A20 inactivation in ocular adnexal MALT lymphoma

Abstract

Recent studies showed A20 inactivation by deletion, mutation and promoter methylation in ocular adnexal mucosa-associated lymphoid tissue lymphoma. However, the incidences of A20 abnormalities and their clinical impact remain for the most part unknown. It is also unknown whether ABIN-1 and ABIN-2, the components of the A20 NF-κB inhibitor complex, are inactivated by genetic changes in ocular adnexal mucosa-associated lymphoid tissue lymphoma. A total of 105 cases were investigated for A20 mutation/deletion, ABIN-1/2 mutation, MALT1 and IGH involved translocation. Somatic mutation was seen frequently in A20 (28.6%) but rarely in ABIN-1 (1%) and ABIN-2 (1%). A20 mutations were significantly associated with A20 heterozygous deletion, and both were mutually exclusive from the MALT1 or IGH involved translocations. A20 mutation/deletion was also significantly associated with increased expression of the NF-κB target genes CCR2, TLR6 and BCL2. The cases with A20 mutation/deletion required significantly higher radiation dosages to achieve complete remission than those without these abnormalities.

Figure 1.

The distribution of mutations in A20, ABIN-1 and ABIN-2 in ocular adnexal MALT lymphoma. The A20 mutations seen in ocular adnexal MALT lymphoma are similar in nature to those reported in DLBCL, Hodgkin’s lymphoma and primary mediastinal large B-cell lymphoma and the vast majority are frameshift or nonsense mutations, and thus would impair A20 function.– The mutations seen in ocular adnexal MALT lymphoma are biased towards the N-terminus. Unlike A20, ABIN-1 and ABIN-2 are rarely affected by somatic mutation in ocular adnexal MALT lymphoma. Nonetheless, a high proportion of these mutations are within or adjacent to a functional domain.

Figure 2.

Increased expression of NF-κB target genes in ocular adnexal MALT lymphoma with A20 inactivating mutation/deletion. The expression of NF-κB target genes CCR2, TLR6, BCL2 and CD69 was measured by qRT-PCR in 18 cases with A20 inactivating mutation with or without A20 deletion, and 17 cases without any evidence of A20, ABIN-1/2, MALT1 and IGH genetic abnormalities. The expression level of CCR2, TLR6 and BCL2, albeit not CD69, was significantly higher in cases with A20 inactivating mutations/deletion than those lacking these abnormalities. M/D: A20 inactivating mutation/deletion; N: no A20, ABIN-1/2, MALT1 and IGH genetic abnormalities.