Ocular Adnexal Marginal Zone B Cell Lymphoma Has Characteristic Deletion at Chromosome Band 6q23.3-24.1 Whose Target Is TNFAIP3.

Marginal zone B cell lymphoma (MZBCL) occupies a distinct disease entity in WHO classification, and it has been suggested that recurrent chromosomal aberrations, such as t(11;18)(q21;q21), t(14;18)(q32;q21), and t(1;14)(p22;q32) are associated with its lymphomagenesis. However, the frequency of chromosomal alteration in marginal zone B cell lymphomas varies according to the anatomical region, and genetic abnormalities other than recurrent translocations involved in the pathogenesis of MZBCL have not yet been fully identified. In this study, we aimed to investigate genomic aberrations in ocular MZBCL and to compare them with those of tumors from other anatomical sites by using genome-wide array comparative genomic hybridization (CGH). The study population comprised 24 cases of primary ocular MZBCL, 11 of pulmonary MZBCL, and seven of nodal MZBCL. FISH analysis for MALT1 gene alteration was performed for ocular and nodal MZBCL and RT-PCR for the detection of API2-MALT1 transcript was performed for pulmonary MZBCL. The recurrent genomic alterations of ocular MZBCL were losses of chromosomes 6q23.3(9/24, 38%), and gains of 3(9/24, 38%), 15(4/24, 16%), 18q(4/24, 16%). T(11;18)(q21;q21) was not detected. The genomic alteration of pulmonary MZBCL included recurrent loss of 13q34 (2/11, 19%). Fusion transcript of t(11;18)(q21;q21) was detected in five out of eight cases (63%). Nodal MZBCL showed neither recurrent genome alteration nor any change in MALT1 gene copy number. In conclusion of genome-wide array CGH analysis, the array CGH profile of ocular MZBCL is distinct from those of pulmonary and nodal MZBCL. The novel finding was recurrent deletion in the 2.9 Mb region at chromosome band 6q23.3–q24.1 including homozygous loss in ocular adnexal marginal zone B cell lymphoma. These findings suggest that deletion of chromosome band 6q23.3–24.1 may constitute a crucial genetic alteration in the lymphomagenesis of ocular MZBCL. For a further examination, we used contig bacterial artificial chromosome (BAC) array CGH, containing the 24 BAC clone to cover the 2.9 Mb region, to analyze nine cases with chromosome band 6q23.3–q24.1 loss. We narrowed the minimal common region down to a length of 586 kb with two genes and four expressed sequence tags (ESTs). All of these genes and ESTs were subjected to RT-PCR and real-time quantitative RT-PCR, and correlation between genomic loss and expression level was found only in TNFAIP3. We thus concluded that the TNFAIP3 gene is the candidate gene for this deleted region. TNFAIP3 is an inhibitor of NF-kB signaling so that loss of this gene may result constitutive activation of NF-kB which was also implicated in MALT lymphomas with t(11;18)(q21;q21) or t(14;18)(q32;q21). Thus, TNFAIP3 may act as a tumor suppressor gene in ocular adnexal marginal zone B cell lymphoma.