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

Francesco  Cucco; Sharon Barrans; Sha Chulin; Alexandra Clipson; Simon Crouch; Rachel  Dobson; Zi  Chen; Joe Sneath  Thompson; Matthew A Care; Thomas  Cummin; Josh  Caddy; Hongxiang Liu; Anne  Robinson; Anna  Schuh; Jude  Fitzgibbon; Daniel Edwin Painter; Alexandra Gwen Smith; Eve Roman; Reuben Tooze; Catherine Burton; Andrew J.  Davies; David R Westhead; Peter W M Johnson; Ming-Qing Du

doi:10.1038/s41375-019-0691-6

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

Francesco Cucco, Sharon Barrans, Sha Chulin, Alexandra Clipson, Simon Crouch, Rachel Dobson, Zi Chen, Joe Sneath Thompson, Matthew A Care, Thomas Cummin, Josh Caddy, Hongxiang Liu, Anne Robinson, Anna Schuh, Jude Fitzgibbon, Daniel Edwin Painter, Alexandra Gwen Smith, Eve Roman, Reuben Tooze, Catherine BurtonAndrew J. Davies, David R Westhead, Peter W M Johnson, Ming-Qing Du

Health Sciences

Research output: Contribution to journal › Article › peer-review

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.

Original language	English
Pages (from-to)	1329–1341
Number of pages	13
Journal	Leukemia
Volume	34
Early online date	16 Dec 2019
DOIs	https://doi.org/10.1038/s41375-019-0691-6
Publication status	Published - 1 May 2020

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10.1038/s41375-019-0691-6

s41375-019-0691-6
© The Author(s) 2019.
Final published version, 2.23 MBLicence: CC BY

Alex Smith
- alexandra.smithyork.acuk
- Health Sciences - Professor
Person: Research

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Cucco, F., Barrans, S., Chulin, S., Clipson, A., Crouch, S., Dobson, R., Chen, Z., Thompson, J. S., Care, M. A., Cummin, T., Caddy, J., Liu, H., Robinson, A., Schuh, A., Fitzgibbon, J., Painter, D. E., Smith, A. G., Roman, E., Tooze, R., ... Du, M.-Q. (2020). Distinct genetic changes reveal evolutionary history and heterogeneous molecular grade of DLBCL with MYC/BCL2 double-hit. Leukemia, 34, 1329–1341. https://doi.org/10.1038/s41375-019-0691-6

@article{b4f5633a9c9f43e2a572b3d30f2e500f,

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

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 forMYC/BCL2 double-hit (MYC/BCL2-DH). The genetic basis underlying MHG-DLBCL and their aggressive clinicalbehaviour remain unknown. We investigated 697 cases of DLBCL, particularly those with MYC/BCL2-DH (n = 62) bytargeted sequencing and gene expression profiling. We showed that DLBCL with MYC/BCL2-DH, and those with BCL2translocation, harbour the characteristic mutation signatures that are associated with follicular lymphoma and its high-gradetransformation. We identified frequent MYC hotspot mutations that affect the phosphorylation site (T58) and its adjacentamino acids, which are important for MYC protein degradation. These MYC mutations were seen in a subset of cases withMYC translocation, but predominantly in those of MHG. The mutations were more frequent in double-hit lymphomas withIG 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 orits precursor lesion, and acquisition of MYC pathogenic mutations may augment MYC function, resulting in aggressiveclinical behaviour.",

author = "Francesco Cucco and Sharon Barrans and Sha Chulin and Alexandra Clipson and Simon Crouch and Rachel Dobson and Zi Chen and Thompson, {Joe Sneath} and Care, {Matthew A} and Thomas Cummin and Josh Caddy and Hongxiang Liu and Anne Robinson and Anna Schuh and Jude Fitzgibbon and Painter, {Daniel Edwin} and Smith, {Alexandra Gwen} and Eve Roman and Reuben Tooze and Catherine Burton and Davies, {Andrew J.} and Westhead, {David R} and Johnson, {Peter W M} and Ming-Qing Du",

note = "{\textcopyright} The Author(s) 2019.",

year = "2020",

month = may,

day = "1",

doi = "10.1038/s41375-019-0691-6",

language = "English",

volume = "34",

pages = "1329–1341",

journal = "Leukemia",

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Cucco, F, Barrans, S, Chulin, S, Clipson, A, Crouch, S, Dobson, R, Chen, Z, Thompson, JS, Care, MA, Cummin, T, Caddy, J, Liu, H, Robinson, A, Schuh, A, Fitzgibbon, J, Painter, DE , Smith, AG , Roman, E, Tooze, R, Burton, C, Davies, AJ, Westhead, DR, Johnson, PWM & Du, M-Q 2020, 'Distinct genetic changes reveal evolutionary history and heterogeneous molecular grade of DLBCL with MYC/BCL2 double-hit', Leukemia, vol. 34, pp. 1329–1341. https://doi.org/10.1038/s41375-019-0691-6

TY - JOUR

T1 - Distinct genetic changes reveal evolutionary history and heterogeneous molecular grade of DLBCL with MYC/BCL2 double-hit

AU - Cucco, Francesco

AU - Barrans, Sharon

AU - Chulin, Sha

AU - Clipson, Alexandra

AU - Crouch, Simon

AU - Dobson, Rachel

AU - Chen, Zi

AU - Thompson, Joe Sneath

AU - Care, Matthew A

AU - Cummin, Thomas

AU - Caddy, Josh

AU - Liu, Hongxiang

AU - Robinson, Anne

AU - Schuh, Anna

AU - Fitzgibbon, Jude

AU - Painter, Daniel Edwin

AU - Smith, Alexandra Gwen

AU - Roman, Eve

AU - Tooze, Reuben

AU - Burton, Catherine

AU - Davies, Andrew J.

AU - Westhead, David R

AU - Johnson, Peter W M

AU - Du, Ming-Qing

PY - 2020/5/1

Y1 - 2020/5/1

N2 - 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 forMYC/BCL2 double-hit (MYC/BCL2-DH). The genetic basis underlying MHG-DLBCL and their aggressive clinicalbehaviour remain unknown. We investigated 697 cases of DLBCL, particularly those with MYC/BCL2-DH (n = 62) bytargeted sequencing and gene expression profiling. We showed that DLBCL with MYC/BCL2-DH, and those with BCL2translocation, harbour the characteristic mutation signatures that are associated with follicular lymphoma and its high-gradetransformation. We identified frequent MYC hotspot mutations that affect the phosphorylation site (T58) and its adjacentamino acids, which are important for MYC protein degradation. These MYC mutations were seen in a subset of cases withMYC translocation, but predominantly in those of MHG. The mutations were more frequent in double-hit lymphomas withIG 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 orits precursor lesion, and acquisition of MYC pathogenic mutations may augment MYC function, resulting in aggressiveclinical behaviour.

AB - 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 forMYC/BCL2 double-hit (MYC/BCL2-DH). The genetic basis underlying MHG-DLBCL and their aggressive clinicalbehaviour remain unknown. We investigated 697 cases of DLBCL, particularly those with MYC/BCL2-DH (n = 62) bytargeted sequencing and gene expression profiling. We showed that DLBCL with MYC/BCL2-DH, and those with BCL2translocation, harbour the characteristic mutation signatures that are associated with follicular lymphoma and its high-gradetransformation. We identified frequent MYC hotspot mutations that affect the phosphorylation site (T58) and its adjacentamino acids, which are important for MYC protein degradation. These MYC mutations were seen in a subset of cases withMYC translocation, but predominantly in those of MHG. The mutations were more frequent in double-hit lymphomas withIG 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 orits precursor lesion, and acquisition of MYC pathogenic mutations may augment MYC function, resulting in aggressiveclinical behaviour.

U2 - 10.1038/s41375-019-0691-6

DO - 10.1038/s41375-019-0691-6

M3 - Article

SN - 0887-6924

VL - 34

SP - 1329

EP - 1341

JO - Leukemia

JF - Leukemia

ER -

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

Abstract

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Alex Smith

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