Abstract
Double/triple hit lymphoma (DH/TH), known as high-grade B-cell lymphoma (HGBL), is an aggressive diffuse large B cell lymphoma (DLBCL), defined as having concurrent MYC, BCL2, and/or BCL6 gene rearrangements. While gene rearrangements represent significant genetic events in cancer, copy number alterations (CNAs) also play an important role, and their contributions to rearrangements have yet to be fully elucidated. Using FISH and high-resolution CNA data, we defined the landscape of concurrent gene rearrangements and copy gains in MYC, BCL2, and BCL6, in a cohort of 479 newly diagnosed DLBCL. We also show that concurrent translocations and copy number alterations, in combinations similar to DH/TH, identify a unique subset of DLBCL, alternative DH/TH, that have survival outcomes similar to DH/TH DLBCL patients.
Highlights
Introduction Diffuse largeB-cell lymphoma (DLBCL) is the most common aggressive non-Hodgkin lymphoma subtype in Western countries[1,2]
We identified a subset of patients that had concurrent events in MYC and BCL2 and/or BCL6, but a translocation in one gene and a copy number alterations (CNAs) in another, distinguishing a subset of a non-canonically defined Double/triple hit lymphoma (DH/TH)
When excluding double hits” (DH)/TH cases, we found that copy number data provided additional information to the fluorescence in situ hybridization (FISH) results in regards to the genomic status of each gene
Summary
Introduction Diffuse largeB-cell lymphoma (DLBCL) is the most common aggressive non-Hodgkin lymphoma subtype in Western countries[1,2]. Factors that predict DLBCL prognosis include clinical characteristics[3], cell-of-origin (COO)[4,5], MYC translocation status[6,7,8], and genomic alterations[9,10,11]. Concurrent rearrangements of c-MYC and BCL2 and/or BCL6 detected by fluorescence in situ hybridization (FISH), known as “double hits” (DH), occur with a frequency of 6–14%6,12, are associated with transcriptional dysregulation of MYC, and have been correlated with poor prognosis in patients treated with chemotherapy alone or with the addition of rituximab[6,12,13,14]. While translocations in MYC, BCL2, and BCL6 represent significant genomic events in lymphoma, less is known about the contribution of chromosomal copy number alterations (CNAs) in these genes to existing translocations. While the DH/TH cases have concurrent rearrangement events in MYC, BCL2, and BCL6, it is not clear whether an expanded definition could include copy
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