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

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.

SUBMITTER: Hilton LK

PROVIDER: S-EPMC6839951 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Double hit lymphomas (DHL) and double expresser lymphomas (DEL) are subsets of diffuse large B cell lymphomas (DLBCL) which are being increasingly recognised as cause of treatment failure. This emphasizes the need for their separation from other DLBCL cases in order to prognosticate and administer more aggressive treatment to this set of patients. The present study was conducted with the aim to identify the DHL/DEL patients and study their distinctive clinicopathological profile and overall survival. This retrospective analysis involved 172 cases of DLBCL sub-classified on the basis of cell of origin. Immunohistochemical (IHC) analysis for MYC, BCL2, BCL6, MUM1 and CD10 was performed. Rearrangement studies were performed using break apart Fluorescent in situ hybridization. Overall survival (OS) was also evaluated. Distinctive clinical and pathological features of DHL and DEL were identified. Rearrangement study by FISH revealed seven cases of DHL (MYC + BCL2 &/or BCL6 rearrangement). Also, 20 patients (11.6%) showed a concurrent expression of BCL2 and MYC oncoproteins (DEL) on IHC. Most (6/7) DHL patients were double expressors also. The DHL patients demonstrated a significant association with female gender, high serum LDH levels (> 750 U/L) and GCB phenotype. DEL patients contrarily predominated amongst males, had intermediate LDH levels (251-500 U/L) and non GCB phenotype. The OS of the patients was 63.8% at 4 years. The OS of the DLBCL, DEL and DHL patients was 71.9%, 46.9%, and 0%, respectively at 4 years (p value 0.010). In case of DEL subtype, factors such as age < 60 years (66.7%), male sex (60.8%), nodal localization (52.5%), early disease stage (84.6%), low IPI score (60%), absence of B symptoms (50%), LDH < 250 U/L (80%) and GCB phenotype (53.3%) were associated with better OS. Further, the OS of DHL cases was 0% at 4 years. Double hit and double expresser lymphomas have poor prognostic outcomes and should be separated from DLBCL. All DELs should be tested for DHLs and especially those with immunoblastic morphology. DHL and DEL subtypes delineate the subtypes with inferior OS and reinstate the need for aggressive interventions.

Project description:BACKGROUND:The poor outcome of high-grade B-cell lymphoma, with rearrangements of MYC, BCL2 and/or BCL6, also known as double-hit lymphoma or triple-hit lymphoma (DHL or THL), has been well documented, while the clinical significance of extra copies of MYC, BCL2 or BCL6 are still less well known. METHODS:In total, 130 cases of diffuse large B-cell lymphoma, not otherwise specified (DLBCL-NOS) were included in our study. Fluorescence in situ hybridization and immunohistochemistry were performed in all cases to evaluate the genetic status and protein expression levels of MYC, BCL2 and BCL6. RESULTS:Among the 130 cases of DLBCL, the prevalence rates of extra copies of MYC, BCL2 and BCL6 were 10.8, 20.0 and 14.6%, respectively, and the corresponding rates of gene rearrangement were 10.0, 14.6 and 16.9%, respectively. In total, 7.7% (10/130) of patients were DHL/THL; 9.2% (12/130) of patients were DLBCL with MYC and BCL2 and/or BCL6 gene abnormalities including rearrangements or extra copies, while excluded DHL/THL. The positive protein expression rates of MYC, BCL2 and BCL6 were 46.9% (61), 75.4% (98) and 70.0% (91), respectively. Among the 51 cases with MYC/BCL2 co-expression, 14 cases showed concurrence of MYC, BCL2 and/or BCL6 genetic abnormalities, and the remaining 37 cases were classified as double-expressor lymphoma (DEL). MYC and BCL2 rearrangement and BCL2 extra copies were all associated with upregulated protein expression. Cases with concurrence of MYC, BCL2 and/or BCL6 genetic abnormalities were both associated with MYC/BCL2 co-expression. Patients with concurrence of MYC, BCL2 and/or BCL6 genetic abnormalities excluded DHL/THL had shorter OS (P?<?0.001) than patients with DLBCL with no genetic change, and showed no statistical different with patients with DHL/THL (P?=?0.419). Extra copies of MYC was independent prognostic factors for DLBCL. CONCLUSIONS:Patients with MYC and BCL2 and/or BCL6 gene extra copies might show a trend towards poor prognosis, and the detection of extra copies of MYC, BCL2 and BCL6 might deserve more attention.

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

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