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Blood. 2019 Oct 31;134(18):1528-1532. doi: 10.1182/blood.2019002600.

The double-hit signature identifies double-hit diffuse large B-cell lymphoma with genetic events cryptic to FISH.

Author information

1
Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, BC, Canada.
2
BC Cancer Centre for Lymphoid Cancer, BC Cancer Research Centre, Vancouver, BC, Canada.
3
Department of Medicine, University of British Columbia, Vancouver, BC, Canada; and.
4
Genome Sciences Center, British Columbia Cancer Agency, Vancouver, BC, Canada.

Abstract

High-grade B-cell lymphomas with MYC and BCL2 and/or BCL6 rearrangements (HGBL-DH/THs) include a group of diffuse large B-cell lymphomas (DLBCLs) with inferior outcomes after standard chemoimmunotherapy. We recently described a gene expression signature that identifies 27% of germinal center B-cell DLBCLs (GCB-DLBCLs) as having a double-hit-like expression pattern (DHITsig) and inferior outcomes; however, only half of these cases have both MYC and BCL2 translocations identifiable using standard breakapart fluorescence in situ hybridization (FISH). Here, 20 DHITsig+ GCB-DLBCLs apparently lacking MYC and/or BCL2 rearrangements underwent whole-genome sequencing. This revealed 6 tumors with MYC or BCL2 rearrangements that were cryptic to breakapart FISH. Copy-number analysis identified 3 tumors with MYC and 6 tumors with MIR17HG gains or amplifications, both of which may contribute to dysregulation of MYC and its downstream pathways. Focal deletions of the PVT1 promoter were observed exclusively among DHITsig+ tumors lacking MYC translocations; this may also contribute to MYC overexpression. These results highlight that FISH fails to identify all HGBL-DH/THs, while revealing a range of other genetic mechanisms potentially underlying MYC dysregulation in DHITsig+ DLBCL, suggesting that gene expression profiling is more sensitive for identifying the biology underlying poor outcomes in GCB-DLBCL.

PMID:
31527075
DOI:
10.1182/blood.2019002600

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