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Genomic Characterization of High-Count MBL Cases Indicates that Early Detection of Driver Mutations and Subclonal Expansion are Predictors of Adverse Clinical Outcome

High-count monoclonal B-cell lymphocytosis (MBL) is an asymptomatic expansion of clonal B-cells in the peripheral blood without other manifestations of chronic lymphocytic leukemia (CLL). Yearly, 1% of MBLs evolve to CLL requiring therapy; thus being critical to understand the biologic events that d...

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Autores principales: Barrio, S., Shanafelt, T. D., Ojha, J., Chaffee, K. G., Secreto, C., Kortüm, K. M., Pathangey, S., Van-Dyke, D. L., Slager, S. L., Fonseca, R., Kay, N. E., Braggio, E.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5215040/
https://www.ncbi.nlm.nih.gov/pubmed/27469216
http://dx.doi.org/10.1038/leu.2016.172
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author Barrio, S.
Shanafelt, T. D.
Ojha, J.
Chaffee, K. G.
Secreto, C.
Kortüm, K. M.
Pathangey, S.
Van-Dyke, D. L.
Slager, S. L.
Fonseca, R.
Kay, N. E.
Braggio, E.
author_facet Barrio, S.
Shanafelt, T. D.
Ojha, J.
Chaffee, K. G.
Secreto, C.
Kortüm, K. M.
Pathangey, S.
Van-Dyke, D. L.
Slager, S. L.
Fonseca, R.
Kay, N. E.
Braggio, E.
author_sort Barrio, S.
collection PubMed
description High-count monoclonal B-cell lymphocytosis (MBL) is an asymptomatic expansion of clonal B-cells in the peripheral blood without other manifestations of chronic lymphocytic leukemia (CLL). Yearly, 1% of MBLs evolve to CLL requiring therapy; thus being critical to understand the biologic events that determine which MBLs progress to intermediate/advanced CLL. In this study, we performed targeted deep-sequencing on 48 high-count MBLs, 47 of them with 2-4 sequential samples analyzed, exploring the mutation status of 21 driver genes and evaluating clonal evolution. We found somatic non-synonymous mutations in 25 MBLs(52%) at the initial time-point analyzed, including 13(27%) with >1 mutated gene. In cases that subsequently progressed to CLL, mutations were detected 41 months (median) prior to progression. Excepting NOTCH1, TP53 and XPO1, which showed a lower incidence in MBL, genes were mutated with a similar prevalence to CLL, indicating the early origin of most driver mutations in the MBL/CLL continuum. MBLs with mutations at the initial time-point analyzed were associated with shorter time-to-treatment (TTT). Furthermore, MBLs showing subclonal expansion of driver mutations on sequential evaluation had shorter progression time to CLL and shorter TTT. These findings support that clonal evolution have prognostic implications already at the pre-malignant MBL stage, anticipating which individuals will progress earlier to CLL.
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spelling pubmed-52150402017-01-06 Genomic Characterization of High-Count MBL Cases Indicates that Early Detection of Driver Mutations and Subclonal Expansion are Predictors of Adverse Clinical Outcome Barrio, S. Shanafelt, T. D. Ojha, J. Chaffee, K. G. Secreto, C. Kortüm, K. M. Pathangey, S. Van-Dyke, D. L. Slager, S. L. Fonseca, R. Kay, N. E. Braggio, E. Leukemia Article High-count monoclonal B-cell lymphocytosis (MBL) is an asymptomatic expansion of clonal B-cells in the peripheral blood without other manifestations of chronic lymphocytic leukemia (CLL). Yearly, 1% of MBLs evolve to CLL requiring therapy; thus being critical to understand the biologic events that determine which MBLs progress to intermediate/advanced CLL. In this study, we performed targeted deep-sequencing on 48 high-count MBLs, 47 of them with 2-4 sequential samples analyzed, exploring the mutation status of 21 driver genes and evaluating clonal evolution. We found somatic non-synonymous mutations in 25 MBLs(52%) at the initial time-point analyzed, including 13(27%) with >1 mutated gene. In cases that subsequently progressed to CLL, mutations were detected 41 months (median) prior to progression. Excepting NOTCH1, TP53 and XPO1, which showed a lower incidence in MBL, genes were mutated with a similar prevalence to CLL, indicating the early origin of most driver mutations in the MBL/CLL continuum. MBLs with mutations at the initial time-point analyzed were associated with shorter time-to-treatment (TTT). Furthermore, MBLs showing subclonal expansion of driver mutations on sequential evaluation had shorter progression time to CLL and shorter TTT. These findings support that clonal evolution have prognostic implications already at the pre-malignant MBL stage, anticipating which individuals will progress earlier to CLL. 2016-06-14 2017-01 /pmc/articles/PMC5215040/ /pubmed/27469216 http://dx.doi.org/10.1038/leu.2016.172 Text en Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:http://www.nature.com/authors/editorial_policies/license.html#terms
spellingShingle Article
Barrio, S.
Shanafelt, T. D.
Ojha, J.
Chaffee, K. G.
Secreto, C.
Kortüm, K. M.
Pathangey, S.
Van-Dyke, D. L.
Slager, S. L.
Fonseca, R.
Kay, N. E.
Braggio, E.
Genomic Characterization of High-Count MBL Cases Indicates that Early Detection of Driver Mutations and Subclonal Expansion are Predictors of Adverse Clinical Outcome
title Genomic Characterization of High-Count MBL Cases Indicates that Early Detection of Driver Mutations and Subclonal Expansion are Predictors of Adverse Clinical Outcome
title_full Genomic Characterization of High-Count MBL Cases Indicates that Early Detection of Driver Mutations and Subclonal Expansion are Predictors of Adverse Clinical Outcome
title_fullStr Genomic Characterization of High-Count MBL Cases Indicates that Early Detection of Driver Mutations and Subclonal Expansion are Predictors of Adverse Clinical Outcome
title_full_unstemmed Genomic Characterization of High-Count MBL Cases Indicates that Early Detection of Driver Mutations and Subclonal Expansion are Predictors of Adverse Clinical Outcome
title_short Genomic Characterization of High-Count MBL Cases Indicates that Early Detection of Driver Mutations and Subclonal Expansion are Predictors of Adverse Clinical Outcome
title_sort genomic characterization of high-count mbl cases indicates that early detection of driver mutations and subclonal expansion are predictors of adverse clinical outcome
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5215040/
https://www.ncbi.nlm.nih.gov/pubmed/27469216
http://dx.doi.org/10.1038/leu.2016.172
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