High throughput sequencing reveals high specificity of TNFAIP3 mutations in ocular adnexal marginal zone B‐cell lymphomas

Abstract

The majority of ocular adnexal (OA) lymphomas (OAL) are extranodal marginal zone lymphomas (MZL). First high throughput sequencing (HTS) studies on OA-MZL showed inconsistent results and the distribution of mutations in reactive lymphoid lesions of this anatomic region has not yet been sufficiently addressed. We characterized OAL and lymphoid lesions of the OA by targeted HTS. The study included 34 OA-MZL, 11 chronic conjunctivitis, five mature small cell B-cell lymphomas spreading to the OA, five diseases with increase of IgG4+ plasma cells, three Burkitt lymphomas (BL), three diffuse large B-cell lymphomas (DLBCL), three mantle cell lymphomas, three idiopathic orbital inflammations/orbital pseudo tumors (PT), and three OA lymphoid hyperplasia. All cases were negative for Chlamydia. The mutational number was highest in BL and lowest in PT. The most commonly (and exclusively) mutated gene in OA-MZL was TNFAIP3 (10 of 34 cases). Altogether, 20 out of 34 patients harbored mutually exclusive mutations of either TNFAIP3, BCL10, MYD88, ATM, BRAF, or NFKBIE, or nonexclusive mutations of IRF8, TNFRSF14, KLHL6, and TBL1XR1, all encoding for NK-κB pathway compounds or regulators. Thirteen patients (38%) had, to a great part, mutually exclusive mutations of chromatin modifier-encoding genes: KMT2D, CREBBP, BCL7A, DNMT3A, EP300, or HIST1H1E. Only four patients harbored co-occurring mutations of genes encoding for NK-κB compounds and chromatin modifiers. Finally, PTEN, KMT2D, PRDM1, and HIST1H2BK mutations were observable in reactive lymphoid lesions too, while such instances were devoid of NF-κB compound mutations and/or mutations of acetyltransferase-encoding genes. In conclusion, 80% of OA-MZL display mutations of either NK-κB compounds or chromatin modifiers. Lymphoid lesions of the OA bearing NF-κB compound mutations and/or mutations of acetyltransferase-encoding genes highly likely represent lymphomas.

Mutational landscape of marginal zone B-cell lymphomas of various origin: organotypic alterations and diagnostic potential for assignment of organ origin

“…Due to the differing cohort numbers, mutational rates are more difficult to describe in EMZL. Ten EMZL [18,19,[33][34][35][36][37][38][39][40] studies extensively looked for TNFAIP3 and TBL1XR1 mutations and detected 140/500 and 66/515 mutant cases, respectively. A total of 29 cases with NOTCH1 mutations was found in 324 samples, while 14 cases with KMT2C mutations were identified in 135 studied instances.…”

“…Two thyroid MZL (TMZL) studies [18,19] showed a high prevalence of TET2 mutations (61%, 11/18), which statistically significantly exceeded that in salivary gland In the two studies with available information on sublocalization of the OMZL (conjunctival versus periorbital) [37,38], total numbers of mutations in conjunctival OMZL were higher than in periorbital OMZL (median 2 versus 1; mean 2.38 versus 1.56, range 0-9 versus 0-5; p = 0.028). TBL1XR1 mutations were enriched in conjunctival OMZL (8/27 versus 1/17, p = 4.63E−02 [37]; 7/22 versus 0/12, p = 0.095 [38]).…”

Discovery of Novel Recurrent Mutations and Clinically Meaningful Subgroups in Nodal Marginal Zone Lymphoma

“…NFKBIE encodes NFKB inhibitor epsilon (NFKBIE), a negative regulator of the NF-κB pathway [ 18 ]. The NFKBIE Y254fs mutation has been reported in aggressive chronic lymphocytic leukemia (CLL), Hodgkin lymphoma (HL), DLBCL, primary mediastinal B-cell lymphoma (PMBCL) and a few cases of low-grade B-cell NHL, including follicular lymphoma (FL), EMZL [ 19 ], and SMZL [ 11 , 20 ]. However, this mutation has never been reported in patients with NMZLs.…”

Development of molecular intervention strategies for B-cell lymphoma

“…The TNFAIP3 gene encoding A20 is highly specific to ocular adnexal lymphomas (OAL) [78]. In DLBCL, the frequency of A20 deletion is similar in germinal center B-celllike (GCB) and non-GCB DLBCL.…”