Distinct genetic changes reveal evolutionary history and heterogeneous molecular grade of DLBCL with MYC/BCL2 double-hit.
Authors
Cucco, Francesco
Barrans, Sharon
Sha, Chulin
Clipson, Alexandra
Crouch, Simon
Dobson, Rachel
Chen, Zi
Thompson, Joe Sneath
Care, Matthew A
Cummin, Thomas
Caddy, Josh
Liu, Hongxiang
Robinson, Anne
Schuh, Anna
Fitzgibbon, Jude
Painter, Daniel
Smith, Alexandra
Roman, Eve
Tooze, Reuben
Burton, Catherine
Davies, Andrew J
Johnson, Peter WM
Du, Ming-Qing
Publication Date
2020-05Journal Title
Leukemia
ISSN
0887-6924
Publisher
Springer Science and Business Media LLC
Volume
34
Issue
5
Pages
1329-1341
Language
eng
Type
Article
This Version
VoR
Physical Medium
Print-Electronic
Metadata
Show full item recordCitation
Cucco, F., Barrans, S., Sha, C., Clipson, A., Crouch, S., Dobson, R., Chen, Z., et al. (2020). Distinct genetic changes reveal evolutionary history and heterogeneous molecular grade of DLBCL with MYC/BCL2 double-hit.. Leukemia, 34 (5), 1329-1341. https://doi.org/10.1038/s41375-019-0691-6
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.
Keywords
Humans, Translocation, Genetic, Proto-Oncogene Proteins c-myc, Proto-Oncogene Proteins c-bcl-2, Prognosis, Survival Rate, Gene Expression Profiling, Gene Expression Regulation, Leukemic, Gene Rearrangement, Phenotype, Mutation, Middle Aged, Female, Male, Lymphoma, Large B-Cell, Diffuse, Clonal Evolution, Biomarkers, Tumor
Sponsorship
Bloodwise (via University of Southampton) (515010)
Bloodwise (15019)
Embargo Lift Date
2100-01-01
Identifiers
External DOI: https://doi.org/10.1038/s41375-019-0691-6
This record's URL: https://www.repository.cam.ac.uk/handle/1810/299198
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