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.

The mutational landscape of ocular marginal zone lymphoma identifies frequent alterations in TNFAIP3 followed by mutations in TBL1XR1 and CREBBP

“…Commonly mutated genes are involved in the NF-kB signaling pathway, B-cell differentiation, and epigenetic modification. These findings are in line with those of previous studies although mutation frequency of each gene was variable according to the study [26, 27]. …”

“…KMT2D affects the methylation of lysine 4 on histone H3 ( H3K 4) and the expression of a set of genes, including those involved in the CD40, JAK-STAT, Toll-like receptor and B cell receptor signaling pathways [48]. KMT2D mutations was reported in 22% of ocular MZL in previous study analyzing FFPE samples by targeted deep sequencing [27]. BRD4 is a BET protein linked to the regulation of NF-κB transcriptional activity.…”

CREBBPandSTAT6co-mutation and 16p13 and 1p36 loss define the t(14;18)-negative diffuse variant of follicular lymphoma

“…Of note, 2 cases from the Siddiqi et al study were not included, as those cases had demonstrable BCL2/IGH rearrangements. The aggregate frequencies of particular alterations found in dFL were contrasted with previously published reports for cFL (4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19) and MZL (26,(29)(30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40)(41). Although the previous studies describing CNVs in cFL used a variety of techniques, most of these studies (8/13, 61%) were performed using SNP-array platforms similar to the present method indicating that the results obtained in these prior studies should be comparable to our findings.…”

Genetic landscape and deregulated pathways in B‐cell lymphoid malignancies

“…Studies to date show no or rare somatic mutations of CD79A, CD79B, CARD11, BIRC3, TRAF3 and TNFRSF11A in MALT lymphoma [142,144], further distinguishing MALT lymphoma from other B-cell lymphomas characterized by constitutive NF-jB activation.…”

“…In a recent study using targeted sequencing, recurrent mutations were identified in NOTCH1 (8%) and NOTCH2 (8%) in ocular adnexal MALT lymphoma [142]. The majority of these mutations…”