Novel <i>GPR34</i> and <i>CCR6</i> mutation and distinct genetic profiles in MALT lymphomas of different sites

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 (<i>GPR34</i> and <i>CCR6</i>) not previously reported in human malignancies, 3 genes (<i>PIK3CD</i>, <i>TET2</i>, <i>TNFRSF14</i>) not previously implicated in MALT lymphoma, and a further 2 genes (<i>TBL1XR1</i>, <i>NOTCH1</i>) recently described in MALT lymphoma. The majority of mutations in <i>GPR34</i> and <i>CCR6</i> 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 <i>TBL1XR1</i> and <i>GPR34</i> mutations, thyroid by frequent <i>TET2</i>, <i>TNFRSF14</i> and <i>PIK3CD</i> mutations, and ocular adnexa by frequent <i>TNFAIP3</i> mutation. Interestingly, in MALT lymphoma of the salivary gland, there was a significant positive association between <i>TBL1XR1</i> mutation and <i>GPR34</i> mutation/translocation (<i>P</i>=0.0002). In those of ocular adnexa, <i>TBL1XR1</i> mutation was mutually exclusive from <i>TNFAIP3</i> mutation (<i>P</i>=0.049), but significantly associated with IGHV3-23 usage (<i>P</i>=0.03) and <i>PIK3CD</i> mutation (<i>P</i>=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.