Hi-C for genome-wide detection of enhancer-hijacking rearrangements in routine lymphoid cancer biopsies

Standard techniques for detecting genomic rearrangements in formalin-fixed paraffin-embedded (FFPE) biopsies have important limitations. We performed FFPE-compatible Hi-C on 44 clinical biopsies comprising large B-cell lymphomas (n=18), plasma cell neoplasms (n=14), and other diverse lymphoid cancers, identifying consistent topological differences between malignant B cell and plasma cell states. Hi-C detected expected oncogene rearrangements at high concordance with fluorescence in-situ hybridization (FISH) and supported enhancer-hijacking in recurrent rearrangements ofBCL2,CCND1, andMYC, plus unanticipated variants involving homologous loci. Hi-C identified unanticipated non-coding rearrangements involving PD-1 ligand genes and other loci of potential therapeutic relevance, distinguished between functionally divergent classes ofBCL6rearrangements, and provided topological information supporting the interpretation of atypicalMYCrearrangements. In biopsies lackingMYC-activating rearrangements, Hi-C revealed differential interactions with functionally-validated disease-specific nativeMYClocus enhancers. FFPE-compatible Hi-C detects oncogene rearrangements and their topological consequences at genome-wide scale, finding clinically-relevant drivers that are missed by standard approaches.