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Non-IG::MYC in diffuse large B-cell lymphoma confers variable genomic configurations and MYC transactivation potential.

Accepted version
Peer-reviewed

Type

Article

Change log

Authors

Zhang, Chunye 
Stelloo, Ellen 
Barrans, Sharon 
Cucco, Francesco 
Jiang, Dan 

Abstract

MYC translocation occurs in 8-14% of diffuse large B-cell lymphoma (DLBCL), and may concur with BCL2 and/or BCL6 translocation, known as double-hit (DH) or triple-hit (TH). DLBCL-MYC/BCL2-DH/TH are largely germinal centre B-cell like subtype, but show variable clinical outcome, with IG::MYC fusion significantly associated with inferior survival. While DLBCL-MYC/BCL6-DH are variable in their cell-of-origin subtypes and clinical outcome. Intriguingly, only 40-50% of DLBCL with MYC translocation show high MYC protein expression (>70%). We studied 186 DLBCLs with MYC translocation including 32 MYC/BCL2/BCL6-TH, 75 MYC/BCL2-DH and 26 MYC/BCL6-DH. FISH revealed a MYC/BCL6 fusion in 59% of DLBCL-MYC/BCL2/BCL6-TH and 27% of DLBCL-MYC/BCL6-DH. Targeted NGS showed a similar mutation profile and LymphGen genetic subtype between DLBCL-MYC/BCL2/BCL6-TH and DLBCL-MYC/BCL2-DH, but variable LymphGen subtypes among DLBCL-MYC/BCL6-DH. MYC protein expression is uniformly high in DLBCL with IG::MYC, but variable in those with non-IG::MYC including MYC/BCL6-fusion. Translocation breakpoint analyses of 8 cases by TLC-based NGS showed no obvious genomic configuration that enables MYC transactivation in 3 of the 4 cases with non-IG::MYC, while a typical promoter substitution or IGH super enhancer juxtaposition in the remaining cases. The findings potentially explain variable MYC expression in DLBCL with MYC translocation, and also bear practical implications in its routine assessment.

Description

Keywords

32 Biomedical and Clinical Sciences, 3201 Cardiovascular Medicine and Haematology, 3211 Oncology and Carcinogenesis, Biotechnology, Lymphoma, Cancer, Hematology, Genetics, Rare Diseases, 2.1 Biological and endogenous factors, 2 Aetiology

Journal Title

Leukemia

Conference Name

Journal ISSN

0887-6924
1476-5551

Volume Title

Publisher

Springer Science and Business Media LLC
Sponsorship
Cancer Research UK (C8333/A29707)
Blood Cancer UK (19010)
Bloodwise (via University of Southampton) (19011 519781101)
Biotechnology and Biological Sciences Research Council (BB/M011194/1)
Blood Cancer UK; BBSRC DTP PhD studentship