Deletion 20q12 is associated with histological transformation of nodal marginal zone lymphoma to diffuse large B‐cell lymphoma

Abstract

The genetic and molecular abnormalities underlying histological transformation (HT) of nodal marginal zone lymphoma (NMZL) to diffuse large B-cell lymphoma (DLBCL) are not well known. While del(20q12) is commonly deleted in myelodysplastic syndrome it has not previously been associated with DLBCL. We recently described a case of DLBCL harboring del(20q12) in a patient with a history of MZL involving lymph nodes and skin. Here we report eight matched cases of transformed MZL(tMZL): six from nodal MZL (tNMZL) and two from splenic MZL (tSMZL). We found >20% del(20q12) in 4/6 tNMZL, but not in tSMZL, nor in unmatched DLBCL, MZL with increased large cells (MZL-ILC), or MZL cases. To examine whether transformation is associated with a specific gene signature, the matched cases were analyzed for multiplexed gene expression using the Nanostring PanCancer Pathways panel. The differential gene expression signature revealed enrichment of inflammatory markers, as previously observed in MZL. Also, tMZL and de novo DLBCL were enriched for extracellular matrix proteins such as collagen and fibronectin, vascular development protein PDGFRβ, DNA repair protein RAD51, and oncogenic secrete protein Wnt11. A subset of genes is expressed differentially in del(20q12) tMZL cases vs non-del(20q12) tMZL cases. These results suggest a specific pathway is involved in the histological transformation of NMZL, which could serve as an indicator of aggressive clinical course in this otherwise indolent neoplasm.

The genetic landscape of histologically transformed marginal zone lymphomas

“…Although MYC rearrangement has rarely been reported, 3,34 we observed one HT-MZL with MYC rearrangement. A unique feature of transformed NMZLs is the 20q12 deletion reported in six of eight DLBCLs transformed from NMZLs [10][11][12] ; nevertheless, three transformed NMZLs investigated by FISH were negative for the 20q12 deletion in our study. Of these three cases, two sequenced cases harbored pathogenic/likely pathogenic mutations in CCND3 and TBL1XR1, suggesting that alternative oncogenic mutations may contribute to the transformation of NMZL.…”

“…HT-MZLs with TBL1XR1 mutations (median, 8.5; range, 4.0-32.0) displayed a numerically but not statistically significant higher number of somatic mutations than HT-MZLs without TBL1XR1 mutations (median, 6.0; range 2.0-14.0; Figure 4B). Deletion 20q12, reported as an indicator of HT of NMZL, [10][11][12] was investigated by FISH in the samples of three NMZLs but was not detected.…”

“…[3][4][5] Epstein-Barr virus infection, 6 BCL6 rearrangement or protein overexpression, 7 and CXCR5 and FOXP1 expression 8 have also been associated with HT. At the genetic level, NOTCH2 and TNFAIP3 mutations and a high degree of genomewide DNA promoter methylation in SMZLs, 9 deletion 20q12 in NMZLs, [10][11][12] and translocation involving t (3;14) and inactivation of TP53 or CDKN2A in EMZLs 13 are all considered potential indicators of HT in MZL. Although multiple studies have revealed HT-associated features of MZLs in all aspects, findings remain inconclusive.…”