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 and may miss rearrangements with clinical significance. 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. Hi-C detected topological differences between malignant B cell and plasma cell states and identified expected oncogene rearrangements with high concordance with FISH. Hi-C revealed enhancer-hijacking in recurrent rearrangements of BCL2, CCND1, and MYC, as well as unanticipated variants involving homologous loci. Hi-C identified other unanticipated non-coding rearrangements at loci of potential therapeutic relevance, distinguished between distinct classes of BCL6 rearrangements, and provided topological information supporting the interpretation of MYC rearrangements. In biopsies lacking MYC-activating rearrangements, Hi-C revealed differential interactions with disease-specific native MYC locus enhancers. FFPE-compatible Hi-C detects oncogene rearrangements and their topological consequences at genome-wide scale, enabling the identification of drivers that may otherwise be missed. ### Competing Interest Statement M.S. is scientific advisor and shareholder of Heidelberg Epignostix and Halo Dx, and a scientific advisor of Arima Genomics, and InnoSIGN, and received research funding from Lilly USA. A.D.S., J. B. and K.S. are employees of Arima Genomics at the time of manuscript preparation. M.P.A., L.V.M., and S.G. are former employees of Arima Genomics. Other authors declare no conflict of interest.