Gene expression identifies DLBCL tumors with BCL2 and MYC translocations detectable by whole genome sequencing but not by break-apart FISH
Additional genetic mechanisms of MYC dysregulation include focal MYC and MIR17HG copy number gains and PVT1 promoter deletions
High-grade B-cell lymphomas with MYC and BCL2 and/or BCL6 rearrangements (HGBL-DH/TH) includes a group of diffuse large B-cell lymphomas with inferior outcomes following standard chemoimmunotherapy. We recently described a gene expression signature that identifies 27% of GCB-DLBCLs as having a double hit-like expression pattern (DHITsig) and inferior outcomes, while only half of those cases have both MYC and BCL2 translocations identifiable using standard break-apart fluorescence in situ hybridization (FISH). Here, 20 DHITsig-positive GCB DLBCLs apparently lacking MYC and/or BCL2 rearrangements were subjected to whole genome sequencing. This revealed six tumors with MYC or BCL2 rearrangements that were cryptic to break-apart FISH. Copy number analysis identified three tumors with MYC and six tumors with MIR17HG gains, both of which may contribute to dysregulation of MYC and its downstream pathways. Focal deletions of the PVT1 promoter were observed exclusively among DHITsig-positive tumors lacking MYC translocations and may also contribute to MYC overexpression. These results highlight that FISH fails to identify all HGBL-DH/TH, while revealing a range of other genetic mechanisms potentially underlying MYC dysregulation in DHITsig positive DLBCL, suggesting that gene expression profiling is more sensitive for identifying the biology underlying poor outcomes within GCB-DLBCL.