Recurrent mutations in NF-κB pathway components, KMT2D, and NOTCH1/2 in ocular adnexal MALT-type marginal zone lymphomas

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.

Keywords: KMT2D; MALT lymphoma; NF-κB; NOTCH; ocular adnexal lymphoma.

Figure 1. Proportion of OAML cases with mutations in the 24 genes analyzed

Given is the proportion of the 63 OAML patients included in the analysis that carried mutations in the 24 genes analyzed.

Figure 2. Distribution of mutated genes in the OAML

Mutated genes are indicated as black fields for the 47 OAML that carried at least one mutated gene.

Figure 3. Pattern and distribution of mutations in NOTCH1, NOTCH2, KMT2D, and TNFAIP3

Depicted are all mutations per gene. A. NOTCH1, B. NOTCH2, C. KMT2D, D. TNFAIP3. Abbreviations: ANK ankyrin; EGF epidermal growth factor; FYRC F/Y-rich, C-terminal; FYRN F/Y-rich, N-terminal; HD-C heterodimerization domain, c-terminal; HD-N heterodimerization domain, N-terminal; HMG high mobility group; LNR Lin12/NOTCH repat; NLS nuclear localization signal; PEST proline-glutamate-serine-threonine rich; PHD plant homeodomain; RAM retinole binding associated molecule; SET Su(var)3-9 - Enhancer of zeste' – Trithorax; TAD trans activating; TM transmembrane; ZNF zink finger.

Figure 4. Variant allele frequencies of the 16 mutated genes

Variant allele frequencies below 20% are considered as subclonal. Depicted are all mutations per gene. Bars depict mean and standard deviation.

Figure 5. Kaplan-Meier estimates for disease-free survival regarding MYD88 mutation status in the OAML patient cohort (n=63 patients)

Note that the association of disease-free survival with MYD88 mutation status is still significant (p=0.0152) even if only the 54 patients with stage I disease, who all received radiotherapy, are considered (not shown).