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.

<p>High-Grade B-Cell Lymphomas, Not Otherwise Specified: A Study of 41 Cases</p>

“…Although MYC gene rearrangement is a characteristic of BL, it can also be found in the DLBCL and the BCLU. 21 HGBL, DH/TH usually progresses more rapidly, is resistant to R-CHOP chemoimmunotherapy, 6 and the mean OS fluctuates between 5 months and 2 years. 22,23 In our study the median OS of HGBL, NOS was 18.0 months.…”

“…For IHC, the positivity cutoff values were 40% for MYC and 50% for BCL-2. 6,9 Lymphomas that do not harbor MYC and BCL2 and/or BCL6 rearrangements but exhibit the MYC and BCL2/BCL6 protein expression are known as double-expressor lymphoma (DEL). 10,11 HGBL, NOS with MYC rearrangement have been defined as single-hit lymphomas (SHL) in this study.…”

“…[1][2][3][4][5] HGBL, R is also called a double/triple-hit lymphoma (HGBL, DH/TH). 6 HGBL, NOS do not contain MYC and BCL2 or BCL6 gene rearrangements, but present morphologies between DLBCL and BL.…”

“…Although the pathological features and clinical characteristics of patients with HGBL, DH/TH have been well characterized in the literature, 5,6 few studies have focused on patients with HGBL, NOS. We retrospectively analyzed a group of patients with HGBL, NOS and summarized the clinical and the pathological features, and explored the patient diagnosis, treatment, and prognosis.…”

Clinical Interest of LMO2 Testing for the Diagnosis of Aggressive Large B-Cell Lymphomas

“…Cryptic rearrangements of MYC have been recently identified in cases of DLBCL with unfavorable prognosis. Those cases shared similar gene expression profile like HGBL-DH/TH and were not recognized by conventional FISH methods [10]. Thus, the global incidence of MYC rearrangements in large B-cell lymphomas (LBCL) being low, it is necessary to clarify whether FISH or other methods have to be applied to all LBCL or just in selected cases.…”