Publications (47) View all
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Article: Analysis of FOXO1 mutations in diffuse large B-cell lymphoma.
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ABSTRACT: Diffuse large B-cell lymphoma (DLBCL) accounts for 30% to 40% of newly diagnosed lymphomas and has an overall cure rate of approximately 60%. Previously, we observed FOXO1 mutations in NHL patient samples. To explore the effects of FOXO1 mutations, we assessed FOXO1 status in 279 DLBCL patient samples and 22 DLBCL-derived cell lines. FOXO1 mutations were found in 8.6% (24/279) of DLBCL cases. 92.3% (24/26) of mutations were in the first exon, 46.2% (12/26) were recurrent mutations affecting the N-terminal region and another 38.5% (10/26) affected the Forkhead DNA binding domain. Recurrent mutations in the N-terminal region resulted in diminished T24 phosphorylation, loss of interaction with 14-3-3, and nuclear retention. FOXO1 mutation was associated with decreased overall survival in patients treated with R-CHOP (P = 0.037), independent of cell-of-origin and the Revised International Prognostic Index. This association was particularly evident (P = 0.003) in patients in the low-risk R-IPI categories. The independent relationship of mutations in FOXO1 to survival, transcending the prognostic influence of the R-IPI and COO, indicates that FOXO1 mutation is a novel prognostic factor that plays an important role in DLBCL pathogenesis.Blood 03/2013; · 9.90 Impact Factor -
Article: New Strategies in Hodgkin Lymphoma: Better Risk Profiling and Novel Treatments.
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ABSTRACT: Recent advances in Hodgkin lymphoma (HL) research are expected to prelude a promising new treatment era for patients and their treating physicians. Scientific investigations over the last few years have provided new insights into risk stratification, and simultaneously, a plethora of novel targeted therapies are emerging for patients with relapsed and refractory disease. These novel therapies will be tested primarily in high risk patients, since 75% of patients are cured with conventional therapies. The challenges, as HL therapy moves forward, will be using these biologic insights to identify the patients who may benefit earlier in treatment from these novel agents, and tailoring the therapy to the patient's tumor biology. These dual aims are intertwined; as our therapeutic arsenal increases, these biologic determinants of risk may themselves inform the design of therapies and the choice of treatments for high risk patients.Clinical Cancer Research 02/2013; · 7.74 Impact Factor -
Article: The E3 ubiquitin ligase UBR5 is recurrently mutated in mantle cell lymphoma.
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ABSTRACT: We have recently reported the application of RNAseq to mantle cell lymphoma (MCL) transcriptomes revealing recurrent mutations in NOTCH1. Here we describe the targeted re-sequencing of 18 genes mutated in this discovery cohort using a larger cohort of MCL tumors. In addition to frequent mutations in ATM, CCND1, TP53 and NOTCH1, mutations were also observed recurrently in MEF2B, TRAF2 and TET2. Interestingly, the third most frequently mutated gene was UBR5, a gene encoding a 2799aa protein, with multiple functions, including E3 ligase activity based on a conserved cysteine residue at the C-terminus. Non-synonymous mutations were detected in 18% (18/102) of tumors, with 61% of the mutations resulting in frameshifts in, or around, exon 58, predicted to result in the loss of this conserved cysteine residue. The recurrence and clustering of deleterious mutations implicate UBR5 mutations as a critical pathogenic event in a subgroup of MCL.Blood 02/2013; · 9.90 Impact Factor -
Article: Lymphotoxin network pathways shape the tumor microenvironment.
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ABSTRACT: Accumulating evidence indicates that Lymphotoxin (LT)-β related cytokines directly contribute to the phenotype of cancer cells and alter the tumor microenvironment. Lymphotoxins are part of a cytokine network well known in controlling the development and homeostasis of secondary lymphoid organs. In the adult, the LT network takes on the responsibility of generating inflammatory microenvironments that control innate and adaptive immune responses involved in host defense. This review provides a perspective of the emerging evidence implicating the LT Network in the development and progression of various cancers including lymphoma. Redirecting the LT Network to alter tumor microenvironments may provide a specific approach to therapeutically target tumor-permissive microenvironments and cancer progression.Current opinion in immunology 01/2013; · 10.88 Impact Factor -
Article: Gene Expression-Based Model Using Formalin-Fixed Paraffin-Embedded Biopsies Predicts Overall Survival in Advanced-Stage Classical Hodgkin Lymphoma.
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ABSTRACT: PURPOSEOur aim was to reliably identify patients with advanced-stage classical Hodgkin lymphoma (cHL) at increased risk of death by developing a robust predictor of overall survival (OS) using gene expression measured in routinely available formalin-fixed paraffin-embedded tissue (FFPET). METHODS Expression levels of 259 genes, including those previously reported to be associated with outcome in cHL, were determined by digital expression profiling of pretreatment FFPET biopsies from 290 patients enrolled onto the E2496 Intergroup trial comparing doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) and Stanford V regimens in locally extensive and advanced-stage cHL. A model for OS separating patients into low- and high-risk groups was produced using penalized Cox regression. The model was tested in an independent cohort of 78 patients enriched for treatment failure but otherwise similar to patients in a population-based registry of patients treated with ABVD. Weighted analysis methods generated unbiased estimates of predictor performance in the population-based registry.ResultsA 23-gene outcome predictor was generated. The model identified a population at increased risk of death in the validation cohort. There was a 29% absolute difference in 5-year OS between the high- and low-risk groups (63% v 92%, respectively; log-rank P < .001; hazard ratio, 6.7; 95% CI, 2.6 to 17.4). The predictor was superior to the International Prognostic Score and CD68 immunohistochemistry in multivariate analyses. CONCLUSIONA gene expression-based predictor, developed in and applicable to routinely available FFPET biopsies, identifies patients with advanced-stage cHL at increased risk of death when treated with standard-intensity up-front regimens.Journal of Clinical Oncology 11/2012; · 18.37 Impact Factor
