The Genetics of Nodal Marginal Zone Lymphoma

Abstract

Key Points• PTPRD lesions are among the most recurrent alterations in NMZL and appear to be enriched in this lymphoma type across mature B-cell tumors.• NMZL and SMZL genetics overlap with the exceptions of PTPRD lesions, supporting their distinction as independent entities.Nodal marginal zone lymphoma (NMZL) is a rare, indolent B-cell tumor that is distinguished from splenic marginal zone lymphoma (SMZL) by the different pattern of dissemination. NMZL still lacks distinct markers and remains orphan of specific cancer gene lesions. By combining whole-exome sequencing, targeted sequencing of tumor-related genes, wholetranscriptome sequencing, and high-resolution single nucleotide polymorphism array analysis, we aimed at disclosing the pathways that are molecularly deregulated in NMZL and we compare the molecular profile of NMZL with that of SMZL. These analyses identified a distinctive pattern of nonsilent somatic lesions in NMZL. In 35 NMZL patients, 41 genes were found recurrently affected in ‡3 (9%) cases, including highly prevalent molecular lesions of MLL2 (also known as KMT2D; 34%), PTPRD (20%), NOTCH2 (20%), and KLF2 (17%).Mutations of PTPRD, a receptor-type protein tyrosine phosphatase regulating cell growth, were enriched in NMZL across mature B-cell tumors, functionally caused the loss of the phosphatase activity of PTPRD, and were associated with cell-cycle transcriptional program deregulation and increased proliferation index in NMZL. Although NMZL shared with SMZL a common mutation profile, NMZL harbored PTPRD lesions that were otherwise absent in SMZL. Collectively, these findings provide new insights into the genetics of NMZL, identify PTPRD lesions as a novel marker for this lymphoma across mature B-cell tumors, and support the distinction of NMZL as an independent clinicopathologic entity within the current lymphoma classification. (Blood. 2016;128(10):1362-1373

Nodal marginal zone mutational signature

“…These PTPRD mutations functionally cause the loss of PTPRD's phosphatase activity and are associated with deregulation of the cellcycle transcriptional program and an increased proliferation index. 1 This finding, if confirmed by other studies, may facilitate the exploration of the potential heterogeneity of this lymphoma type, reducing the variability in the NMZL diagnosis and eventually making possible a more comprehensive characterization of the molecular alterations driving the growth of this neoplasm.…”

Genetic landscape and deregulated pathways in B‐cell lymphoid malignancies

“…(11%), CARD11 (8%), BIRC3 (6%) and TRAF3 (6%), and is observed in 50% of cases [156]. Apart from these mutations, this WES study also revealed a novel driver mutation involving PTPRD (protein tyrosine phosphatase, receptor type D; 20%), and a high incidence of KTM2D mutation (34%) [156].…”

“…The mutation profile of NMZL as shown by WES is similar to that of SMZL (Table 3). KLF2 mutation is found in 17% of NMZLs [156]. Mutation in the NOTCH signalling pathway involves mainly NOTCH2 (20%), SPEN (11%) and RBPJL (6%), and these mutations are seen overall in 40% of NMZLs, whilst mutation in the NF-jB signalling pathway mainly involves TNFAIP3 (14%), BCL10 Table 3.…”

“…(11%), CARD11 (8%), BIRC3 (6%) and TRAF3 (6%), and is observed in 50% of cases [156]. Apart from these mutations, this WES study also revealed a novel driver mutation involving PTPRD (protein tyrosine phosphatase, receptor type D; 20%), and a high incidence of KTM2D mutation (34%) [156]. PTPRD mutation appears to be enriched in NZML, being absent in other MZL entities; in addition, the mutation inactivates the phosphatase activities and is associated with cell cycle transcriptional programme deregulation and increased proliferation index in NMZL [156].…”

Constitutive Ras signaling and Ink4a/Arf inactivation cooperate during the development of B-ALL in mice

“…9 Our findings presented in this article demonstrate that, although Ras activation as the initiating event may not be sufficient by itself to induce high-grade leukemia/lymphoma, it can in fact induce dramatic transcriptional changes that prime cells to become hypersensitive to proliferative stimuli, as well as leading to the development of clonal low-grade B-cell lymphoproliferative disorder. However, because Kras mutations have not been reported in human MALT and LPL, 46,47 the possible role of such mutations in the development of these types of low-grade B-cell lymphoproliferative disorders needs to be further investigated.…”