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Distinct genetic changes reveal evolutionary history and heterogeneous molecular grade of DLBCL with MYC/BCL2 double-hit

Distinct genetic changes reveal evolutionary history and heterogeneous molecular grade of DLBCL with MYC/BCL2 double-hit
Distinct genetic changes reveal evolutionary history and heterogeneous molecular grade of DLBCL with MYC/BCL2 double-hit
Using a Burkitt lymphoma-like gene expression signature, we recently defined a high-risk molecular high-grade (MHG) group mainly within germinal centre B-cell like diffuse large B-cell lymphomas (GCB-DLBCL), which was enriched for MYC/BCL2 double-hit (MYC/BCL2-DH). The genetic basis underlying MHG-DLBCL and their aggressive clinical behaviour remain unknown. We investigated 697 cases of DLBCL, particularly those with MYC/BCL2-DH (n = 62) by targeted sequencing and gene expression profiling. We showed that DLBCL with MYC/BCL2-DH, and those with BCL2 translocation, harbour the characteristic mutation signatures that are associated with follicular lymphoma and its high-grade transformation. We identified frequent MYC hotspot mutations that affect the phosphorylation site (T58) and its adjacent amino acids, which are important for MYC protein degradation. These MYC mutations were seen in a subset of cases with MYC translocation, but predominantly in those of MHG. The mutations were more frequent in double-hit lymphomas with IG as the MYC translocation partner, and were associated with higher MYC protein expression and poor patient survival. DLBCL with MYC/BCL2-DH and those with BCL2 translocation alone are most likely derived from follicular lymphoma or its precursor lesion, and acquisition of MYC pathogenic mutations may augment MYC function, resulting in aggressive clinical behaviour.
0887-6924
Cucco, Francesco
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Barrans, Sharon
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Clipson, Alexandra
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Sha, Chulin
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Crouch, Simon
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Dobson, Rachel
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Chen, Zi
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Sneath Thompson, Joe
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Care, Matthew
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Cummin, Thomas EC
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Caddy, Joshua
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Robinson, Anne
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Schuh, Anna
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Fitzgibbon, Jude
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Smith, Alexandra
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Roman, Eve
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Davies, Andrew
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Westhead, David
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Johnson, Peter
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Du, Ming-Qing
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Cucco, Francesco
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Barrans, Sharon
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Clipson, Alexandra
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Sha, Chulin
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Crouch, Simon
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Dobson, Rachel
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Chen, Zi
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Sneath Thompson, Joe
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Care, Matthew
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Cummin, Thomas EC
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Caddy, Joshua
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Liu, Hongxiang
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Robinson, Anne
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Schuh, Anna
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Fitzgibbon, Jude
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Painter, Daniel
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Smith, Alexandra
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Roman, Eve
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Tooze, Reuben
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Burton, Catherine
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Davies, Andrew
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Westhead, David
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Johnson, Peter
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Du, Ming-Qing
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Cucco, Francesco, Barrans, Sharon, Clipson, Alexandra, Sha, Chulin, Crouch, Simon, Dobson, Rachel, Chen, Zi, Sneath Thompson, Joe, Care, Matthew, Cummin, Thomas EC, Caddy, Joshua, Liu, Hongxiang, Robinson, Anne, Schuh, Anna, Fitzgibbon, Jude, Painter, Daniel, Smith, Alexandra, Roman, Eve, Tooze, Reuben, Burton, Catherine, Davies, Andrew, Westhead, David, Johnson, Peter and Du, Ming-Qing (2019) Distinct genetic changes reveal evolutionary history and heterogeneous molecular grade of DLBCL with MYC/BCL2 double-hit. Leukemia. (doi:10.1038/s41375-019-0691-6).

Record type: Article

Abstract

Using a Burkitt lymphoma-like gene expression signature, we recently defined a high-risk molecular high-grade (MHG) group mainly within germinal centre B-cell like diffuse large B-cell lymphomas (GCB-DLBCL), which was enriched for MYC/BCL2 double-hit (MYC/BCL2-DH). The genetic basis underlying MHG-DLBCL and their aggressive clinical behaviour remain unknown. We investigated 697 cases of DLBCL, particularly those with MYC/BCL2-DH (n = 62) by targeted sequencing and gene expression profiling. We showed that DLBCL with MYC/BCL2-DH, and those with BCL2 translocation, harbour the characteristic mutation signatures that are associated with follicular lymphoma and its high-grade transformation. We identified frequent MYC hotspot mutations that affect the phosphorylation site (T58) and its adjacent amino acids, which are important for MYC protein degradation. These MYC mutations were seen in a subset of cases with MYC translocation, but predominantly in those of MHG. The mutations were more frequent in double-hit lymphomas with IG as the MYC translocation partner, and were associated with higher MYC protein expression and poor patient survival. DLBCL with MYC/BCL2-DH and those with BCL2 translocation alone are most likely derived from follicular lymphoma or its precursor lesion, and acquisition of MYC pathogenic mutations may augment MYC function, resulting in aggressive clinical behaviour.

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DLBCL-MYC mutation_ Leukemia Accepted version - Accepted Manuscript
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DLBCL_MYC mutation_Leukemia_2019 - Version of Record
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Accepted/In Press date: 6 December 2019
Published date: 16 December 2019

Identifiers

Local EPrints ID: 436718
URI: http://eprints.soton.ac.uk/id/eprint/436718
ISSN: 0887-6924
PURE UUID: 40e5c6b6-2b85-4f52-b497-cdd18cc6599a
ORCID for Andrew Davies: ORCID iD orcid.org/0000-0002-7517-6938
ORCID for Peter Johnson: ORCID iD orcid.org/0000-0003-2306-4974

Catalogue record

Date deposited: 03 Jan 2020 11:03
Last modified: 26 Nov 2021 07:14

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Contributors

Author: Francesco Cucco
Author: Sharon Barrans
Author: Alexandra Clipson
Author: Chulin Sha
Author: Simon Crouch
Author: Rachel Dobson
Author: Zi Chen
Author: Joe Sneath Thompson
Author: Matthew Care
Author: Thomas EC Cummin
Author: Joshua Caddy
Author: Hongxiang Liu
Author: Anne Robinson
Author: Anna Schuh
Author: Jude Fitzgibbon
Author: Daniel Painter
Author: Alexandra Smith
Author: Eve Roman
Author: Reuben Tooze
Author: Catherine Burton
Author: Andrew Davies ORCID iD
Author: David Westhead
Author: Peter Johnson ORCID iD
Author: Ming-Qing Du

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