loci with identified tumor suppressors, such as the region 9p21 containing the CDKN2Alocus. Moreover, the deregulation of novel genes, such as CUL4A, ING1, and MCPH1, may affect the 2 crucial pathogenetic mechanisms in MCL, the disturbance of the proliferation, and DNA damage response pathways. Deregulation of the Hippo pathway may have a pathogenetic role in MCL because decreased expression of its members MOBKL2A, MOBKL2B, and LATS2was associated with inferior outcome, including an independent validation series of 32 MCLs.
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- 2010
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48. Molecular signatures to improve diagnosis in peripheral T-cell lymphoma and prognostication in angioimmunoblastic T-cell lymphoma
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Iqbal, Javeed, Weisenburger, Dennis D., Greiner, Timothy C., Vose, Julie M., McKeithan, Timothy, Kucuk, Can, Geng, Huimin, Deffenbacher, Karen, Smith, Lynette, Dybkaer, Karen, Nakamura, Shigeo, Seto, Masao, Delabie, Jan, Berger, Francoise, Loong, Florence, Au, Wing Y., Ko, Young-Hyeh, Sng, Ivy, Armitage, James Olen, and Chan, Wing C.
- Abstract
Peripheral T-cell lymphoma (PTCL) is often challenging to diagnose and classify. Gene expression profiling was performed on 144 cases of PTCL and natural killer cell lymphoma and robust molecular classifiers were constructed for angioimmunoblastic T-cell lymphoma (AITL), anaplastic lymphoma kinase-positive (ALK+) anaplastic large-cell lymphoma (ALCL), and adult T-cell leukemia/lymphoma. PTCL-unclassifiable was molecularly heterogeneous, but we were able to identify a molecular subgroup with features of cytotoxic T lymphocytes and a poor survival compared with the remaining PTCL–not otherwise specified cases. Many of the pathologic features and substantial components of the molecular signature of AITL are contributed by the follicular dendritic cells, B-cell, and other stromal components. The expression of Th17-associated molecules in ALK+ ALCL was noted and may represent aberrant activation of Th17-cell differentiation by abnormal cytokine secretion. Adult T-cell leukemia/lymphoma has a homogeneous molecular signature demonstrating high expression of human T-lymphotropic virus type 1–induced genes. These classifiers reflect the biology of the tumor cells as well as their microenvironment. We also constructed a molecular prognosticator for AITL that appears to be largely related to the microenvironmental signature, and the high expression of 2 immunosuppressive signatures are associated with poor outcome. Oncogenic pathways and tumor-host interactions also were identified, and these findings may lead to better therapies and outcome in the future.
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- 2010
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49. Urinary biomarkers suggest that estrogen-DNA adducts may play a role in the aetiology of non-Hodgkin lymphoma
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Gaikwad, Nilesh W., Yang, Li, Weisenburger, Dennis D., Vose, Julie, Beseler, Cheryl, Rogan, Eleanor G., and Cavalieri, Ercole L.
- Abstract
A variety of evidence suggests that estrogens may induce non-Hodgkin lymphoma (NHL). The reaction of catechol estrogen quinones with DNA to form depurinating estrogen-DNA adducts is hypothesized to initiate this process. These adducts are released from DNA, shed from cells into the bloodstream and excreted in urine. The aim of this study was to determine whether or not the depurinating estrogen-DNA adducts might be involved in the aetiology of human NHL. Estrogen metabolites, conjugates and depurinating DNA adducts were identified and quantified in spot urine samples from 15 men with NHL and 30 healthy control men by using ultraperformance liquid chromatography/tandem mass spectrometry. The levels of estrogen-DNA adducts were significantly higher in the men with NHL than in the healthy control men. Thus, formation of estrogen-DNA adducts may play a critical role in the aetiology of NHL, and these adducts could be potential biomarkers of NHL risk.
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- 2009
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50. t(14;18)-negative follicular lymphomas are associated with a high frequency of BCL6 rearrangement at the alternative breakpoint region
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Gu, Keni, Fu, Kai, Jain, Smrati, Liu, Zhongfen, Iqbal, Javeed, Li, Min, Sanger, Warren G, Weisenburger, Dennis D, Greiner, Timothy C, Aoun, Patricia, Dave, Bhavana J, and Chan, Wing C
- Abstract
A frequent chromosomal translocation in mature B-cell non-Hodgkin lymphoma affects band 3q27 and results in the deregulation of the B-cell lymphoma 6 (BCL6) gene. Two breakpoint clusters have been described thus far, the major breakpoint region (MBR) and an alternative breakpoint region (ABR) that is located 245–285 kb 5′ to BCL6. Translocation at the MBR predominates in diffuse large B-cell lymphoma, whereas translocation at the ABR is reported to be frequently associated with grade 3B follicular lymphoma. However, translocation at the ABR has not been studied in a large series of follicular lymphomas, particularly t(14;18)-negative follicular lymphomas. Therefore, we studied BLC6 rearrangements at the MBR and ABR by using break-apart fluorescence in situ hybridization (FISH) probes in 142 cases of follicular lymphomas, including 63 t(14;18)-negative and 79 t(14;18)-positive cases. Conventional cytogenetic (karyotype) analysis was also performed in 58 of the 63 t(14;18)-negative cases. BCL6 rearrangement was found in 26% of t(14;18)-negative and 19% of t(14;18)-positive follicular lymphoma. t(14;18)-negative cases showed a high frequency of rearrangement at the ABR (12%) with an ABR/MBR ratio of 0.86, compared with only 5% with an ABR/MBR ratio of 0.36 in the t(14;18)-positive cases. BCL6 rearrangements were found in all grades of follicular lymphoma but were most frequent in grade 3 t(14;18)-negative follicular lymphoma (60%). FISH analysis had a higher sensitivity for detecting BCL6 rearrangements than conventional cytogenetics. In conclusion, BCL6 rearrangements occur at a similar frequency in t(14;18)-negative follicular lymphoma and diffuse large B-cell lymphoma. However, t(14;18)-negative follicular lymphoma appears to have a higher frequency of rearrangement at the ABR compared with t(14;18)-positive follicular lymphoma and diffuse large B-cell lymphoma. Therefore, it is important to perform FISH analysis with ABR to determine possible involvement of BCL6 rearrangement in follicular lymphoma, especially in t(14;18)-negative cases.
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- 2009
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