Unraveling the genomic underpinnings of unbalanced MYC break-apart FISH results using whole genome sequencing analysis

This is the authors' abstract. We don't add key points for this paper.

MYC rearrangements ( MYC -R) constitute an integral defining feature in the diagnostic classification of mature aggressive B-cell lymphoma (BCL) [ 1 , 2 , 3 ]. Specifically, diffuse large B-cell lymphoma (DLBCL)/high-grade B-cell lymphoma (HGBCL) with MYC and BCL2 rearrangements (and/or BCL6 rearrangements) circumscribe a subset of higher-risk tumors. Current guidelines recommend investigating MYC -R with fluorescence in situ hybridization (FISH) [ 4 ]. In accordance with the diversity of rearrangement partners including immunoglobin (IG) and non-IG partners and the variability of breakpoints in the MYC locus, a break-apart (BAP) FISH probe is commonly utilized. Dual-color dual-fusion FISH probes (D-FISH) spanning MYC and IGH, IG-lambda (IGL) or IG-kappa (IGK) may also be used. We have previously demonstrated that in suspected HGBCL unbalanced rearrangements are identified in 11.9% of cases with abnormal results with the MYC BAP probe. In approximately 8.5% of cases, these cannot be reconciled with IGH/ MYC D-FISH results and remain of ambiguous significance [ 5 ]. Forty-three percent of unbalanced cases also harbor a concurrent BCL2 rearrangement (unpublished data), thereby emphasizing the importance of informed interpretation of results for accurate diagnostic classification and therapeutic management. In this study, we sought to elucidate the significance of these unbalanced rearrangements with whole genome sequencing (WGS) analysis.