Array-CGH Identifies Both Common and Subtype-Specific Genomic Aberrations in Marginal Zone Lymphomas

Background and Aim. In the current WHO classification, marginal zone B-cell lymphomas (MZL) have been divided into three distinct subtypes (extranodal, EMZL; nodal, NMZL; splenic, SMZL) according to clinical, pathological and cytogenetic features, however the relationship between any of the different subtypes is still unclear. We thus performed a comprehensive analysis of genomic DNA copy number changes in a very large series of MZL cases with the aim of addressing this question.

Materials and Methods. DNA extracted from frozen samples of MZL was analyzed with Affymetrix Human Mapping 250K SNP arrays.

Results. Samples from 193 patients with MZL (23 NMZL, 63 EMZL, 84 SMZL and 23 not better specified MZL) from 15 Institutions were analyzed. Among EMZL, main primary sites were orbital adnexa in 28%, GI-tract in 16%, lung and salivary glands 5% each. Overall, MZL displayed more recurrent deletions than gains. Gains of 3q and 18 gains were common to all three MZL subtypes as were losses at 1p32.3-pter, 7p22.1-pter, 7q11.21–q11.23, 9q33.3-qter, 16p, 17p and 19. EMZL had significantly more gains at 3p14.2-pter, 6p and 7q31.3-qter and losses at 6q15, 6q23.3 and 14q11.2 than SMZL. Conversely, the latter had deletions of 7q31.32-qter and 14q23.3–q32.13 more frequently than EMZL. NMZL profiles showed the EMZL-specific 6q losses and the SMZL-related 7q losses at very low frequency while presented recurrent gains of chromosome 11, which was unique of NZML among the three subtypes. The 6q23.3 region contains the gene coding for TNFAIP3/A20, a negative regulator of the NFkB pathway. In SMZL a minimal deleted region was observed in 7q32.1. Regarding chromosome 3, gains targeted the whole chromosome in EMZL while, in SMZL and NMZL, the long arm was more commonly affected.

Conclusions. EMZL, NMLZ and SMLZL share genetic alterations, which differ from other B-cell lymphomas. However subtype-specific genetic lesions are observed. In particular, gains of 6p and losses of 6q23.3 (TNFAIP3) are specific for EMZL, and 7q31-qter for SMZL.