Whole-exome analysis reveals novel somatic genomic alterations associated with outcome in immunochemotherapytreated diffuse large B-cell lymphoma

Anne J Novak, Yan Asmann, M. J. Maurer, Chen Wang, Susan L Slager, L. S. Hodge, M. Manske, T. Price-Troska, Z. Z. Yang, M. T. Zimmermann, Grzegorz S Nowakowski, Stephen Maxted Ansell, Thomas Elmer Witzig, Ellen McPhail, R. Ketterling, Andrew L Feldman, A. Dogan, B. K. Link, Thomas Matthew Habermann, James R Cerhan

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Abstract

Lack of remission or early relapse remains a major clinical issue in diffuse large B-cell lymphoma (DLBCL), with 30% of patients failing standard of care. Although clinical factors and molecular signatures can partially predict DLBCL outcome, additional information is needed to identify high-risk patients, particularly biologic factors that might ultimately be amenable to intervention. Using whole-exome sequencing data from 51 newly diagnosed and immunochemotherapy-treated DLBCL patients, we evaluated the association of somatic genomic alterations with patient outcome, defined as failure to achieve event-free survival at 24 months after diagnosis (EFS24). We identified 16 genes with mutations, 374 with copy number gains and 151 with copy number losses that were associated with failure to achieve EFS24 (P <0.05). Except for FOXO1 and CIITA, known driver mutations did not correlate with EFS24. Gene losses were localized to 6q21-6q24.2, and gains to 3q13.12-3q29, 11q23.1-11q23.3 and 19q13.12-19q13.43. Globally, the number of gains was highly associated with poor outcome (P = 7.4 10-12) and when combined with FOXO1 mutations identified 77% of cases that failed to achieve EFS24. One gene (SLC22A16) at 6q21, a doxorubicin transporter, was lost in 54% of EFS24 failures and our findings suggest it functions as a doxorubicin transporter in DLBCL cells.

Original languageEnglish (US)
Article numbere346
JournalBlood Cancer Journal
Volume5
Issue number8
DOIs
StatePublished - Aug 14 2015

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Exome
Lymphoma, Large B-Cell, Diffuse
Doxorubicin
Mutation
Genes
Biological Factors
Standard of Care
Disease-Free Survival
Recurrence

ASJC Scopus subject areas

  • Oncology
  • Hematology

Cite this

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title = "Whole-exome analysis reveals novel somatic genomic alterations associated with outcome in immunochemotherapytreated diffuse large B-cell lymphoma",
abstract = "Lack of remission or early relapse remains a major clinical issue in diffuse large B-cell lymphoma (DLBCL), with 30{\%} of patients failing standard of care. Although clinical factors and molecular signatures can partially predict DLBCL outcome, additional information is needed to identify high-risk patients, particularly biologic factors that might ultimately be amenable to intervention. Using whole-exome sequencing data from 51 newly diagnosed and immunochemotherapy-treated DLBCL patients, we evaluated the association of somatic genomic alterations with patient outcome, defined as failure to achieve event-free survival at 24 months after diagnosis (EFS24). We identified 16 genes with mutations, 374 with copy number gains and 151 with copy number losses that were associated with failure to achieve EFS24 (P <0.05). Except for FOXO1 and CIITA, known driver mutations did not correlate with EFS24. Gene losses were localized to 6q21-6q24.2, and gains to 3q13.12-3q29, 11q23.1-11q23.3 and 19q13.12-19q13.43. Globally, the number of gains was highly associated with poor outcome (P = 7.4 10-12) and when combined with FOXO1 mutations identified 77{\%} of cases that failed to achieve EFS24. One gene (SLC22A16) at 6q21, a doxorubicin transporter, was lost in 54{\%} of EFS24 failures and our findings suggest it functions as a doxorubicin transporter in DLBCL cells.",
author = "Novak, {Anne J} and Yan Asmann and Maurer, {M. J.} and Chen Wang and Slager, {Susan L} and Hodge, {L. S.} and M. Manske and T. Price-Troska and Yang, {Z. Z.} and Zimmermann, {M. T.} and Nowakowski, {Grzegorz S} and Ansell, {Stephen Maxted} and Witzig, {Thomas Elmer} and Ellen McPhail and R. Ketterling and Feldman, {Andrew L} and A. Dogan and Link, {B. K.} and Habermann, {Thomas Matthew} and Cerhan, {James R}",
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T1 - Whole-exome analysis reveals novel somatic genomic alterations associated with outcome in immunochemotherapytreated diffuse large B-cell lymphoma

AU - Novak, Anne J

AU - Asmann, Yan

AU - Maurer, M. J.

AU - Wang, Chen

AU - Slager, Susan L

AU - Hodge, L. S.

AU - Manske, M.

AU - Price-Troska, T.

AU - Yang, Z. Z.

AU - Zimmermann, M. T.

AU - Nowakowski, Grzegorz S

AU - Ansell, Stephen Maxted

AU - Witzig, Thomas Elmer

AU - McPhail, Ellen

AU - Ketterling, R.

AU - Feldman, Andrew L

AU - Dogan, A.

AU - Link, B. K.

AU - Habermann, Thomas Matthew

AU - Cerhan, James R

PY - 2015/8/14

Y1 - 2015/8/14

N2 - Lack of remission or early relapse remains a major clinical issue in diffuse large B-cell lymphoma (DLBCL), with 30% of patients failing standard of care. Although clinical factors and molecular signatures can partially predict DLBCL outcome, additional information is needed to identify high-risk patients, particularly biologic factors that might ultimately be amenable to intervention. Using whole-exome sequencing data from 51 newly diagnosed and immunochemotherapy-treated DLBCL patients, we evaluated the association of somatic genomic alterations with patient outcome, defined as failure to achieve event-free survival at 24 months after diagnosis (EFS24). We identified 16 genes with mutations, 374 with copy number gains and 151 with copy number losses that were associated with failure to achieve EFS24 (P <0.05). Except for FOXO1 and CIITA, known driver mutations did not correlate with EFS24. Gene losses were localized to 6q21-6q24.2, and gains to 3q13.12-3q29, 11q23.1-11q23.3 and 19q13.12-19q13.43. Globally, the number of gains was highly associated with poor outcome (P = 7.4 10-12) and when combined with FOXO1 mutations identified 77% of cases that failed to achieve EFS24. One gene (SLC22A16) at 6q21, a doxorubicin transporter, was lost in 54% of EFS24 failures and our findings suggest it functions as a doxorubicin transporter in DLBCL cells.

AB - Lack of remission or early relapse remains a major clinical issue in diffuse large B-cell lymphoma (DLBCL), with 30% of patients failing standard of care. Although clinical factors and molecular signatures can partially predict DLBCL outcome, additional information is needed to identify high-risk patients, particularly biologic factors that might ultimately be amenable to intervention. Using whole-exome sequencing data from 51 newly diagnosed and immunochemotherapy-treated DLBCL patients, we evaluated the association of somatic genomic alterations with patient outcome, defined as failure to achieve event-free survival at 24 months after diagnosis (EFS24). We identified 16 genes with mutations, 374 with copy number gains and 151 with copy number losses that were associated with failure to achieve EFS24 (P <0.05). Except for FOXO1 and CIITA, known driver mutations did not correlate with EFS24. Gene losses were localized to 6q21-6q24.2, and gains to 3q13.12-3q29, 11q23.1-11q23.3 and 19q13.12-19q13.43. Globally, the number of gains was highly associated with poor outcome (P = 7.4 10-12) and when combined with FOXO1 mutations identified 77% of cases that failed to achieve EFS24. One gene (SLC22A16) at 6q21, a doxorubicin transporter, was lost in 54% of EFS24 failures and our findings suggest it functions as a doxorubicin transporter in DLBCL cells.

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