Novel GPR34 and CCR6 mutation and distinct genetic profiles in MALT lymphomas of different sites
Sarah Moody,
Joe Sneath Thompson,
Shih-Sung Chuang,
Hongxiang Liu,
Markus Raderer,
George Vassiliou,
Iwona Wlodarska,
Fangtian Wu,
Sergio Cogliatti,
Alistair Robson,
Margaret Ashton-Key,
Yingwen Bi,
John Goodlad,
Ming-Qing Du
Affiliations
Sarah Moody
Division of Cellular and Molecular Pathology, Department of Pathology, University of Cambridge, UK
Joe Sneath Thompson
Division of Cellular and Molecular Pathology, Department of Pathology, University of Cambridge, UK
Shih-Sung Chuang
Department of Pathology, Chi-Mei Medical Centre, Tainan, Taiwan
Hongxiang Liu
Molecular Malignancy Laboratory, Addenbrooke’s Hospital, Cambridge University Hospitals NHS Foundation Trust, UK
Markus Raderer
Department of Medicine I, Clinical Division of Oncology, Medical University of Vienna, Austria
George Vassiliou
The Wellcome Trust Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge, UK
Iwona Wlodarska
Center for Human Genetics, KU Leuven, Belgium
Fangtian Wu
Division of Cellular and Molecular Pathology, Department of Pathology, University of Cambridge, UK
Sergio Cogliatti
Institute of Pathology, State Hospital St. Gallen, Switzerland
Alistair Robson
Department of Dermatopathology, St John’s Institute of Dermatology, London, UK
Margaret Ashton-Key
Department of Cellular Pathology, Southampton University Hospitals National Health Service Trust, UK
Yingwen Bi
Department of Pathology, Eye & ENT Hospital, Fudan University, Shanghai, PR China
John Goodlad
Department of Pathology, Western General Hospital, NHS Lothian University Hospitals Trust, Edinburgh, UK
Ming-Qing Du
Division of Cellular and Molecular Pathology, Department of Pathology, University of Cambridge, UK;Molecular Malignancy Laboratory, Addenbrooke’s Hospital, Cambridge University Hospitals NHS Foundation Trust, UK;Department of Histopathology, Addenbrooke’s Hospital, Cambridge University Hospitals NHS Foundation Trust, UK
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.
