High-resolution architecture and partner genes of rearrangements in lymphoma with DLBCL morphology.

Genomic rearrangements in the locus occur in ∼12% of lymphomas with diffuse large B-cell lymphoma (DLBCL) morphology and are associated with inferior outcome. Previous studies exploring rearrangements have primarily used fluorescence in situ hybridization (FISH) assays to characterize break-apart status but have rarely examined breakpoint location, and in some cases have not examined partner identity. We performed targeted sequencing of , , , and the immunoglobulin () loci in 112 tumors with DLBCL morphology harboring rearrangement. We characterized the location of the rearrangement at base pair resolution and identified the partner in 88 cases. We observed a cluster of breakpoints upstream of the coding region and in intron 1 (the "genic cluster"). Genic cluster rearrangements were enriched for translocations involving (80%), whereas nongenic rearrangements occurred mostly downstream of the gene with a variety of partners, including and Other recurrent partners included , , and , which has not previously been described as a partner. We compared 2 commercially available FISH break-apart assays for the locus and observed discordant results in 32% of cases examined, including some with - and - rearrangements. In cases of high-grade B-cell lymphoma with and and/or rearrangement (HGBL-DH), so-called "double-hit" lymphomas, the majority of rearrangements had non- partners (65%), with breakpoints outside the genic cluster (72%). In patients with de novo HGBL-DH of DLBCL morphology, - rearrangements showed a trend toward inferior time to progression and overall survival compared with -non- rearrangements. Our data reveal clinically relevant architecture of rearrangements in lymphomas with DLBCL morphology.