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Novel GPCR mutation in MALT lymphoma
cases with PIK3CD mutation, but in only 5 of 112 (4%) cases without PIK3CD mutation (Figure 4 and Online Supplementary Figure S5). TBL1XR1 mutation was also mutually exclusive from IGHV4-34 rearrangement, but sig- nificantly associated with IGHV3-23 usage (P=0.03), with TBL1XR1 mutation seen in 3 of 11 (27%) cases with IGHV3-23 rearrangement, but in only 2 of 52 (4%) cases with other rearrangements (Figure 4). MYD88 mutation also appeared to be more frequent in TBL1XR1 mutated cases (2 of 7, 29%) compared to non-mutated cases (6 of 108, 6%), although this did not reach significance (P=0.07).
In gastric MALT lymphoma, t(11;18) API2-MALT1 was mutually exclusive from other genetic changes (P=0.025) (Online Supplementary Figure S5).
Correlation between genetic changes and clinicopatho- logical parameters
This was carried out in 98 cases of ocular adnexal MALT lymphoma where clinicopathological data were available (Online Supplementary Table S8). TBL1XR1 mutation and IGHV3-23 usage were significantly associated with involve- ment of the conjunctiva (P=0.002 in each, respectively), while TNFRSF14 mutation was significantly associated with involvement of the orbit (P=0.04). MYD88 and TP53 mutations were much higher in cases involving both orbit and conjunctiva than those involving only a single site but
only the former showing a statistical significance (4 of 23, 17% vs. 2 of 75, 3%; P=0.03). With the exception of TNFAIP3 deletion/mutation that was significantly associat- ed with higher radiation dosages to achieve complete remission as reported previously,16 none of the other genetic changes showed any significant association with radiation dosages.
Discussion
By WES of 21 cases of MALT lymphomas of the salivary gland and thyroid, we have identified several novel genetic changes in MALT lymphoma, including GPR34 and CCR6 mutations not yet previously reported in human malignan- cies. Screening these newly identified mutations revealed distinct mutation profiles in MALT lymphoma of various sites, and provides further evidence of potential oncogenic co-operation between receptor signaling and genetic changes.
GPR34 and CCR6 mutations in MALT lymphoma
Both GPR34 and CCR6 are members of class A G pro- tein-coupled receptor (GPCR) superfamily, which transduce extracellular stimulation into intracellular signaling through G protein and b-arrestin. By interacting with G protein,
Figure 2. Nature and distribution of mutations in newly identified mucosa-associated lymphoid tissue (MALT) lymphoma-associated genes. Site of MALT lymphoma in which the mutation was identified is indicated by color (blue: salivary gland; red: thyroid; green: ocular adnexa; orange: stomach; purple: lung; gray: other sites). TM: transmembrane domain; ABD: adaptor binding domain; RBD: ras binding domain; DSBH: double-stranded b-helix.
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