1. Non-IG::MYC in diffuse large B-cell lymphoma confers variable genomic configurations and MYC transactivation potential
- Author
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Zhang, Chunye, Stelloo, Ellen, Barrans, Sharon, Cucco, Francesco, Jiang, Dan, Tzioni, Maria-Myrsini, Chen, Zi, Li, Yan, Swennenhuis, Joost F., Makker, Jasmine, Rásó-Barnett, Lívia, Liu, Hongxiang, El-Daly, Hesham, Soilleux, Elizabeth, Shah, Nimish, Nagumantry, Sateesh Kumar, Kyaw, Maw, Prahladan, Mahesh Panatt, Tooze, Reuben, Westhead, David R., Feitsma, Harma, Davies, Andrew J., Burton, Catherine, Johnson, Peter W. M., and Du, Ming-Qing
- Abstract
MYCtranslocation occurs in 8–14% of diffuse large B-cell lymphoma (DLBCL), and may concur with BCL2and/or BCL6translocation, 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::MYCfusion 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 MYCtranslocation show high MYC protein expression (>70%). We studied 186 DLBCLs with MYCtranslocation including 32 MYC/BCL2/BCL6-TH, 75 MYC/BCL2-DH and 26 MYC/BCL6-DH. FISH revealed a MYC/BCL6fusion 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::MYCincluding MYC/BCL6-fusion. Translocation breakpoint analyses of 8 cases by TLC-based NGS showed no obvious genomic configuration that enables MYCtransactivation in 3 of the 4 cases with non-IG::MYC, while a typical promoter substitution or IGHsuper enhancer juxtaposition in the remaining cases. The findings potentially explain variable MYC expression in DLBCL with MYCtranslocation, and also bear practical implications in its routine assessment.
- Published
- 2024
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