THE TOPOLOGY OF MYC REARRANGEMENTS IN DOUBLE‐HIT LYMPHOMA IS CONSTRAINED BY THE PRECEDING IGH ‐BCL2 REARRANGEMENT – AN LLMPP PROJECT

Introduction: High-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements (HGBL-DH/TH) are aggressive tumors poor prognosis. In virtually all HGBL-DH/TH-BCL2 tumors, is rearranged to the variable region of IGH locus, which thought occur early in differentiation during RAG-mediated VDJ recombination, leading constitutive overexpression driven by potent Eµ enhancer. We explored topology double-hit lymphomas compared Burkitt (BL) single-hit diffuse large (DLBCL), reveal patterns imposed preceding IGH-BCL2 rearrangement. Methods: identified 112 55 de novo DLBCL break-apart fluorescence situ hybridization, included 96 MYC-rearranged BL as a comparison group. A combination whole genome capture sequencing was used identify MYC, breakpoint sequences. Sequencing data were aligned hg38 bwa-mem, structural variants called using Manta, GRIDSS, Delly. RNAseq quantified Salmon normalized variance stabilizing transformation interrogate expression levels. Results: The sequence recovered 77% tumors. Among over 80% have an partner, less than 10% partnered IGL, IGK, or non-IG loci (Figure 1). contrast, only 35% while 21% IGL 40% partners show that comparable among IG most recurrent partners. Strikingly, IGH-MYC, rearrangement involved previously allele, breakpoints exclusively localized recipient switch regions. This leaves intact enhancer proximity on doubly allele leaving second intact. IGH-MYC breaks equally distributed Sµ (the donor IGHM region) equivalent breakpoints. Keywords: Genomics, Epigenomics, Other -Omics, Aggressive non-Hodgkin lymphoma, Pathology Classification Lymphomas No conflicts interests pertinent abstract.