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

Abstract

Ocular marginal zone lymphoma is a common type of low-grade B-cell lymphoma. To investigate the genomic changes that occur in ocular marginal zone lymphoma, we analyzed 10 cases of ocular marginal zone lymphoma using whole-genome and RNA sequencing and an additional 38 cases using targeted sequencing. Major genetic alterations affecting genes involved in nuclear factor (NF)-κB pathway activation (60%), chromatin modification and transcriptional regulation (44%), and B-cell differentiation (23%) were identified. In whole-genome sequencing, the 6q23.3 region containing TNFAIP3 was deleted in 5 samples (50%). In addition, 5 structural variation breakpoints in the first intron of IL20RA located in the 6q23.3 region was found in 3 samples (30%). In targeted sequencing, a disruptive mutation of TNFAIP3 was the most common alteration (54%), followed by mutations of TBL1XR1 (18%), cAMP response element binding proteins (CREBBP) (17%) and KMT2D (6%). All TBL1XR1 mutations were located within the WD40 domain, and TBL1XR1 mutants transfected into 293T cells increased TBL1XR1 binding with nuclear receptor corepressor (NCoR), leading to increased degradation of NCoR and the activation of NF-κB and JUN target genes. This study confirms genes involving in the activation of the NF-kB signaling pathway is the major driver in the oncogenesis of ocular MZL.

Genomic evolution of ibrutinib‐resistant clones in Waldenström macroglobulinaemia

“…In two patients (IBR1 and IBR3), we also found chromosome 3q amplifications that encompassed a copy number neutral loss of heterozygosity region of approximately seven million base pairs that included TBL1XR1 , a transcriptional regulator of NF‐κB and WNT signalling (Jung et al , ). Mutations of TBL1XR1 are the most frequent variants found in MYD88 wild‐type WM patients (Hunter et al , ), who show poor responses to ibrutinib monotherapy (Treon et al , ), though no somatic mutations in TBL1XR1 were identified in this study.…”

Ocular adnexal marginal zone lymphoma (OAMZL)

“…For OAMZLs, data on cytogenetic abnormalities are limited: trisomy of chromosome 3 (38-62%) and 18 (14-47%) have been observed, and the latter has been associated with a higher risk of local recurrence . Jung et al, 2017.…”

“…Biased usage of IGHV genes with ongoing somatic mutations points out the pathogenetic mechanism of antigenic selection (Dagklis et al, 2012). The most frequent immunoglobulin rearrangements involve IGHV4-34 and IGHV3-23 families and are associated with auto-reactive B-cell receptors (Jung et al, 2017). A number of mutations leading to constitutive activation of NF-kB pathway, consequently promoting lymphocyte stimulation, proliferation and survival, have been detected in about 60% of the cases analyzed (Jung et al, 2017).…”

“…The most frequent immunoglobulin rearrangements involve IGHV4-34 and IGHV3-23 families and are associated with auto-reactive B-cell receptors (Jung et al, 2017). A number of mutations leading to constitutive activation of NF-kB pathway, consequently promoting lymphocyte stimulation, proliferation and survival, have been detected in about 60% of the cases analyzed (Jung et al, 2017). Among these, structural variations (deletions or mutations) at 6q23.3 involving TNFAIP3 (A20), a negative regulator of NF-kB, have been described in 54% of cases in OAMZL; structural breakpoints (deletions, intra-and inter-chromosomal translocations) in the same locus involving IL20RA have also been found (Johansson et al, 2016;Jung et al, 2017).…”

“…A number of mutations leading to constitutive activation of NF-kB pathway, consequently promoting lymphocyte stimulation, proliferation and survival, have been detected in about 60% of the cases analyzed (Jung et al, 2017). Among these, structural variations (deletions or mutations) at 6q23.3 involving TNFAIP3 (A20), a negative regulator of NF-kB, have been described in 54% of cases in OAMZL; structural breakpoints (deletions, intra-and inter-chromosomal translocations) in the same locus involving IL20RA have also been found (Johansson et al, 2016;Jung et al, 2017). The transcription regulator and chromatin modifier TBL1XR1 is frequently mutated (6-18%); loss of function mutations can involve the chromatin modifiers CREBBP and KMT2D (Moody et al, 2017;Jung et al, 2017;Johansson et al, 2016).…”