Novel GPR34 and CCR6 mutation and distinct genetic profiles in MALT lymphomas of different sites

Abstract

Mucosa-associated lymphoid tissue (MALT) lymphoma originates from a background of diverse chronic inflammatory disorders at various anatomic sites. The genetics underlying its development, particularly in those associated with autoimmune disorders, is poorly characterized. By whole exome sequencing of 21 cases of MALT lymphomas of the salivary gland and thyroid, we have identified recurrent somatic mutations in 2 G-protein coupled receptors (GPR34 and CCR6) not previously reported in human malignancies, 3 genes (PIK3CD, TET2, TNFRSF14) not previously implicated in MALT lymphoma, and a further 2 genes (TBL1XR1, NOTCH1) recently described in MALT lymphoma. The majority of mutations in GPR34 and CCR6 were nonsense and frameshift changes clustered in the C-terminal cytoplasmic tail, and would result in truncated proteins that lack the phosphorylation motif important for β-arrestin-mediated receptor desensitization and internalization. Screening of these newly identified mutations, together with previously defined genetic changes, revealed distinct mutation profiles in MALT lymphoma of various sites, with those of salivary gland characterized by frequent TBL1XR1 and GPR34 mutations, thyroid by frequent TET2, TNFRSF14 and PIK3CD mutations, and ocular adnexa by frequent TNFAIP3 mutation. Interestingly, in MALT lymphoma of the salivary gland, there was a significant positive association between TBL1XR1 mutation and GPR34 mutation/translocation (P=0.0002). In those of ocular adnexa, TBL1XR1 mutation was mutually exclusive from TNFAIP3 mutation (P=0.049), but significantly associated with IGHV3-23 usage (P=0.03) and PIK3CD mutation (P=0.009). These findings unravel novel insights into the molecular mechanisms of MALT lymphoma and provide further evidence for potential oncogenic co-operation between receptor signaling and genetic changes.

Identifying Genetic Lesions in Ocular Adnexal Extranodal Marginal Zone Lymphomas of the MALT Subtype by Whole Genome, Whole Exome and Targeted Sequencing

“…We focus in the following discussion on those of the 38 genes that were mutated in at least two of the cases (Figure 1). The most frequently mutated gene was TBL1XR1, with mutations in 14% of the cases, validating two prior studies that detected frequent TBL1XR1 mutations in OAML [17,19]. This gene can activate the transcription of transcription factors such as NF-κB and JUN, and hence may contribute to the strong NF-κB activity in OAML.…”

“…Moreover, we identified NOTCH1, NOTCH2, and KMT2D, encoding an epigenetic regulator, as further recurrently mutated genes in OAML [16]. Another candidate gene analysis revealed recurrent mutations in TBL1XR1 (transducin beta like 1 X-linked receptor 1; 6% of cases), TNFRSF14, (tumor necrosis factor receptor family member 14; 5%), and TET2 (tet methycytosine dioxygenase 2; 4% of cases), besides a few less frequently mutated genes [17]. A further candidate gene mutation analysis validated several genes identified by the other studies, mainly adding KMT2C to the list of genes recurrently mutated in OAML [18].…”

Pleiotropic Immune Functions of Chemokine Receptor 6 in Health and Disease

“…This demonstrates chemotaxis via CCR6 might be a common mechanism adopted by malignant cancers when metastasizing to the liver [33]. Mutations in Ccr6 also have been associated with a case of mucosaassociated lymphoid tissue (MALT) lymphoma [64].…”

Rare and Potentially Pathogenic Variants in Hydroxycarboxylic Acid Receptor Genes Identified in Breast Cancer Cases.

“…Interestingly, distinct mutation pro les, corresponding to clusters of nonsense and frameshift mutations in the C-termini of GPCRs, GPR34, CCR6, and CCR4, have been reported in mucosa-associated lymphoid tissue (MALT) lymphoma and adult T cell leukemia/lymphoma (ATLL) as gainof-function mutations (42)(43)(44). Even though the nonsense and frameshift mutations reported in GPR34, CCR6, and CCR4 truncate the encoded proteins, PSORT predicted that HCAR3 p.Gln373Lysfs*82 abolishes a prenylation motif in a manner similar to how the GPR34 mutations eliminate a key phosphorylation motif and ultimately dysregulate the receptor's desensitization process (42,43). Additionally, the mutant HCAR3 protein gains an ER Membrane Retention Signal, potentially affecting internalization patterns, which is also disrupted with CCR4 gain-of-function mutations (42,44).…”