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

Research output: Contribution to journalArticlepeer-review


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 languageEnglish
Pages (from-to)1329–1341
Number of pages13
Early online date16 Dec 2019
Publication statusPublished - 1 May 2020

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© The Author(s) 2019.

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