Del(6)(q22) and <i>BCL6</i> Rearrangements in Primary CNS Lymphoma Are Indicators of an Aggressive Clinical Course

Cady, Francois M.; O’Neill, Brian Patrick; Law, Mark E.; Decker, Paul A.; Kurtz, David M.; Giannini, Caterina; Porter, Alyx; Kurtin, Paul J.; Johnston, Patrick B.; Doğan, Ahmet; Remstein, Ellen D.

doi:10.1200/jco.2008.16.1455

Cited by 108 publications

(92 citation statements)

References 41 publications

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“…27 Some studies have suggested that patients who harbor such abnormalities have a shorter overall survival. 23,25 In our study, despite the apparent trend toward shorter survival in these patients, the difference was not statistically significant. The lack of statistical significance may be related to the small number of our patient sample.…”

Section: Discussioncontrasting

confidence: 79%

“…Earlier studies of primary central nervous system lymphomas in immunocompetent hosts revealed similar rates of MYC/IGH and IGH/BCL2 abnormalities. [23][24][25] Interestingly, both in our study and in earlier reports, the majority of primary central nervous system lymphomas show strong expression of Bcl-2 and C-MYC, indicating that overexpression at protein and mRNA levels is poorly correlated with the rearrangements of BCL2 and C-MYC genes. 25,26 Thirty-three percent (7/21) of cases showed additional signals for IGH, BCL2, and C-MYC.…”

Section: Discussionsupporting

confidence: 62%

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Most primary central nervous system diffuse large B-cell lymphomas occurring in immunocompetent individuals belong to the nongerminal center subtype: a retrospective analysis of 31 cases

et al. 2010

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Primary central nervous system lymphomas are rare neoplasms characterized by a dismal prognosis relative to other extranodal lymphomas. Approximately 98% of primary central nervous system lymphomas are of B-cell origin, and most belong to the diffuse large B-cell type. Recently, diffuse large B-cell lymphomas have been subcategorized into germinal center and nongerminal center types based on gene expression profiles and immunohistochemical expression of CD10, Bcl-6, and MUM1. Studies have shown that the overall survival rate of the germinal center group is better than that of the nongerminal center lymphomas. In this study, 31 cases of primary central nervous system lymphomas of the diffuse large B-cell type were retrieved, reviewed, and immunostained for CD10, Bcl-6, MUM1, and Ki-67. Subclassification was carried out as described earlier, where CD10 and/or Bcl-6 positivity and negativity for MUM1 were considered characteristic of germinal center subtype and the opposite expression of nongerminal center subtype. Furthermore, the proliferative activity was semiquantitatively assessed using percent positive cells staining with Ki-67. Of the 31 cases examined, 26 (84%) were found to belong to the nongerminal center type. The Ki-67 index in these 26 cases ranged from 30 to 90% (mean, 69%). Five cases were categorized as the germinal center subtype. They had an Ki-67 index between 70 and 90% (mean, 78%). Interestingly, none of our patients were known to be HIV positive. One patient had a 10-year history of orthotopic liver transplant. We also performed fluorescence in situ hybridization analysis on formalin-fixed material and found that 38% of the cases where tissue was available had abnormalities of MYC/ IGH and/or IGH/BCL2. We conclude that most primary central nervous system diffuse large B-cell lymphomas are of the nongerminal center origin. Regardless of the germinal center status, all cases showed a high proliferative rate. A statistically significant difference in the overall survival between the two groups was not seen.

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Section: Discussioncontrasting

confidence: 79%

Section: Discussionsupporting

confidence: 62%

Most primary central nervous system diffuse large B-cell lymphomas occurring in immunocompetent individuals belong to the nongerminal center subtype: a retrospective analysis of 31 cases

et al. 2010

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“…Interestingly, the loss of the PTPRK locus on 6q22 has been associated with a poor outcome in PCNSL patients in 2 previous studies. However, patient clinical characteristics were not available (39) or treatments not detailed (14,39). In the present study, we observed a significantly shorter PFS and OS in PCNSL patients with 6q22 loss in multivariate analysis.…”

Section: Discussionmentioning

confidence: 99%

Recurrent Mutations of MYD88 and TBL1XR1 in Primary Central Nervous System Lymphomas

González-Aguilar

Idbaïh

Boisselier

et al. 2012

Clinical Cancer Research

223

171

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Purpose: Our objective was to identify the genetic changes involved in primary central nervous system lymphoma (PCNSL) oncogenesis and evaluate their clinical relevance.Experimental Design: We investigated a series of 29 newly diagnosed, HIV-negative, PCNSL patients using high-resolution single-nucleotide polymorphism (SNP) arrays (n ¼ 29) and whole-exome sequencing (n ¼ 4) approaches. Recurrent homozygous deletions and somatic gene mutations found were validated by quantitative real-time PCR and Sanger sequencing, respectively. Molecular results were correlated with prognosis.Results: All PCNSLs were diffuse large B-cell lymphomas, and the patients received chemotherapy without radiotherapy as initial treatment. The SNP analysis revealed recurrent large and focal chromosome imbalances that target candidate genes in PCNSL oncogenesis. The most frequent genomic abnormalities were (i) 6p21.32 loss (HLA locus), (ii) 6q loss, (iii) CDKN2A homozygous deletions, (iv) 12q12-q22, and (v) chromosome 7q21 and 7q31 gains. Homozygous deletions of PRMD1, TOX, and DOCK5 and the amplification of HDAC9 were also detected. Sequencing of matched tumor and blood DNA samples identified novel somatic mutations in MYD88 and TBL1XR1 in 38% and 14% of the cases, respectively. The correlation of genetic abnormalities with clinical outcomes using multivariate analysis showed that 6q22 loss (P ¼ 0.006 and P ¼ 0.01) and CDKN2A homozygous deletion (P ¼ 0.02 and P ¼ 0.01) were significantly associated with shorter progression-free survival and overall survival.Conclusions: Our study provides new insights into the molecular tumorigenesis of PCNSL and identifies novel genetic alterations in this disease, especially MYD88 and TBL1XR1 mutations activating the NF-kB signaling pathway, which may be promising targets for future therapeutic strategies.

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“…Interestingly, the authors showed that chromosome 6q loss was found at a significantly higher rate in PCNSL than in systemic DLBCL and was correlated with shorter survival [22]. An independent study of 75 newly diagnosed HIV-negative PCNSL patients investigated by interphase fluorescence in situ hybridization analysis confirmed frequent del(6)(q22) chromosome deletion, with a prevalence of 45%, and its negative impact on overall survival (OS) [23]. Chromosome 6q loss therefore represents a prognostic marker in PCNSL.…”

Section: Pathology and Pathogenesismentioning

confidence: 99%

“…Chromosome 6q loss therefore represents a prognostic marker in PCNSL. Further, the BCL-6 gene has been found to be mutated and its chromosomal locus (3q27) is often translocated (20%), suggesting that BCL-6 activation through genomic rearrangements may play a role in PCNSL pathogenesis [23][24][25]. BCL-6 is frequently expressed in PCNSL, but there are conflicting data on its prognostic value as an immunohistochemical marker [16, 26 -29].…”

Section: Pathology and Pathogenesismentioning

confidence: 99%

Primary CNS Lymphoma in Immunocompetent Patients

et al. 2009

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Primary central nervous system lymphoma (PCNSL) constitutes a rare group of extranodal non-Hodgkin's lymphomas (NHLs), primarily of B cell origin, whose incidence has markedly increased in the last three decades. Immunodeficiency is the main risk factor, but the large majority of patients are immunocompetent. Recent evidence suggests a specific tumorigenesis that may explain their particular clinical behavior compared with systemic NHL. The addition of i.v. high-dose methotrexate (MTX) chemotherapy to whole-brain radiotherapy (WBRT) has considerably improved the prognosis, leading to a threefold longer median survival time compared with WBRT alone and represents the current standard of care. However, this combined treatment exposes the patient, especially the elderly, to a high risk for delayed neurotoxicity. In the older population (>60 years), there is growing evidence that MTX-based chemotherapy alone as initial treatment is the best approach to achieve effective tumor control without compromising patient quality of life. In the younger population, the risk for neurotoxicity is much lower, and this strategy is controversial because it may be associated with higher relapse rates. Future efforts should focus on the development of new polychemotherapy regimens allowing the reduction or deferral of WBRT in order to minimize the risk for delayed neurotoxicity. In this setting, intensive chemotherapy with autologous blood stem cell transplantation was recently demonstrated to be feasible and efficient as salvage therapy and is currently being evaluated as part of primary treatment. This review highlights the recent advances in the pathogenesis and treatment of PCNSL in the immunocompetent population.

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Del(6)(q22) and BCL6 Rearrangements in Primary CNS Lymphoma Are Indicators of an Aggressive Clinical Course

Cited by 108 publications

References 41 publications

Most primary central nervous system diffuse large B-cell lymphomas occurring in immunocompetent individuals belong to the nongerminal center subtype: a retrospective analysis of 31 cases

Most primary central nervous system diffuse large B-cell lymphomas occurring in immunocompetent individuals belong to the nongerminal center subtype: a retrospective analysis of 31 cases

Recurrent Mutations of MYD88 and TBL1XR1 in Primary Central Nervous System Lymphomas

Primary CNS Lymphoma in Immunocompetent Patients

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