The genetic landscape of histologically transformed marginal zone lymphomas

Abstract Background Marginal zone lymphomas (MZLs) comprise a diverse group of indolent lymphoproliferative disorders; however, some patients develop histologic transformation (HT) with rapid progression to aggressive lymphoma. Methods Forty‐three MZLs with HT (HT‐MZLs), 535 MZLs, and 174 de novo diffuse large B‐cell lymphomas (DLBCLs) without rearrangements of MYC , BCL2 , and BCL6 were collected. Among these, 22 HT‐MZLs, 39 MZLs, and 174 DLBCLs were subjected to 148‐gene targeted exome sequencing. The clinicopathologic features of patients who had HT‐MZL and their genetic alterations were compared with those of patients who had MZLs and DLBCLs. Results All 43 HT‐MZLs corresponded to DLBCLs. No HT‐MZLs harbored BCL2 and MYC and/or BCL6 rearrangements. Bone marrow involvement and higher levels of lactate dehydrogenase were significantly more common in HT‐MZLs than in MZLs. Furthermore, upregulated BCL6, MUM1, C‐MYC, and Ki‐67 expression was observed more frequently in HT‐MZLs than in MZLs. TBL1XR1 was the most frequently altered gene (63.6%) in HT‐MZLs, followed by CCND3 (31.8%), CARD11 , ID3 , and TP53 (22.7%). A trend toward worse progression‐free survival in patients with TBL1XR1 mutations was observed. Compared with MZLs and non–germinal center B‐cell (GCB) type DLBCLs, significantly higher frequencies of TBL1XR1 and ID3 mutations were identified in HT‐MZLs. PIM1 mutations frequently occurred in DLBCLs and were significantly associated with TBL1XR1 mutations but were mutated less in HT‐MZLs that had TBL1XR1 mutations. Conclusions The current findings reveal the clinicopathologic and genetic features of HT‐MZLs, suggesting that these tumors might constitute a group distinct from MZL and de novo non–GCB type DLBCL. TBL1XR1 mutations may be considered a predictor of HT in MZL.