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Diffuse large B-cell lymphoma: can genomics improve treatment options for a curable cancer?

Gene-expression profiling and next-generation sequencing have defined diffuse large B-cell lymphoma (DLBCL), the most common lymphoma diagnosis, as a heterogeneous group of subentities. Despite ongoing explosions of data illuminating disparate pathogenic mechanisms, however, the five-drug chemoimmun...

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Autores principales: Amin, Amit Dipak, Peters, Tara L., Li, Lingxiao, Rajan, Soumya Sundara, Choudhari, Ramesh, Puvvada, Soham D., Schatz, Jonathan H.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cold Spring Harbor Laboratory Press 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5411687/
https://www.ncbi.nlm.nih.gov/pubmed/28487884
http://dx.doi.org/10.1101/mcs.a001719
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author Amin, Amit Dipak
Peters, Tara L.
Li, Lingxiao
Rajan, Soumya Sundara
Choudhari, Ramesh
Puvvada, Soham D.
Schatz, Jonathan H.
author_facet Amin, Amit Dipak
Peters, Tara L.
Li, Lingxiao
Rajan, Soumya Sundara
Choudhari, Ramesh
Puvvada, Soham D.
Schatz, Jonathan H.
author_sort Amin, Amit Dipak
collection PubMed
description Gene-expression profiling and next-generation sequencing have defined diffuse large B-cell lymphoma (DLBCL), the most common lymphoma diagnosis, as a heterogeneous group of subentities. Despite ongoing explosions of data illuminating disparate pathogenic mechanisms, however, the five-drug chemoimmunotherapy combination R-CHOP remains the frontline standard treatment. This has not changed in 15 years, since the anti-CD20 monoclonal antibody rituximab was added to the CHOP backbone, which first entered use in the 1970s. At least a third of patients are not cured by R-CHOP, and relapsed or refractory DLBCL is fatal in ∼90%. Targeted small-molecule inhibitors against distinct molecular pathways activated in different subgroups of DLBCL have so far translated poorly into the clinic, justifying the ongoing reliance on R-CHOP and other long-established chemotherapy-driven combinations. New drugs and improved identification of biomarkers in real time, however, show potential to change the situation eventually, despite some recent setbacks. Here, we review established and putative molecular drivers of DLBCL identified through large-scale genomics, highlighting among other things the care that must be taken when differentiating drivers from passengers, which is influenced by the promiscuity of activation-induced cytidine deaminase. Furthermore, we discuss why, despite having so much genomic data available, it has been difficult to move toward personalized medicine for this umbrella disorder and some steps that may be taken to hasten the process.
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spelling pubmed-54116872017-05-09 Diffuse large B-cell lymphoma: can genomics improve treatment options for a curable cancer? Amin, Amit Dipak Peters, Tara L. Li, Lingxiao Rajan, Soumya Sundara Choudhari, Ramesh Puvvada, Soham D. Schatz, Jonathan H. Cold Spring Harb Mol Case Stud Review Gene-expression profiling and next-generation sequencing have defined diffuse large B-cell lymphoma (DLBCL), the most common lymphoma diagnosis, as a heterogeneous group of subentities. Despite ongoing explosions of data illuminating disparate pathogenic mechanisms, however, the five-drug chemoimmunotherapy combination R-CHOP remains the frontline standard treatment. This has not changed in 15 years, since the anti-CD20 monoclonal antibody rituximab was added to the CHOP backbone, which first entered use in the 1970s. At least a third of patients are not cured by R-CHOP, and relapsed or refractory DLBCL is fatal in ∼90%. Targeted small-molecule inhibitors against distinct molecular pathways activated in different subgroups of DLBCL have so far translated poorly into the clinic, justifying the ongoing reliance on R-CHOP and other long-established chemotherapy-driven combinations. New drugs and improved identification of biomarkers in real time, however, show potential to change the situation eventually, despite some recent setbacks. Here, we review established and putative molecular drivers of DLBCL identified through large-scale genomics, highlighting among other things the care that must be taken when differentiating drivers from passengers, which is influenced by the promiscuity of activation-induced cytidine deaminase. Furthermore, we discuss why, despite having so much genomic data available, it has been difficult to move toward personalized medicine for this umbrella disorder and some steps that may be taken to hasten the process. Cold Spring Harbor Laboratory Press 2017-05 /pmc/articles/PMC5411687/ /pubmed/28487884 http://dx.doi.org/10.1101/mcs.a001719 Text en © 2017 Amin et al.; Published by Cold Spring Harbor Laboratory Press http://creativecommons.org/licenses/by-nc/4.0/ This article is distributed under the terms of the Creative Commons Attribution-NonCommercial License (http://creativecommons.org/licenses/by-nc/4.0/) , which permits reuse and redistribution, except for commercial purposes, provided that the original author and source are credited.
spellingShingle Review
Amin, Amit Dipak
Peters, Tara L.
Li, Lingxiao
Rajan, Soumya Sundara
Choudhari, Ramesh
Puvvada, Soham D.
Schatz, Jonathan H.
Diffuse large B-cell lymphoma: can genomics improve treatment options for a curable cancer?
title Diffuse large B-cell lymphoma: can genomics improve treatment options for a curable cancer?
title_full Diffuse large B-cell lymphoma: can genomics improve treatment options for a curable cancer?
title_fullStr Diffuse large B-cell lymphoma: can genomics improve treatment options for a curable cancer?
title_full_unstemmed Diffuse large B-cell lymphoma: can genomics improve treatment options for a curable cancer?
title_short Diffuse large B-cell lymphoma: can genomics improve treatment options for a curable cancer?
title_sort diffuse large b-cell lymphoma: can genomics improve treatment options for a curable cancer?
topic Review
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5411687/
https://www.ncbi.nlm.nih.gov/pubmed/28487884
http://dx.doi.org/10.1101/mcs.a001719
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