134 results on '"Braziel, Rita M."'
Search Results
2. 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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3. 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-TP53 axis and PTEN-PI3K pathways. Co-occurring gains/amplifications of STAT3 and MYC occurred 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 IDH2R172 mutation. CN losses were enriched in genes regulating PI3K–AKT–mTOR signaling in cases without IDH2 mutation. 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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4. Genomic alterations important for the prognosis in patients with follicular lymphoma treated in SWOG study S0016
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Qu, Xiaoyu, Li, Hongli, Braziel, Rita M., Passerini, Verena, Rimsza, Lisa M., Hsi, Eric D., Leonard, John P., Smith, Sonali M., Kridel, Robert, Press, Oliver, Weigert, Oliver, LeBlanc, Michael, Friedberg, Jonathan W., and Fang, Min
- Abstract
Although recent advances in molecular genetics have enabled improved risk classification of follicular lymphoma (FL) using, for example, the m7-FLIPI score, the impact on treatment has been limited. We aimed to assess the prognostic significance of copy-number aberrations (CNAs) and copy-neutral loss of heterozygosity (cnLOH) identified by chromosome genomic-array testing (CGAT) at FL diagnosis using prospectively collected clinical trial specimens from 255 patients enrolled in the SWOG study S0016. The impact of genomic aberrations was assessed for early progression (progressed or died within 2 years after registration), progression-free survival (PFS), and overall survival (OS). We showed that increased genomic complexity (ie, the total number of aberration calls) was associated with poor outcome in FL. Certain chromosome arms were critical for clinical outcome. Prognostic CNAs/cnLOH were identified: whereas early progression was correlated with 2p gain (P= .007; odds ratio [OR] = 2.55 [1.29, 5.03]) and 2p cnLOH (P= .005; OR = 10.9 [2.08, 57.2]), 2p gain specifically encompassing VRK2and FANCLpredicted PFS (P= .01; hazard ratio = 1.80 [1.14, 2.68]) as well as OS (P= .005; 2.40 [1.30, 4.40]); CDKN2A/B(9p) deletion correlated with worse PFS (P= .004, 3.50 [1.51, 8.28]); whereas CREBBP(16p) (P< .001; 6.70 [2.52, 17.58]) and TP53(17p) (P< .001; 3.90 [1.85, 8.31]) deletion predicted worse OS. An independent cohort from the m7-FLIPI study was explored, and the prognostic significance of aberration count, and TP53and CDKN2A/Bdeletion were further validated. In conclusion, assessing genomic aberrations at FL diagnosis with CGAT improves risk stratification independent of known clinical parameters, and provides a framework for development of future rational targeted therapies.
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- 2019
- Full Text
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5. Genomic alterations important for the prognosis in patients with follicular lymphoma treated in SWOG study S0016
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Qu, Xiaoyu, Li, Hongli, Braziel, Rita M., Passerini, Verena, Rimsza, Lisa M., Hsi, Eric D., Leonard, John P., Smith, Sonali M., Kridel, Robert, Press, Oliver, Weigert, Oliver, LeBlanc, Michael, Friedberg, Jonathan W., and Fang, Min
- Abstract
Although recent advances in molecular genetics have enabled improved risk classification of follicular lymphoma (FL) using, for example, the m7-FLIPI score, the impact on treatment has been limited. We aimed to assess the prognostic significance of copy-number aberrations (CNAs) and copy-neutral loss of heterozygosity (cnLOH) identified by chromosome genomic-array testing (CGAT) at FL diagnosis using prospectively collected clinical trial specimens from 255 patients enrolled in the SWOG study S0016. The impact of genomic aberrations was assessed for early progression (progressed or died within 2 years after registration), progression-free survival (PFS), and overall survival (OS). We showed that increased genomic complexity (ie, the total number of aberration calls) was associated with poor outcome in FL. Certain chromosome arms were critical for clinical outcome. Prognostic CNAs/cnLOH were identified: whereas early progression was correlated with 2p gain (P = .007; odds ratio [OR] = 2.55 [1.29, 5.03]) and 2p cnLOH (P = .005; OR = 10.9 [2.08, 57.2]), 2p gain specifically encompassing VRK2 and FANCL predicted PFS (P = .01; hazard ratio = 1.80 [1.14, 2.68]) as well as OS (P = .005; 2.40 [1.30, 4.40]); CDKN2A/B (9p) deletion correlated with worse PFS (P = .004, 3.50 [1.51, 8.28]); whereas CREBBP (16p) (P < .001; 6.70 [2.52, 17.58]) and TP53 (17p) (P < .001; 3.90 [1.85, 8.31]) deletion predicted worse OS. An independent cohort from the m7-FLIPI study was explored, and the prognostic significance of aberration count, and TP53 and CDKN2A/B deletion were further validated. In conclusion, assessing genomic aberrations at FL diagnosis with CGAT improves risk stratification independent of known clinical parameters, and provides a framework for development of future rational targeted therapies.
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- 2019
- Full Text
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6. 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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7. 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
- Full Text
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8. New Molecular Assay for the Proliferation Signature in Mantle Cell Lymphoma Applicable to Formalin-Fixed Paraffin-Embedded Biopsies.
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Scott, David W., Abrisqueta, Pau, Wright, George W., Slack, Graham W., Mottok, Anja, Villa, Diego, Jares, Pedro, Rauert-Wunderlich, Hilka, Royo, Cristina, Clot, Guillem, Pinyol, Magda, Boyle, Merrill, Fong Chun Chan, Braziel, Rita M., Chan, Wing C., Weisenburger, Dennis D., Cook, James R., Greiner, Timothy C., Fu, Kai, and Ott, German
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- 2017
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9. 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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10. 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 (TCF3 and 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 BCL2 translocation and mutation and elevated BCL2 mRNA 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 BCL2 and MYC translocations and/or KMT2D (MLL2) mutation. Gain/amplification of MIR17HG and 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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11. BCL2 antibodies targeted at different epitopes detect varying levels of protein expression and correlate with frequent gene amplification in diffuse large B-cell lymphoma.
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Kendrick, Samantha L., Redd, Lucas, Muranyi, Andrea, Henricksen, Leigh A., Stanislaw, Stacey, Smith, Lynette M., Perry, Anamarija M., Kai Fu, Weisenburger, Dennis D., Rosenwald, Andreas, Ott, German, Gascoyne, Randy D., Jaffe, Elaine S., Campo, Elías, Delabie, Jan, Braziel, Rita M., Cook, James R., Tubbs, Raymond R., Staudt, Louis M., and Wing Chung Chan
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- 2014
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12. B-Cell Lymphomas.
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Leonard, Debra G. B., Caliendo, Angela M., Kaul, Karen L., Van Deerlin, Vivianna M., Bagg, Adam, Braziel, Rita M., and Fan, Guang
- Abstract
The B-cell lymphomas (BCLs) represent 80% to 90% of non-Hodgkin lymphomas in the Western world and include multiple lymphoma subtypes with different biologies, natural histories, morphologic characteristics, immunophenotypes, genetic features, prognoses, and responses to therapy.1 Numerous subtypes of B-cell malignancies are defined according to the World Health Organization (WHO) classification (Table 32-1). Accurate subclassification of these BCLs has always been a challenge for pathologists, resulting in early application of new techniques in genetic analysis to these tumors to improve diagnostic accuracy. Today, the genetic features of BCLs are used not only to aid in rendering an accurate primary diagnosis, but also to predict prognosis, to assess for minimal residual disease after therapy, and even to help determine optimal therapy. [ABSTRACT FROM AUTHOR]
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- 2007
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13. 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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14. Activation of the STAT3 Signaling Pathway Is Associated With Poor Survival in Diffuse Large B-Cell Lymphoma Treated With R-CHOP.
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Xin Huang, Bin Meng, Iqbal, Javeed, Ding, B. Belinda, Perry, Anamarija M., Wenfeng Cao, Smith, Lynette M., Chengfeng Bi, Chunsun Jiang, Greiner, Timothy C., Weisenburger, Dennis D., Rimsza, Lisa, Rosenwald, Andreas, Ott, German, Delabie, Jan, Campo, Elias, Braziel, Rita M., Gascoyne, Randy D., Cook, James R., and Tubbs, Raymond R.
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- 2013
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15. 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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16. Phase III Randomized Intergroup Trial of CHOP Plus Rituximab Compared With CHOP Chemotherapy Plus 131Iodine-Tositumomab for Previously Untreated Follicular Non-Hodgkin Lymphoma: SWOG S0016.
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Press, Oliver W., Unger, Joseph M., Rimsza, Lisa M., Friedberg, Jonathan W., LeBlanc, Michael, Czuczman, Myron S., Kaminski, Mark, Braziel, Rita M., Spier, Catherine, Gopal, Ajay K., Maloney, David G., Cheson, Bruce D., Dakhil, Shaker R., Miller, Thomas P., and Fisher, Richard I.
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- 2013
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17. Multiplex high-throughput gene mutation analysis in acute myeloid leukemia.
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Dunlap, Jennifer, Beadling, Carol, Warrick, Andrea, Neff, Tanaya, Fleming, William H., Loriaux, Marc, Heinrich, Michael C., Kovacsovics, Tibor, Kelemen, Katalin, Leeborg, Nicky, Gatter, Ken, Braziel, Rita M., Press, Richard, Corless, Christopher L., and Fan, Guang
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ACUTE myeloid leukemia ,POLYMERASE chain reaction ,CYTOGENETICS ,HIGH throughput screening (Drug development) ,GENETIC mutation ,MASS spectrometry - Abstract
Classification of acute myeloid leukemia increasingly depends on genetic analysis. However, the number of known mutations in acute myeloid leukemia is expanding rapidly. Therefore, we tested a high-throughput screening method for acute myeloid leukemia mutation analysis using a multiplex mass spectrometry-based approach. To our knowledge, this is the first reported application of this approach to genotype leukemias in a clinical setting. One hundred seven acute myeloid leukemia cases were screened for mutations using a panel that covers 344 point mutations across 31 genes known to be associated with leukemia. The analysis was performed by multiplex polymerase chain reaction for mutations in genes of interest followed by primer extension reactions. Products were analyzed on a Sequenom MassARRAY system (San Diego, CA). The multiplex panel yielded mutations in 58% of acute myeloid leukemia cases with normal cytogenetics and 21% of cases with abnormal cytogenetics. Cytogenetics and routine polymerase chain reaction-based screening of NPM1, CEBPA, FLT3-ITD, and KIT was also performed on a subset of cases. When combined with the results of these standard polymerase chain reaction-based tests, the mutation frequency reached 78% in cases with normal cytogenetics. Of these, 42% harbored multiple mutations primarily involving NPM1 with NRAS, KRAS, CEBPA, PTPN11, IDH1, or FLT3. In contrast, cases with abnormal cytogenetics rarely harbored more than 1 mutation (1.5%), suggesting different underlying biology. This study demonstrates the feasibility and utility of broad-based mutation profiling of acute myeloid leukemia in a clinical setting. This approach will be helpful in defining prognostic subgroups of acute myeloid leukemia and contribute to the selection of patients for enrollment into trials with novel inhibitors. [ABSTRACT FROM AUTHOR]
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- 2012
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18. Concurrent Expression of MYC and BCL2 in Diffuse Large B-Cell Lymphoma Treated With Rituximab Plus Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone.
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Johnson, Nathalie A., Slack, Graham W., Savage, Kerry J., Connors, Joseph M., Ben-Neriah, Susana, Rogic, Sanja, Scott, David W., Tan, King L., Steidl, Christian, Sehn, Laurie H., Chan, Wing C., Iqbal, Javeed, Meyer, Paul N., Lenz, Georg, Wright, George, Rimsza, Lisa M., Valentino, Carlo, Brunhoeber, Patrick, Grogan, Thomas M., and Braziel, Rita M.
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- 2012
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19. 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
- Full Text
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20. 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 IDH2 mutation 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
- Full Text
- View/download PDF
21. 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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22. 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
- Full Text
- View/download PDF
23. 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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24. EZH2mutations are frequent and represent an early event in follicular lymphoma
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Bödör, Csaba, Grossmann, Vera, Popov, Nikolay, Okosun, Jessica, O'Riain, Ciarán, Tan, King, Marzec, Jacek, Araf, Shamzah, Wang, Jun, Lee, Abigail M., Clear, Andrew, Montoto, Silvia, Matthews, Janet, Iqbal, Sameena, Rajnai, Hajnalka, Rosenwald, Andreas, Ott, German, Campo, Elias, Rimsza, Lisa M., Smeland, Erlend B., Chan, Wing C., Braziel, Rita M., Staudt, Louis M., Wright, George, Lister, T. Andrew, Elemento, Olivier, Hills, Robert, Gribben, John G., Chelala, Claude, Matolcsy, András, Kohlmann, Alexander, Haferlach, Torsten, Gascoyne, Randy D., and Fitzgibbon, Jude
- Abstract
Gain of function mutations in the H3K27 methyltransferase EZH2 represent a promising therapeutic target in germinal center lymphomas. In this study, we assessed the frequency and distribution of EZH2mutations in a large cohort of patients with follicular lymphoma (FL) (n = 366) and performed a longitudinal analysis of mutation during the disease progression from FL to transformed FL (tFL) (n = 33). Mutations were detected at 3 recurrent mutation hot spots (Y646, A682, and A692) in 27% of FL cases with variant allele frequencies (VAF) ranging from 2% to 61%. By comparing VAF of EZH2with other mutation targets (CREBBP, MLL2, TNFRSF14, and MEF2B), we were able to distinguish patients harboring clonal EZH2mutation from rarer cases with subclonal mutations. Overall, the high incidence of EZH2mutations in FL and their stability during disease progression makes FL an appropriate disease to evaluate EZH2 targeted therapy.
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- 2013
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25. EZH2 mutations are frequent and represent an early event in follicular lymphoma
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Bödör, Csaba, Grossmann, Vera, Popov, Nikolay, Okosun, Jessica, O’Riain, Ciarán, Tan, King, Marzec, Jacek, Araf, Shamzah, Wang, Jun, Lee, Abigail M., Clear, Andrew, Montoto, Silvia, Matthews, Janet, Iqbal, Sameena, Rajnai, Hajnalka, Rosenwald, Andreas, Ott, German, Campo, Elias, Rimsza, Lisa M., Smeland, Erlend B., Chan, Wing C., Braziel, Rita M., Staudt, Louis M., Wright, George, Lister, T. Andrew, Elemento, Olivier, Hills, Robert, Gribben, John G., Chelala, Claude, Matolcsy, András, Kohlmann, Alexander, Haferlach, Torsten, Gascoyne, Randy D., and Fitzgibbon, Jude
- Abstract
Gain of function mutations in the H3K27 methyltransferase EZH2 represent a promising therapeutic target in germinal center lymphomas. In this study, we assessed the frequency and distribution of EZH2 mutations in a large cohort of patients with follicular lymphoma (FL) (n = 366) and performed a longitudinal analysis of mutation during the disease progression from FL to transformed FL (tFL) (n = 33). Mutations were detected at 3 recurrent mutation hot spots (Y646, A682, and A692) in 27% of FL cases with variant allele frequencies (VAF) ranging from 2% to 61%. By comparing VAF of EZH2 with other mutation targets (CREBBP, MLL2, TNFRSF14, and MEF2B), we were able to distinguish patients harboring clonal EZH2 mutation from rarer cases with subclonal mutations. Overall, the high incidence of EZH2 mutations in FL and their stability during disease progression makes FL an appropriate disease to evaluate EZH2 targeted therapy.
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- 2013
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26. 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.
- Abstract
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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27. 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.
- Abstract
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
- Full Text
- View/download PDF
28. 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.
- Abstract
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
- Full Text
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29. 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.
- Abstract
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
- Full Text
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30. 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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31. 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.
- Published
- 2010
- Full Text
- View/download PDF
32. Pathway discovery in mantle cell lymphoma by integrated analysis of high-resolution gene expression and copy number profiling
- Author
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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 CDKN2A locus. 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 LATS2 was associated with inferior outcome, including an independent validation series of 32 MCLs.
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- 2010
- Full Text
- View/download PDF
33. Follicular lymphomas with and without translocation t(14;18) differ in gene expression profiles and genetic alterations
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Leich, Ellen, Salaverria, Itziar, Bea, Silvia, Zettl, Andreas, Wright, George, Moreno, Victor, Gascoyne, Randy D., Chan, Wing-Chung, Braziel, Rita M., Rimsza, Lisa M., Weisenburger, Dennis D., Delabie, Jan, Jaffe, Elaine S., Lister, Andrew, Fitzgibbon, Jude, Staudt, Louis M., Hartmann, Elena M., Mueller-Hermelink, Hans-Konrad, Campo, Elias, Ott, German, and Rosenwald, Andreas
- Abstract
Follicular lymphoma (FL) is genetically characterized by the presence of the t(14;18)(q32;q21) chromosomal translocation in approximately 90% of cases. In contrast to FL carrying the t(14;18), their t(14;18)-negative counterparts are less well studied about their immunohistochemical, genetic, molecular, and clinical features. Within a previously published series of 184 FLs grades 1 to 3A with available gene expression data, we identified 17 FLs lacking the t(14;18). Comparative genomic hybridization and high-resolution single nucleotide polymorphism (SNP) array profiling showed that gains/amplifications of the BCL2gene locus in 18q were restricted to the t(14;18)-positive FL subgroup. A comparison of gene expression profiles showed an enrichment of germinal center B cell–associated signatures in t(14;18)-positive FL, whereas activated B cell–like, NFκB, proliferation, and bystander cell signatures were enriched in t(14;18)-negative FL. These findings were confirmed by immunohistochemistry in an independent validation series of 84 FLs, in which 32% of t(14;18)-negative FLs showed weak or absent CD10 expression and 91% an increased Ki67 proliferation rate. Although overall survival did not differ between FL with and without t(14;18), our findings suggest distinct molecular features of t(14;18)-negative FL.
- Published
- 2009
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34. Follicular lymphomas with and without translocation t(14;18) differ in gene expression profiles and genetic alterations
- Author
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Leich, Ellen, Salaverria, Itziar, Bea, Silvia, Zettl, Andreas, Wright, George, Moreno, Victor, Gascoyne, Randy D., Chan, Wing-Chung, Braziel, Rita M., Rimsza, Lisa M., Weisenburger, Dennis D., Delabie, Jan, Jaffe, Elaine S., Lister, Andrew, Fitzgibbon, Jude, Staudt, Louis M., Hartmann, Elena M., Mueller-Hermelink, Hans-Konrad, Campo, Elias, Ott, German, and Rosenwald, Andreas
- Abstract
Follicular lymphoma (FL) is genetically characterized by the presence of the t(14;18)(q32;q21) chromosomal translocation in approximately 90% of cases. In contrast to FL carrying the t(14;18), their t(14;18)-negative counterparts are less well studied about their immunohistochemical, genetic, molecular, and clinical features. Within a previously published series of 184 FLs grades 1 to 3A with available gene expression data, we identified 17 FLs lacking the t(14;18). Comparative genomic hybridization and high-resolution single nucleotide polymorphism (SNP) array profiling showed that gains/amplifications of the BCL2 gene locus in 18q were restricted to the t(14;18)-positive FL subgroup. A comparison of gene expression profiles showed an enrichment of germinal center B cell–associated signatures in t(14;18)-positive FL, whereas activated B cell–like, NFκB, proliferation, and bystander cell signatures were enriched in t(14;18)-negative FL. These findings were confirmed by immunohistochemistry in an independent validation series of 84 FLs, in which 32% of t(14;18)-negative FLs showed weak or absent CD10 expression and 91% an increased Ki67 proliferation rate. Although overall survival did not differ between FL with and without t(14;18), our findings suggest distinct molecular features of t(14;18)-negative FL.
- Published
- 2009
- Full Text
- View/download PDF
35. Structural profiles of TP53 gene mutations predict clinical outcome in diffuse large B-cell lymphoma: an international collaborative study
- Author
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Young, Ken H., Leroy, Karen, Møller, Michael B., Colleoni, Gisele W. B., Sánchez-Beato, Margarita, Kerbauy, Fábio R., Haioun, Corinne, Eickhoff, Jens C., Young, Allen H., Gaulard, Philippe, Piris, Miguel A., Oberley, Terry D., Rehrauer, William M., Kahl, Brad S., Malter, James S., Campo, Elias, Delabie, Jan, Gascoyne, Randy D., Rosenwald, Andreas, Rimsza, Lisa, Huang, James, Braziel, Rita M., Jaffe, Elaine S., Wilson, Wyndham H., Staudt, Louis M., Vose, Julie M., Chan, Wing C., Weisenburger, Dennis D., and Greiner, Timothy C.
- Abstract
The purpose of this study is to correlate the presence of TP53 gene mutations with the clinical outcome of a cohort of patients with diffuse large B-cell lymphoma (DLBCL) assembled from 12 medical centers. TP53 mutations were identified in 102 of 477 patients, and the overall survival (OS) of patients with TP53 mutations was significantly worse than those with wild-type TP53 (P < .001). However, subsets of TP53 mutations were found to have different effects on OS. Mutations in the TP53 DNA-binding domains were the strongest predictors of poor OS (P < .001). Mutations in the Loop-Sheet-Helix and Loop-L3 were associated with significantly decreased OS (P = .002), but OS was not significantly affected by mutations in Loop-L2. A subset of missense mutations (His158, His175, Ser245, Gln248, His273, Arg280, and Arg282) in the DNA-binding domains had the worst prognosis. Multivariate analysis confirmed that the International Prognostic Index and mutations in the DNA-binding domains were independent predictors of OS. TP53 mutations also stratified patients with germinal center B cell–like DLBCL, but not nongerminal center B cell–like DLBCL, into molecularly distinct subsets with different survivals. This study shows the prognostic importance of mutations in the TP53 DNA-binding domains in patients with DLBCL.
- Published
- 2008
- Full Text
- View/download PDF
36. Gene expression predicts overall survival in paraffin-embedded tissues of diffuse large B-cell lymphoma treated with R-CHOP
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Rimsza, Lisa M., LeBlanc, Michael L., Unger, Joseph M., Miller, Thomas P., Grogan, Thomas M., Persky, Daniel O., Martel, Ralph R., Sabalos, Constantine M., Seligmann, Bruce, Braziel, Rita M., Campo, Elias, Rosenwald, Andreas, Connors, Joseph M., Sehn, Laurie H., Johnson, Nathalie, and Gascoyne, Randy D.
- Abstract
Gene expression profiling (GEP) on frozen tissues has identified genes predicting outcome in patients with diffuse large B-cell lymphoma (DLBCL). Confirmation of results in current patients is limited by availability of frozen samples and addition of monoclonal antibodies to treatment regimens. We used a quantitative nuclease protection assay (qNPA) to analyze formalin-fixed, paraffin-embedded tissue blocks for 36 previously identified genes (N = 209, 93 chemotherapy; 116 rituximab + chemotherapy). By qNPA, 208 cases were successfully analyzed (99.5%). In addition, 15 of 36 and 11 of 36 genes, representing each functional group previously identified by GEP, were associated with survival (P < .05) in the 2 treatment groups, respectively. In addition, 30 of 36 hazard ratios of death trended in the same direction versus the original studies. Multivariate and variable cut-off point analysis identified low levels of HLA-DRB (< 20%) and high levels of MYC (> 80%) as independent indicators of survival, together distinguishing cases with the worst prognosis. Our results solve a clinical research problem by demonstrating that prognostic genes can be meaningfully quantified using qNPA technology on formalin-fixed, paraffin-embedded tissues; previous GEP findings in DLBCL are relevant with current treatments; and 2 genes, representing immune escape and proliferation, are the common features of the most aggressive DLBCL.
- Published
- 2008
- Full Text
- View/download PDF
37. Gene expression predicts overall survival in paraffin-embedded tissues of diffuse large B-cell lymphoma treated with R-CHOP
- Author
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Rimsza, Lisa M., LeBlanc, Michael L., Unger, Joseph M., Miller, Thomas P., Grogan, Thomas M., Persky, Daniel O., Martel, Ralph R., Sabalos, Constantine M., Seligmann, Bruce, Braziel, Rita M., Campo, Elias, Rosenwald, Andreas, Connors, Joseph M., Sehn, Laurie H., Johnson, Nathalie, and Gascoyne, Randy D.
- Abstract
Gene expression profiling (GEP) on frozen tissues has identified genes predicting outcome in patients with diffuse large B-cell lymphoma (DLBCL). Confirmation of results in current patients is limited by availability of frozen samples and addition of monoclonal antibodies to treatment regimens. We used a quantitative nuclease protection assay (qNPA) to analyze formalin-fixed, paraffin-embedded tissue blocks for 36 previously identified genes (N = 209, 93 chemotherapy; 116 rituximab + chemotherapy). By qNPA, 208 cases were successfully analyzed (99.5%). In addition, 15 of 36 and 11 of 36 genes, representing each functional group previously identified by GEP, were associated with survival (P< .05) in the 2 treatment groups, respectively. In addition, 30 of 36 hazard ratios of death trended in the same direction versus the original studies. Multivariate and variable cut-off point analysis identified low levels of HLA-DRB(< 20%) and high levels of MYC(> 80%) as independent indicators of survival, together distinguishing cases with the worst prognosis. Our results solve a clinical research problem by demonstrating that prognostic genes can be meaningfully quantified using qNPA technology on formalin-fixed, paraffin-embedded tissues; previous GEP findings in DLBCL are relevant with current treatments; and 2 genes, representing immune escape and proliferation, are the common features of the most aggressive DLBCL.
- Published
- 2008
- Full Text
- View/download PDF
38. Structural profiles of TP53gene mutations predict clinical outcome in diffuse large B-cell lymphoma: an international collaborative study
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Young, Ken H., Leroy, Karen, Møller, Michael B., Colleoni, Gisele W.B., Sánchez-Beato, Margarita, Kerbauy, Fábio R., Haioun, Corinne, Eickhoff, Jens C., Young, Allen H., Gaulard, Philippe, Piris, Miguel A., Oberley, Terry D., Rehrauer, William M., Kahl, Brad S., Malter, James S., Campo, Elias, Delabie, Jan, Gascoyne, Randy D., Rosenwald, Andreas, Rimsza, Lisa, Huang, James, Braziel, Rita M., Jaffe, Elaine S., Wilson, Wyndham H., Staudt, Louis M., Vose, Julie M., Chan, Wing C., Weisenburger, Dennis D., and Greiner, Timothy C.
- Abstract
The purpose of this study is to correlate the presence of TP53gene mutations with the clinical outcome of a cohort of patients with diffuse large B-cell lymphoma (DLBCL) assembled from 12 medical centers. TP53mutations were identified in 102 of 477 patients, and the overall survival (OS) of patients with TP53mutations was significantly worse than those with wild-type TP53(P< .001). However, subsets of TP53mutations were found to have different effects on OS. Mutations in the TP53DNA-binding domains were the strongest predictors of poor OS (P< .001). Mutations in the Loop-Sheet-Helix and Loop-L3 were associated with significantly decreased OS (P= .002), but OS was not significantly affected by mutations in Loop-L2. A subset of missense mutations (His158, His175, Ser245, Gln248, His273, Arg280, and Arg282) in the DNA-binding domains had the worst prognosis. Multivariate analysis confirmed that the International Prognostic Index and mutations in the DNA-binding domains were independent predictors of OS. TP53mutations also stratified patients with germinal center B cell–like DLBCL, but not nongerminal center B cell–like DLBCL, into molecularly distinct subsets with different survivals. This study shows the prognostic importance of mutations in the TP53DNA-binding domains in patients with DLBCL.
- Published
- 2008
- Full Text
- View/download PDF
39. Drug resistance in B‐cell chronic lymphocytic leukemia: Predictable by in vitro evaluation with a multiparameter flow cytometric cytotoxicity assay
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Zhong, Yanping, Bakke, Antony C., Fan, Guang, Braziel, Rita M., Gatter, Ken M., Leis, Jose F., Maziarz, Richard T., and Huang, James Z.
- Abstract
Patients with B‐cell chronic lymphocytic leukemia (B‐CLL) often demonstrate variable responses to similar treatments. It would be highly desirable to develop a personalized therapeutic strategy for selection of appropriate drugs or regimens based on the drug sensitivity profiles of leukemic cells from individuals.We applied a multiparameter flow cytometric drug cytotoxicity assay to evaluate drug effects specifically on B‐CLL cells from 43 individuals after leukemic cells were incubated in vitro with fludarabine, chlorambucil, cladribine, or prednisolone.We demonstrated that different B‐CLL cell populations from 43 individuals showed a marked variability in drug sensitivity. In vitro resistance to fludarabine was greatest in B‐CLL cells with deletions of p53, a cytogenetic abnormality that is almost invariably associated with a poor therapeutic response clinically.In vitro drug sensitivity profiles analyzed by a multiparameter flow cytometric cytotoxicity assay may serve as a tool to facilitate individualized selection of appropriate drugs for treatment in B‐CLL. Prospective trials will be needed to validate the clinical utility of this flow cytometric cytotoxicity assay. © 2007 International Society for Analytical Cytology
- Published
- 2007
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40. Loss of major histocompatibility class II expression in non-immune-privileged site diffuse large B-cell lymphoma is highly coordinated and not due to chromosomal deletions
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Rimsza, Lisa M., Roberts, Robin A., Campo, Elias, Grogan, Thomas M., Bea, Silvia, Salaverria, Itziar, Zettl, Andreas, Rosenwald, Andreas, Ott, German, Muller-Hermelink, H. Konrad, Delabie, Jan, Fisher, Richard I., Unger, Joseph M., LeBlanc, Michael, Staudt, Louis M., Jaffe, Elaine S., Gascoyne, Randy D., Chan, Wing C., Weisenburger, Dennis D., Greiner, Timothy, Braziel, Rita M., and Miller, Thomas P.
- Abstract
Decreased major histocompatibility class II (MHCII) expression is associated with poor survival in diffuse large B-cell lymphoma (DLBCL). Immune-privileged site DLBCL (IP-DLBCL) patients reportedly have frequent large deletions at the MHCII locus whereas the mechanism of decreased expression in non-IP-DLBCL is unknown. Gene expression profiling data were used for correlation analyses between expression levels of MHCII genes with each other and their transcriptional regulator, CIITA. Comparative genomic hybridization (CGH) assessed chromosomal alterations at MHCII-related loci. Finally, a map was created of expression of genes that are telomeric, within, or centromeric to the MHCII locus. Correlation coefficients among MHCII genes ranged from 0.73 to 0.92, whereas those between adjacent and intervening genes were lower (-0.12 to 0.49). Correlations between MHCII and CIITA expression were higher (0.53 to 0.60) than between CIITA and neighboring genes (-0.05 to 0.22). In 23 MHCII-cases, CGH detected 2 losses and 2 gains at MHCII loci. Expression of genes telomeric, within, and centromeric to MHCII loci were near normal in most MHCII-cases. Large deletions of the MHCII locus are uncommon in non-IP-DLBCL, implicating altered transcription as the operative mechanism for decreased expression.
- Published
- 2006
- Full Text
- View/download PDF
41. Loss of major histocompatibility class II expression in non-immune-privileged site diffuse large B-cell lymphoma is highly coordinated and not due to chromosomal deletions
- Author
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Rimsza, Lisa M., Roberts, Robin A., Campo, Elias, Grogan, Thomas M., Bea, Silvia, Salaverria, Itziar, Zettl, Andreas, Rosenwald, Andreas, Ott, German, Muller-Hermelink, H. Konrad, Delabie, Jan, Fisher, Richard I., Unger, Joseph M., LeBlanc, Michael, Staudt, Louis M., Jaffe, Elaine S., Gascoyne, Randy D., Chan, Wing C., Weisenburger, Dennis D., Greiner, Timothy, Braziel, Rita M., and Miller, Thomas P.
- Abstract
Decreased major histocompatibility class II (MHCII) expression is associated with poor survival in diffuse large B-cell lymphoma (DLBCL). Immune-privileged site DLBCL (IP-DLBCL) patients reportedly have frequent large deletions at the MHCII locus whereas the mechanism of decreased expression in non-IP-DLBCL is unknown. Gene expression profiling data were used for correlation analyses between expression levels of MHCII genes with each other and their transcriptional regulator, CIITA. Comparative genomic hybridization (CGH) assessed chromosomal alterations at MHCII-related loci. Finally, a map was created of expression of genes that are telomeric, within, or centromeric to the MHCII locus. Correlation coefficients among MHCII genes ranged from 0.73 to 0.92, whereas those between adjacent and intervening genes were lower (-0.12 to 0.49). Correlations between MHCII and CIITA expression were higher (0.53 to 0.60) than between CIITA and neighboring genes (-0.05 to 0.22). In 23 MHCII- cases, CGH detected 2 losses and 2 gains at MHCII loci. Expression of genes telomeric, within, and centromeric to MHCII loci were near normal in most MHCII- cases. Large deletions of the MHCII locus are uncommon in non-IP-DLBCL, implicating altered transcription as the operative mechanism for decreased expression.
- Published
- 2006
- Full Text
- View/download PDF
42. Cyclin D1–negative mantle cell lymphoma: a clinicopathologic study based on gene expression profiling
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Fu, Kai, Weisenburger, Dennis D., Greiner, Timothy C., Dave, Sandeep, Wright, George, Rosenwald, Andreas, Chiorazzi, Michael, Iqbal, Javeed, Gesk, Stefan, Siebert, Reiner, De Jong, Daphne, Jaffe, Elaine S., Wilson, Wyndham H., Delabie, Jan, Ott, German, Dave, Bhavana J., Sanger, Warren G., Smith, Lynette M., Rimsza, Lisa, Braziel, Rita M., Müller-Hermelink, H. Konrad, Campo, Elias, Gascoyne, Randy D., Staudt, Louis M., and Chan, Wing C.
- Abstract
Cyclin D1 overexpression is believed to be essential in the pathogenesis of mantle cell lymphoma (MCL). Hence, the existence of cyclin D1-negative MCL has been controversial and difficult to substantiate. Our previous gene expression profiling study identified several cases that lacked cyclin D1 expression, but had a gene expression signature typical of MCL. Herein, we report the clinical, pathologic, and genetic features of 6 cases of cyclin D1-negative MCL. All 6 cases exhibited the characteristic morphologic features and the unique gene expression signature of MCL but lacked the t(11;14)(q13; q32) by fluorescence in situ hybridization (FISH) analysis. The tumor cells also failed to express cyclin D1 protein, but instead expressed either cyclin D2 (2 cases) or cyclin D3 (4 cases). There was good correlation between cyclin D protein expression and the corresponding mRNA expression levels by gene expression analysis. Using interphase FISH, we did not detect chromosomal translocations or amplifications involving CCND2and CCND3loci in these cases. Patients with cyclin D1-negative MCL were similar clinically to those with cyclin D1-positive MCL. In conclusion, cases of cyclin D1-negative MCL do exist and are part of the spectrum of MCL. Up-regulation of cyclin D2 or D3 may substitute for cyclin D1 in the pathogenesis of MCL.
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- 2005
- Full Text
- View/download PDF
43. Cyclin D1–negative mantle cell lymphoma: a clinicopathologic study based on gene expression profiling
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Fu, Kai, Weisenburger, Dennis D., Greiner, Timothy C., Dave, Sandeep, Wright, George, Rosenwald, Andreas, Chiorazzi, Michael, Iqbal, Javeed, Gesk, Stefan, Siebert, Reiner, De Jong, Daphne, Jaffe, Elaine S., Wilson, Wyndham H., Delabie, Jan, Ott, German, Dave, Bhavana J., Sanger, Warren G., Smith, Lynette M., Rimsza, Lisa, Braziel, Rita M., Müller-Hermelink, H. Konrad, Campo, Elias, Gascoyne, Randy D., Staudt, Louis M., and Chan, Wing C.
- Abstract
Cyclin D1 overexpression is believed to be essential in the pathogenesis of mantle cell lymphoma (MCL). Hence, the existence of cyclin D1-negative MCL has been controversial and difficult to substantiate. Our previous gene expression profiling study identified several cases that lacked cyclin D1 expression, but had a gene expression signature typical of MCL. Herein, we report the clinical, pathologic, and genetic features of 6 cases of cyclin D1-negative MCL. All 6 cases exhibited the characteristic morphologic features and the unique gene expression signature of MCL but lacked the t(11;14)(q13; q32) by fluorescence in situ hybridization (FISH) analysis. The tumor cells also failed to express cyclin D1 protein, but instead expressed either cyclin D2 (2 cases) or cyclin D3 (4 cases). There was good correlation between cyclin D protein expression and the corresponding mRNA expression levels by gene expression analysis. Using interphase FISH, we did not detect chromosomal translocations or amplifications involving CCND2 and CCND3 loci in these cases. Patients with cyclin D1-negative MCL were similar clinically to those with cyclin D1-positive MCL. In conclusion, cases of cyclin D1-negative MCL do exist and are part of the spectrum of MCL. Up-regulation of cyclin D2 or D3 may substitute for cyclin D1 in the pathogenesis of MCL.
- Published
- 2005
- Full Text
- View/download PDF
44. Proteomic profiling of mature CD10+ B-cell lymphomas.
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Fan, Guang, Molstad, Michael, Braziel, Rita M, Standley, Melissa, Huang, James, Rodgers, William, and Nagalla, Srinivasa
- Abstract
Proteomic profiling with protein-chip technology has been used successfully to discover biomarkers with potential clinical usefulness in several cancer types. Little proteomic study has been done in B-cell lymphomas. We determined whether the expression of a set of proteins by protein-chip technology coupled with new informatics tools could be used to build a model to molecularly classify B-cell lymphoma subgroups. We used surface-enhanced laser desorption/ionization time-of-flight mass spectrometry to analyze 18 CD10+ B-cell lymphomas, including 6 grade 1 (G1) follicular lymphomas (FLs), 7 grade 3 (G3) FLs, and 5 Burkitt lymphomas. We used 7 reactive follicular hyperplasia cases as a control group. By using SAX2 ProteinChip arrays (Ciphergen Biosystems, Fremont, CA), we found a unique protein expression profile for each type of lesion. Two-way hierarchical clustering analysis of these protein expression profiles differentiated reactive follicular hyperplasia, FL, and Burkitt lymphoma, with 5 major clusters of differentially expressed protein peaks. In addition, we identified histone H4 as a potential differentially expressed protein marker that seems to distinguish G1 from G3 FL. To our knowledge, this is the first proteomic study using protein-chip technology for molecular classification of B-cell lymphoma subtypes with clinical samples.
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- 2005
45. Effects of MLN518, a dual FLT3 and KIT inhibitor, on normal and malignant hematopoiesis
- Author
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Griswold, Ian J., Shen, Lei J., La Rosée, Paul, Demehri, Shadmehr, Heinrich, Michael C., Braziel, Rita M., McGreevey, Laura, Haley, Andrea D., Giese, Neill, Druker, Brian J., and Deininger, Michael W.N.
- Abstract
Internal tandem duplications (ITDs) of the FMS-like tyrosine kinase 3 (FLT3) receptor tyrosine kinase are found in approximately 30% of patients with acute myelogenous leukemia (AML) and are associated with a poor prognosis. FLT3 ITD mutations result in constitutive kinase activation and are thought to be pathogenetically relevant, implicating FLT3 as a plausible therapeutic target. MLN518 (formerly CT53518) is a small molecule inhibitor of the FLT3, KIT, and platelet-derived growth-factor receptor (PDGFR) tyrosine kinases with significant activity in murine models of FLT3 ITD-positive leukemia. Given the importance of FLT3 and KIT for normal hematopoietic progenitor cells, we analyzed the effect of MLN518 on murine hematopoiesis under steady-state conditions, after chemotherapy-induced myelosuppression, and during bone marrow transplantation. In these assays, we show that MLN518 has mild toxicity toward normal hematopoiesis at concentrations that are effective in treating FLT3 ITD-positive leukemia in mice. We also demonstrate that MLN518 preferentially inhibits the growth of blast colonies from FLT3 ITD-positive compared with ITD-negative patients with AML, at concentrations that do not significantly affect colony formation by normal human progenitor cells. In analogy to imatinib mesylate in BCR-ABL–positive acute leukemia, MLN518-induced remissions may not be durable. Our studies provide the basis for integrating this compound into chemotherapy and transplantation protocols.
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- 2004
- Full Text
- View/download PDF
46. Effects of MLN518, a dual FLT3 and KIT inhibitor, on normal and malignant hematopoiesis
- Author
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Griswold, Ian J., Shen, Lei J., La Rosée, Paul, Demehri, Shadmehr, Heinrich, Michael C., Braziel, Rita M., McGreevey, Laura, Haley, Andrea D., Giese, Neill, Druker, Brian J., and Deininger, Michael W.N.
- Abstract
Internal tandem duplications (ITDs) of the FMS-like tyrosine kinase 3 (FLT3) receptor tyrosine kinase are found in approximately 30% of patients with acute myelogenous leukemia (AML) and are associated with a poor prognosis. FLT3 ITD mutations result in constitutive kinase activation and are thought to be pathogenetically relevant, implicating FLT3 as a plausible therapeutic target. MLN518 (formerly CT53518) is a small molecule inhibitor of the FLT3, KIT, and platelet-derived growth-factor receptor (PDGFR) tyrosine kinases with significant activity in murine models of FLT3 ITD-positive leukemia. Given the importance of FLT3 and KIT for normal hematopoietic progenitor cells, we analyzed the effect of MLN518 on murine hematopoiesis under steady-state conditions, after chemotherapy-induced myelosuppression, and during bone marrow transplantation. In these assays, we show that MLN518 has mild toxicity toward normal hematopoiesis at concentrations that are effective in treating FLT3 ITD-positive leukemia in mice. We also demonstrate that MLN518 preferentially inhibits the growth of blast colonies from FLT3 ITD-positive compared with ITD-negative patients with AML, at concentrations that do not significantly affect colony formation by normal human progenitor cells. In analogy to imatinib mesylate in BCR-ABL–positive acute leukemia, MLN518-induced remissions may not be durable. Our studies provide the basis for integrating this compound into chemotherapy and transplantation protocols.
- Published
- 2004
- Full Text
- View/download PDF
47. BCL2Translocation Defines a Unique Tumor Subset within the Germinal Center B-Cell-Like Diffuse Large B-Cell Lymphoma
- Author
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Iqbal, Javeed, Sanger, Warren G., Horsman, Douglas E., Rosenwald, Andreas, Pickering, Diane L., Dave, Bhavana, Dave, Sandeep, Xiao, Li, Cao, Kajia, Zhu, Quiming, Sherman, Simon, Hans, Christine P., Weisenburger, Dennis D., Greiner, Timothy C., Gascoyne, Randy D., Ott, German, Müller-Hermelink, H. Konrad, Delabie, Jan, Braziel, Rita M., Jaffe, Elaine S., Campo, Elias, Lynch, James C., Connors, Joseph M., Vose, Julie M., Armitage, James O., Grogan, Thomas M., Staudt, Louis M., and Chan, Wing C.
- Abstract
Gene expression profiling of diffuse large B-cell lymphoma (DLBCL) has revealed prognostically important subgroups: germinal center B-cell-like (GCB) DLBCL, activated B cell-like (ABC) DLBCL, and primary mediastinal large B-cell lymphoma. The t(14;18)(q32;q21) has been reported previously to define a unique subset within the GCB-DLBCL. We evaluated for the translocation in 141 cases of DLBCL that were successfully gene expression profiled. Using a dual-probe fluorescence in situhybridization assay, we detected the t(14;18) in 17% of DLBCLs and in 34% of the GCB subgroup which contained the vast majority of positive cases. In addition, 12 t(14;18)-positive cases detected by polymerase chain reaction assays on additional samples were added to the fluorescence in situhybridization-positive cases for subsequent analysis. Immunohistochemical data indicated that BCL2, BCL6, and CD10 protein were preferentially expressed in the t(14;18)-positive cases as compared to t(14;18)-negative cases. Within the GCB subgroup, the expression of BCL2 and CD10, but not BCL6, differed significantly between cases with or without the t(14;18): 88%versus24% for BCL2 and 72%versus32% for CD10, respectively. In the GCB-DLBCL subgroup, a heterogeneous group of genes is overexpressed in the t(14;18)-positive subset, among which BCL2is a significant discriminator. Interestingly, the t(14;18)-negative subset is dominated by overexpression of cell cycle-associated genes, indicating that these tumors are significantly more proliferative, suggesting distinctive pathogenetic mechanisms. However, despite this higher proliferative activity, there was no significant difference in overall or failure-free survival between the t(14;18)-positive and -negative subsets within the GCB subgroup.
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- 2004
- Full Text
- View/download PDF
48. Loss of MHC class II gene and protein expression in diffuse large B-cell lymphoma is related to decreased tumor immunosurveillance and poor patient survival regardless of other prognostic factors: a follow-up study from the Leukemia and Lymphoma Molecular Profiling Project
- Author
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Rimsza, Lisa M., Roberts, Robin A., Miller, Thomas P., Unger, Joseph M., LeBlanc, Michael, Braziel, Rita M., Weisenberger, Dennis D., Chan, Wing C., Muller-Hermelink, H. Konrad, Jaffe, Elaine S., Gascoyne, Randy D., Campo, Elias, Fuchs, Deborah A., Spier, Catherine M., Fisher, Richard I., Delabie, Jan, Rosenwald, Andreas, Staudt, Louis M., and Grogan, Thomas M.
- Abstract
The Leukemia and Lymphoma Molecular Profiling Project recently published results from DNA microarray analyses of 240 diffuse large B-cell lymphomas (DLBCLs). Four gene expression “signatures” were identified as correlated with patient outcome, including the major histocompatibility complex (MHC) class II genes (eg, HLA-DRA) which correlated with better survival. We further analyzed the effects of HLA-DRA on survival and correlated gene expression with protein status and tumor-infiltrating lymphocytes. The 5-year overall survival was 24% in the lowest 10% of HLA-DRA expression, 37% in the 10% to 25% group, 50% in the 25% to 50% group, and 55% for patients in the highest 50%. Further analysis demonstrated that the hazard ratio of death was a nonlinear function of HLA-DRA expression. Adjustment for the International Prognostic Index did not alter the impact of HLA-DRA on survival. Other MHC class II genes were found to predict survival similarly. Microarray HLA-DRA expression correlated with the presence or absence of human leukocyte antigen-DR (HLA-DR) protein in 20 of 22 cases assessed. Fewer tumor-infiltrating CD8+ T cells were detected in MHC class II-negative cases compared with positive cases (2.8% versus 11.0%; P = .001), supporting the hypothesis that loss of tumor immunosurveillance has a devastating effect on patient outcome in DLBCL. (Blood. 2004; 103:4251-4258)
- Published
- 2004
- Full Text
- View/download PDF
49. Loss of MHC class II gene and protein expression in diffuse large B-cell lymphoma is related to decreased tumor immunosurveillance and poor patient survival regardless of other prognostic factors: a follow-up study from the Leukemia and Lymphoma Molecular Profiling Project
- Author
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Rimsza, Lisa M., Roberts, Robin A., Miller, Thomas P., Unger, Joseph M., LeBlanc, Michael, Braziel, Rita M., Weisenberger, Dennis D., Chan, Wing C., Muller-Hermelink, H. Konrad, Jaffe, Elaine S., Gascoyne, Randy D., Campo, Elias, Fuchs, Deborah A., Spier, Catherine M., Fisher, Richard I., Delabie, Jan, Rosenwald, Andreas, Staudt, Louis M., and Grogan, Thomas M.
- Abstract
The Leukemia and Lymphoma Molecular Profiling Project recently published results from DNA microarray analyses of 240 diffuse large B-cell lymphomas (DLBCLs). Four gene expression “signatures” were identified as correlated with patient outcome, including the major histocompatibility complex (MHC) class II genes (eg, HLA-DRA) which correlated with better survival. We further analyzed the effects of HLA-DRAon survival and correlated gene expression with protein status and tumor-infiltrating lymphocytes. The 5-year overall survival was 24% in the lowest 10% of HLA-DRAexpression, 37% in the 10% to 25% group, 50% in the 25% to 50% group, and 55% for patients in the highest 50%. Further analysis demonstrated that the hazard ratio of death was a nonlinear function of HLA-DRAexpression. Adjustment for the International Prognostic Index did not alter the impact of HLA-DRAon survival. Other MHC class II genes were found to predict survival similarly. Microarray HLA-DRAexpression correlated with the presence or absence of human leukocyte antigen-DR (HLA-DR) protein in 20 of 22 cases assessed. Fewer tumor-infiltrating CD8+T cells were detected in MHC class II-negative cases compared with positive cases (2.8% versus 11.0%; P= .001), supporting the hypothesis that loss of tumor immunosurveillance has a devastating effect on patient outcome in DLBCL. (Blood. 2004; 103:4251-4258)
- Published
- 2004
- Full Text
- View/download PDF
50. Prominent clonal B-cell populations identified by flow cytometry in histologically reactive lymphoid proliferations.
- Author
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Kussick, Steven J, Kalnoski, Michael, Braziel, Rita M, and Wood, Brent L
- Abstract
We describe 6 cases from the University of Washington Hematopathology Laboratory (Seattle) in which prominent, clonal, follicle center B-cell populations were identified by flow cytometry and confirmed by molecular methods, but in which the histologic features showed reactive follicular hyperplasia without evidence of bcl-2 overexpression or the t(14;18). The 6 cases included 5 lymph node biopsy specimens and 1 tonsillectomy specimen. Of the 6 cases, 5 occurred in young males (8-28 years) with no known immunologic abnormality; the other case was a 32-year-old, HIV-positive woman. In all 6 cases, clonal CD10+ B cells representing at least 20% of the total B cells were identified. Available clinical follow-up ranging from 13 to 56 months revealed no evidence of lymphoma in any of the 6 patients. Our findings add rare cases of follicular hyperplasia to the list of histologically reactive settings in which clonal B-cell populations might be present.
- Published
- 2004
- Full Text
- View/download PDF
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