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and 15 missense mutations. Of these, the majority of frameshift (8 of 11) and nonsense (3 of 4) mutations were found in MALT lymphomas of the thyroid.
To our surprise, TNFRSF14 mutation was highly frequent in MALT lymphoma of thyroid (6 of 13, 46%), albeit infre- quent in those of other sites (Figure 1). A total of 21 TNFRSF14 mutations were detected in 18 cases, and all mutations were deleterious changes comprising 6 non- sense, 2 frameshift indel, one inframe deletion, 11 missense changes including 2 in the first codon thus abolishing the translation start site, and a single splice site mutation (Figure 2). As TNFRSF14 mutation is common in pediatric-type fol- licular lymphoma and the mutations identified are of a sim- ilar nature,25 we carefully reviewed the histopathology and immunophenotype of our cases with TNFRSF14 muta- tions, where necessary performing further immunohisto- chemistry for CD10 and BCL6, and also FISH for BCL2 and BCL6 translocation. These additional analyses confirmed the original diagnosis of MALT lymphoma in these cases.
PIK3CD was another gene frequently mutated in MALT lymphoma of thyroid (3 of 13, 23%), followed by salivary gland (5 of 58, 9%), but rarely in those of other sites (Figure 1). A total of 11 PIK3CD mutations were identified in 11 MALT lymphomas, and the vast majority of these muta- tions were missense changes including N334K and E1021K, previously reported in patients with activated PI3Kδ syn- drome (hyper IgM syndrome) and in DLBCL (Figure 2).26-29
Mutation in the remaining genes was relevantly infre-
quent, without any apparent bias among the sites exam- ined. Mutation in CCR6 was recurrent, and seen in a total of 7 MALT lymphomas, with 7 mutations including 5 dele- terious changes (3 nonsense, 3 frameshift indels) and 2 mis- sense changes, largely clustered in the C-terminal regulato- ry region (Figures 1 and 2). Interestingly, mutations in GPR34 and CCR6, both members of the GPCR family, were mutually exclusive.
Distinct association of genetic changes in MALT lymphoma of various sites
Correlation analysis revealed several distinct associations among genetic changes in MALT lymphoma of different sites. In salivary gland MALT lymphoma, there was a sig- nificant association between TBL1XR1 mutation and GPR34 mutation/translocation (P=0.0002), with TBL1XR1 mutation seen in 8 of 11 (73%) cases with GPR34 muta- tion/translocation, but only in 6 of 47 (13%) cases without GPR34 genetic abnormalities (Figure 4 and Online Supplementary Figure S5). Both GPR34 and TBL1XR1 genetic changes were more frequently seen in the cases with non- IGHV1-69 than those with IGHV1-69 rearrangement (29% vs. 9%; 57% vs. 18%, respectively) although this does not reach statistical significance.
In ocular adnexal MALT lymphoma, TBL1XR1 mutation was mutually exclusive from TNFAIP3 mutation (P=0.049), but significantly associated with PIK3CD mutation (P=0.009), with TBL1XR1 mutation seen in 2 of 3 (67%)
Figure 1. Distinct mutation profiles in mucosa-associated lymphoid tissue (MALT) lymphoma of various sites. A total of 27 genes including the 10 MALT lymphoma- associated genes indentified in the present study were screened for mutation by targeted sequencing, but only those showing recurrent changes are presented here. API2-MALT1 denotes t(11;18)(q21;q21) from previous studies.11,12 GPR34 results in MALT lymphoma of the salivary gland include both mutation and t(X;14)(p11;q32)/GPR34-IGH. MALT lymphomas of the salivary gland are featured by frequent TBL1XR1 and GPR34 mutations, while those of the thyroid by fre- quent TET2, TNFRSF14 and PIK3CD mutations, and ocular adnexa by frequent TNFAIP3 mutation.
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