Abstract
The pathogenesis of ocular adnexal marginal zone lymphomas of mucosa-associated lymphatic tissue-type (OAML) is still poorly understood. We analyzed 63 cases of such lymphomas for non-synonymous mutations in 24 candidate genes by amplicon sequencing. We validated frequent mutations in the NF-κB regulators MYD88, TNFAIP3 and TNIP1 in OAML, but also identified recurrent mutations in several additional components of the NF-κB pathway, including BCL10 and NFKBIA. Overall, 60% of cases had mutations in at least one component of NF-κB signaling, pointing to a central role of its genetic deregulation in OAML pathogenesis. Mutations in NOTCH1 and NOTCH2 were each found in 8% of cases, indicating a pathogenetic function of these factors in OAML. KMT2D was identified as the first epigenetic regulator with mutations in OAML, being mutated in 22% of cases. Mutations in MYD88 were associated with an inferior disease-free survival. Overall, we identified here highly recurrent genetic lesions in components of the NF-κB pathway, of NOTCH1 and NOTCH2 as well as KMT2D in OAML and thereby provide major novel insights into the pathogenesis of this B cell malignancy.
Highlights
Lymphomas of the ocular adnexa account for about 1-2% of Non-Hodgkin lymphomas (NHL) [1]
As we studied formalin-fixed paraffin embedded (FFPE) material, which often causes higher rates of false positive mutations in sequence analyses than good quality DNA, and as a substantial number of mutations were detected with relatively low variant allele frequency (VAF), it was important to clarify the reliability of our mutation analysis
The genetic lesions involved in the pathogenesis of OAML are still largely unknown
Summary
Lymphomas of the ocular adnexa account for about 1-2% of Non-Hodgkin lymphomas (NHL) [1]. A number of recurrent chromosomal aberrations and genetic lesions have been identified for OAML. Exclusive chromosomal translocations in OAML include t(1;14) (p22;q32) (BCL10/IgH), t(14;18)(q32;p21) (IgH/MALT1), t(11;18)(q21;q21) (BIRC3/MALT1), and t(3;14)(p14;q32) (FOXP1/IgH) [12,13,14,15,16,17]. BCL10 and MALT1 are positive regulators of NF-κB signaling, and FOXP1 supports NF-κB activity, indicating a role of NF-κB deregulation in OAML pathogenesis. Presumably activating mutations of MYD88, a factor physiologically linking toll-like receptor signaling to NF-κB activation, were found in about 6% of cases, and one analysis revealed recurrent BCL10 mutations, whereas no or only very rare mutations were identified in BIRC3, CARD11, CD79A, CD79B, and TNIP2 (ABIN2), further components of the NF-κB pathway [22, 23]
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