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Genetic and evolutionary patterns of treatment resistance in relapsed B-cell lymphoma

Genetic and evolutionary patterns of treatment resistance in relapsed B-cell lymphoma
Genetic and evolutionary patterns of treatment resistance in relapsed B-cell lymphoma
Diffuse large B-cell lymphoma (DLBCL) patients are typically treated with immunochemotherapy containing rituximab (rituximab, cyclophosphamide, hydroxydaunorubicin-vincristine (Oncovin), and prednisone [R-CHOP]); however, prognosis is extremely poor if R-CHOP fails. To identify genetic mechanisms contributing to primary or acquired R-CHOP resistance, we performed target-panel sequencing of 135 relapsed/refractory DLBCLs (rrDLBCLs), primarily comprising circulating tumor DNA from patients on clinical trials. Comparison with a metacohort of 1670 diagnostic DLBCLs identified 6 genes significantly enriched for mutations upon relapse. TP53 and KMT2D were mutated in the majority of rrDLBCLs, and these mutations remained clonally persistent throughout treatment in paired diagnostic-relapse samples, suggesting a role in primary treatment resistance. Nonsense and missense mutations affecting MS4A1, which encodes CD20, are exceedingly rare in diagnostic samples but show recurrent patterns of clonal expansion following rituximab-based therapy. MS4A1 missense mutations within the transmembrane domains lead to loss of CD20 in vitro, and patient tumors harboring these mutations lacked CD20 protein expression. In a time series from a patient treated with multiple rounds of therapy, tumor heterogeneity and minor MS4A1-harboring subclones contributed to rapid disease recurrence, with MS4A1 mutations as founding events for these subclones. TP53 and KMT2D mutation status, in combination with other prognostic factors, may be used to identify high-risk patients prior to R-CHOP for posttreatment monitoring. Using liquid biopsies, we show the potential to identify tumors with loss of CD20 surface expression stemming from MS4A1 mutations. Implementation of noninvasive assays to detect such features of acquired treatment resistance may allow timely transition to more effective treatment regimens.
Key points, Kmt2d and tp53 are predominantly mutated in rrdlbcl and remain clonally stable following therapy., Ms4a1 mutations are commonly acquired and undergo clonal expansion following treatment with rituximabcontaining therapy
2473-9529
2886–2898
Rushton, Christopher K.
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Arthur, Sarah E.
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Alcaide, Miguel
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Cheung, Matthew
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Jiang, Aixiang
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Coyle, Krysta M.
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Cleary, Kirstie L.S.
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Thomas, Nicole
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Hilton, Laura K.
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Michaud, Neil
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Daigle, Scott
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Davidson, Jordan
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Bushell, Kevin
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Yu, Stephen
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Rys, Ryan N.
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Marra, Marco A.
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Crump, Michael
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Mann, Koren
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Assouline, Sarit
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Connors, Joseph M.
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Steidl, Christian
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Cragg, Mark
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Scott, David W.
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Johnson, Nathalie A.
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Rushton, Christopher K.
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Arthur, Sarah E.
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Alcaide, Miguel
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Cheung, Matthew
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Jiang, Aixiang
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Coyle, Krysta M.
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Cleary, Kirstie L.S.
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Thomas, Nicole
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Hilton, Laura K.
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Michaud, Neil
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Daigle, Scott
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Davidson, Jordan
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Bushell, Kevin
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Yu, Stephen
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Rys, Ryan N.
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Jain, Michael
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Shepherd, Lois
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Marra, Marco A.
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Kuruvilla, John
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Crump, Michael
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Mann, Koren
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Assouline, Sarit
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Connors, Joseph M.
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Steidl, Christian
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Cragg, Mark
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Scott, David W.
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Johnson, Nathalie A.
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Morin, Ryan D.
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Rushton, Christopher K., Arthur, Sarah E., Alcaide, Miguel, Cheung, Matthew, Jiang, Aixiang, Coyle, Krysta M., Cleary, Kirstie L.S., Thomas, Nicole, Hilton, Laura K., Michaud, Neil, Daigle, Scott, Davidson, Jordan, Bushell, Kevin, Yu, Stephen, Rys, Ryan N., Jain, Michael, Shepherd, Lois, Marra, Marco A., Kuruvilla, John, Crump, Michael, Mann, Koren, Assouline, Sarit, Connors, Joseph M., Steidl, Christian, Cragg, Mark, Scott, David W., Johnson, Nathalie A. and Morin, Ryan D. (2020) Genetic and evolutionary patterns of treatment resistance in relapsed B-cell lymphoma. Blood Advances, 4 (13), 2886–2898. (doi:10.1182/bloodadvances.2020001696).

Record type: Article

Abstract

Diffuse large B-cell lymphoma (DLBCL) patients are typically treated with immunochemotherapy containing rituximab (rituximab, cyclophosphamide, hydroxydaunorubicin-vincristine (Oncovin), and prednisone [R-CHOP]); however, prognosis is extremely poor if R-CHOP fails. To identify genetic mechanisms contributing to primary or acquired R-CHOP resistance, we performed target-panel sequencing of 135 relapsed/refractory DLBCLs (rrDLBCLs), primarily comprising circulating tumor DNA from patients on clinical trials. Comparison with a metacohort of 1670 diagnostic DLBCLs identified 6 genes significantly enriched for mutations upon relapse. TP53 and KMT2D were mutated in the majority of rrDLBCLs, and these mutations remained clonally persistent throughout treatment in paired diagnostic-relapse samples, suggesting a role in primary treatment resistance. Nonsense and missense mutations affecting MS4A1, which encodes CD20, are exceedingly rare in diagnostic samples but show recurrent patterns of clonal expansion following rituximab-based therapy. MS4A1 missense mutations within the transmembrane domains lead to loss of CD20 in vitro, and patient tumors harboring these mutations lacked CD20 protein expression. In a time series from a patient treated with multiple rounds of therapy, tumor heterogeneity and minor MS4A1-harboring subclones contributed to rapid disease recurrence, with MS4A1 mutations as founding events for these subclones. TP53 and KMT2D mutation status, in combination with other prognostic factors, may be used to identify high-risk patients prior to R-CHOP for posttreatment monitoring. Using liquid biopsies, we show the potential to identify tumors with loss of CD20 surface expression stemming from MS4A1 mutations. Implementation of noninvasive assays to detect such features of acquired treatment resistance may allow timely transition to more effective treatment regimens.

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Accepted/In Press date: 14 May 2020
e-pub ahead of print date: 26 June 2020
Published date: 14 July 2020
Keywords: Key points, Kmt2d and tp53 are predominantly mutated in rrdlbcl and remain clonally stable following therapy., Ms4a1 mutations are commonly acquired and undergo clonal expansion following treatment with rituximabcontaining therapy

Identifiers

Local EPrints ID: 441034
URI: http://eprints.soton.ac.uk/id/eprint/441034
ISSN: 2473-9529
PURE UUID: c22c6f33-ec7e-491d-a751-c639e1eab661
ORCID for Mark Cragg: ORCID iD orcid.org/0000-0003-2077-089X

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Date deposited: 28 May 2020 16:30
Last modified: 26 Nov 2021 02:40

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Contributors

Author: Christopher K. Rushton
Author: Sarah E. Arthur
Author: Miguel Alcaide
Author: Matthew Cheung
Author: Aixiang Jiang
Author: Krysta M. Coyle
Author: Kirstie L.S. Cleary
Author: Nicole Thomas
Author: Laura K. Hilton
Author: Neil Michaud
Author: Scott Daigle
Author: Jordan Davidson
Author: Kevin Bushell
Author: Stephen Yu
Author: Ryan N. Rys
Author: Michael Jain
Author: Lois Shepherd
Author: Marco A. Marra
Author: John Kuruvilla
Author: Michael Crump
Author: Koren Mann
Author: Sarit Assouline
Author: Joseph M. Connors
Author: Christian Steidl
Author: Mark Cragg ORCID iD
Author: David W. Scott
Author: Nathalie A. Johnson
Author: Ryan D. Morin

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