Genomic analysis of marginal zone and lymphoplasmacytic lymphomas identified common and disease-specific abnormalities

Abstract

Lymphoplasmacytic lymphomas and marginal zone lymphomas of nodal, extra-nodal and splenic types account for 10% of non-Hodgkin lymphomas. They are similar at the cell differentiation level, sometimes making difficult to distinguish them from other indolent non-Hodgkin lymphomas. To better characterize their genetic basis, we performed array-based comparative genomic hybridization in 101 marginal zone lymphomas (46 MALT, 35 splenic and 20 nodal marginal zone lymphomas) and 13 lymphoplasmacytic lymphomas. Overall, 90% exhibited copy-number abnormalities. Lymphoplasmacytic lymphomas demonstrated the most complex karyotype (median=7 copy-number abnormalities), followed by MALT (4), nodal (3.5) and splenic marginal zone lymphomas (3). A comparative analysis exposed a group of copy-number abnormalities shared by several or all the entities with few disease-specific abnormalities. Gain of chromosomes 3, 12 and 18 and loss of 6q23-q24 (TNFAIP3) were identified in all entities. Losses of 13q14.3 (MIRN15A-MIRN16-1) and 17p13.3-p12 (TP53) were found in lymphoplasmacytic and splenic marginal zone lymphomas; loss of 11q21-q22 (ATM) was found in nodal, splenic marginal zone and lymphoplasmacytic lymphomas and loss of 7q32.1-q33 was found in MALT, splenic and lymphoplasmacytic lymphomas. Abnormalities affecting the nuclear factor kappa B pathway were observed in 70% of MALT and lymphoplasmacytic lymphomas and 30% of splenic and nodal marginal zone lymphomas, suggesting distinct roles of this pathway in the pathogenesis/progression of these subtypes. Elucidation of the genetic alterations contributing to the pathogenesis of these lymphomas may guide to design-specific therapeutic approaches.

Figure 1

Overview of the copy-number abnormalities identified in marginal zone and lymphoplasmacytic lymphomas. Chromosomes 1 to Y are represented from left to right. Light gray blocks represent chromosome gains, whereas dark gray blocks represent chromosome losses. The amplitude in each abnormal region represents the frequency of each copy-number abnormality.

Figure 2

Copy-number abnormality comparison between MALT lymphomas with and without t(11;18) API2-MALT1. Chromosomes 1 to Y are represented from left to right. Light gray blocks represent chromosome gains, whereas dark gray blocks represent chromosome losses. The amplitude in each abnormal region represents the frequency of each copy-number abnormality.

Figure 3

Venn diagram summarizing the common and distinct copy-number abnormalities between entities. Abnormalities found in >10% of at least one entity are shown.

Figure 4

A) Bar graphic showing the frequency of copy-number abnormality affecting key regulators of the NF-kB signaling pathways per entity. B) Bar graphic showing the frequency of copy-number abnormality affecting key regulators of the NF-kB signaling pathways in MALT lymphomas depending on the anatomic site of origin. LG: lacrimal glands; SG: salivary glands; BS: Bowel and stomach.