Page 93 - Haematologica August 2018

Non-Hodgkin Lymphoma
Novel GPR34 and CCR6 mutation and distinct genetic profiles in MALT lymphomas of different sites
Ferrata Storti Foundation
Sarah Moody,1 Joe Sneath Thompson,1 Shih-Sung Chuang,2 Hongxiang
Liu,3 Markus Raderer,4 George Vassiliou,5 Iwona Wlodarska,6 Fangtian Wu,1 Sergio Cogliatti,7 Alistair Robson,8 Margaret Ashton-Key,9 Yingwen Bi,10
John Goodlad11 and Ming-Qing Du1,3,12
1Division of Cellular and Molecular Pathology, Department of Pathology, University of Cambridge, UK; 2Department of Pathology, Chi-Mei Medical Centre, Tainan, Taiwan; 3Molecular Malignancy Laboratory, Addenbrooke's Hospital, Cambridge University Hospitals NHS Foundation Trust, UK; 4Department of Medicine I, Clinical Division of Oncology, Medical University of Vienna, Austria; 5The Wellcome Trust Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge, UK; 6Center for Human Genetics, KU Leuven, Belgium; 7Institute of Pathology, State Hospital St. Gallen, Switzerland; 8Department of Dermatopathology, St John's Institute of Dermatology, London, UK; 9Department of Cellular Pathology, Southampton University Hospitals National Health Service Trust, UK; 10Department of Pathology, Eye & ENT Hospital, Fudan University, Shanghai, PR China; 11Department of Pathology, Western General Hospital, NHS Lothian University Hospitals Trust, Edinburgh, UK and 12Department of Histopathology, Addenbrooke's Hospital, Cambridge University Hospitals NHS Foundation Trust, UK
Haematologica 2018 Volume 103(8):1329-1336
ABSTRACT
Mucosa-associated lymphoid tissue (MALT) lymphoma origi- nates from a background of diverse chronic inflammatory dis- orders at various anatomic sites. The genetics underlying its development, particularly in those associated with autoimmune disor- ders, 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 lym- phoma, and a further 2 genes (TBL1XR1, NOTCH1) recently described in MALTlymphoma. ThemajorityofmutationsinGPR34andCCR6were nonsense and frameshift changes clustered in the C-terminal cytoplasmic tail, and would result in truncated proteins that lack the phosphorylation motif important for b-arrestin-mediated receptor desensitization and internalization. Screening of these newly identified mutations, together with previously defined genetic changes, revealed distinct mutation pro- files 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.
Correspondence:
mqd20@cam.ac.uk
Received: February 19, 2018. Accepted: April 18, 2018. Pre-published: April 19, 2018.
doi:10.3324/haematol.2018.191601
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/103/8/1329
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