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

Pathology of nodal marginal zone lymphomas

“…In NMZL, the occurring mutations are responsible for the removal of the entire gene or the tyrosine phosphatase portion of its protein and exert their lymphomagenetic action in a STAT3-independent manner. On these grounds the almost exclusive, although not constant, occurrence of mutations in PTPRD gene further support the view of keeping separate NMZL from other types of marginal zone lymphomas [45].…”

“…With the exception of MLL2, which is present in more than one third of cases, the other affected genes occur in about 20% of cases. Notably, PTPRD is mutated in 20% on these patients and this defect seems restricted to NMZL across mature B-cell tumors [45]. PTPRD appears a critical molecule since it is a receptor-type protein tyrosine phosphatase known to regulate cell growth and behaves like a tumor suppressor.…”

Genetic landscape and deregulated pathways in B‐cell lymphoid malignancies

“…The mutation profile of NMZL as shown by WES is similar to that of SMZL (Table ). KLF2 mutation is found in 17% of NMZLs . 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‐κB signalling pathway mainly involves TNFAIP3 (14%), BCL10 (11%), CARD11 (8%), BIRC3 (6%) and TRAF3 (6%), and is observed in 50% of cases .…”

The role of G protein-coupled receptors in lymphoid malignancies

“…Deep sequencing of nodal MZL patients found that 5/35 (14%) cases had a mutation in the adhesion receptor ADGRV1 (also known as GPR98) and the cadherin receptors CELSR1, CELSR2 and CELSR3 were each mutated in 2/35 (6%) cases [183]. In addition to mutation, t(X;14) translocations causing upregulation of purinergic receptor GPR34 were observed in 2/61 (3%) cases of MALT, 1/43 (2%) cases of nodal MZL and 1/19 (5%) cases of extranodal DLBCL [184].…”

“…Exome sequencing found 2/35 (6%) cases of MZL had a mutation in CXCR4 [183] and the CXCR4 WHIM mutation was found in 1/20 (5%) MZL patients [192]. A significant correlation has been observed between CXCR4 expression and bone marrow involvement and loss of CXCR4 expression combined with upregulation of CXCR7 has been suggested to correlate with MALT progression to DLBCL [173].…”