Non-IG::MYC in diffuse large B-cell lymphoma confers variable genomic configurations and MYC transactivation potential-Reference-Cited by-同舟云学术

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

Published:2023-10-09 Issue: Volume: Page:
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Author:

Du Ming-Qing¹^ORCID,Zhang Chunye²,Stelloo Ellen³,Barrans Sharon⁴,Cucco Francesco⁵,Jiang Dan⁶,Tzioni Maria-Myrsini⁷,Chen Zi²,Li Yan⁷,Swennenhuis Joost F³,Makker Jasmine⁸,Raso-Barnett Livia⁹,Liu Hongxiang¹⁰,daly Hesham El¹¹,Soilleux Elizabeth¹²,Shah Nimish¹³,Nagumantry Sateesh Kumar¹⁴,Kyaw Maw¹⁵,Prahladan Mahesh Panatt¹⁶,Tooze Reuben¹⁷^ORCID,Westhead David¹⁷^ORCID,Feitsma Harma¹⁸,Davies Andrew¹⁹,Burton Catherine²⁰,Johnson Peter²¹^ORCID

Affiliation:

1. Division of Cellular and Molecular Pathology, Department of Pathology, University of Cambridge, Cambridge

2. University of Cambridge

3. Cergentis BV,

4. St James's University Hospital

5. Univeristy of Cambridge

6. Cambridge University Hospitals NHS Foundation Trust,

7. Division of Cellular and Molecular Pathology, Department of Pathology, University of Cambridge

8. University of Cambridg

9. Addenbrooke's Hospital

10. Addenbrooke's Hospital, Cambridge University Hospitals NHS Foundation Trust

11. University Hospitals Coventry and Warwickshire NHS Trust,

12. University of Cambridge, C

13. Derriford Hospital

14. Peterborough City Hospital,

15. James Paget University Hospitals NHS Foundation Trust

16. East Suffolk and North Essex Foundation Trust

17. University of Leeds

18. Cergentis

19. Cancer Research UK Centre, Cancer Sciences Unit, University of Southampton Faculty of Medicine, Southampton General Hospital

20. St James’ University Hospital

21. University of Southampton

Abstract

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.

Publisher

Research Square Platform LLC

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