title: TRPM4 expression is associated with activated B cell subtype and poor survival in diffuse large B cell lymphoma.
abstract: OBJECTIVE
  Transient receptor potential channel melastatin 4 (TRPM4) is an ion channel that regulates influx of calcium cations (Ca2+). Recent studies suggest that TRPM4 is an oncoprotein, and its up-regulated transcript level has been reported in diffuse large B cell lymphoma (DLBCL). We aimed to investigate TRPM4 protein expression pattern in non-malignant tissues and DLBCL cases, and its association with clinico-demographic parameters and survival in DLBCL.
  
  
  RESULTS
  Analysis of publicly available DLBCL microarray data sets showed that TRPM4 transcripts were up-regulated in DLBCL compared to normal germinal centre B (GCB) cells, were expressed more highly in the activated B cell-like DLBCL (ABC-DLBCL) subtype and higher TRPM4 transcripts conferred worse overall survival (OS) in R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone)-treated DLBCL cases (P < 0.05). Our immunohistochemical analysis showed that TRPM4 was expressed in various human tissues but not in normal B cells within lymphoid tissues (reactive tonsil, lymph node and appendix). TRPM4 protein was present in 26% (n = 49 of 189) of our cohort of R-CHOP-treated DLBCL cases and this was associated significantly with more aggressive clinical parameters, including higher lactate dehydrogenase (LDH), Eastern Cooperative Oncology Group (ECOG) scores or stage (P < 0.01 for each of the parameters) and the ABC-DLBCL subtype (P = 0.016). TRPM4 positivity conferred significantly worse OS (P = 0.004) and progression-free survival (PFS) (P = 0.005). Worse OS remained associated significantly with TRPM4 positivity in multivariate analysis, including higher International Prognostic Index (IPI) or the non-GCB DLBCL phenotype (P < 0.05).
  
  
  CONCLUSIONS
  TRPM4 protein expression is up-regulated in DLBCL cases compared to non-malignant B cells with preferential expression in ABC-DLBCL cases, and it confers significantly poorer DLBCL patient outcomes.
authors.affiliation: Department of Immunology, School of Medical Sciences, Universiti Sains Malaysia, Kelantan, Malaysia.
authors.forename: Suet K
authors.initials: SK
authors.lastname: Loo
authors.affiliation: Advanced Medical and Dental Institute, Universiti Sains Malaysia, Bertam, Malaysia.
authors.forename: Ewe S
authors.initials: ES
authors.lastname: Ch'ng
authors.affiliation: Department of Pathology, School of Medical Sciences, Universiti Sains Malaysia, Kelantan, Malaysia.
authors.forename: Md Salzihan
authors.initials: MS
authors.lastname: Md Salleh
authors.affiliation: Nuffield Division of Clinical Laboratory Sciences, Radcliffe Department of Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK.
authors.forename: Alison H
authors.initials: AH
authors.lastname: Banham
authors.affiliation: Department of Haematology, Herlev University Hospital, Copenhagen, Denmark.
authors.forename: Lars M
authors.initials: LM
authors.lastname: Pedersen
authors.affiliation: Department of Pathology, Odense University Hospital, Odense, Denmark.
authors.forename: Michael B
authors.initials: MB
authors.lastname: Møller
authors.affiliation: Department of Pathology, Odense University Hospital, Odense, Denmark.
authors.forename: Tina M
authors.initials: TM
authors.lastname: Green
authors.affiliation: Department of Immunology, School of Medical Sciences, Universiti Sains Malaysia, Kelantan, Malaysia.
authors.forename: Kah K
authors.identifier: http://orcid.org/0000-0001-7359-6202
authors.initials: KK
authors.lastname: Wong
mesh_terms: D000328:Adult; D000368:Aged; D001402:B-Lymphocytes / Q000276:immunology / Q000473:pathology*; D014408:Biomarkers, Tumor / Q000032:analysis*; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D008213:Lymphocyte Activation / Q000276:immunology; D016403:Lymphoma, Large B-Cell, Diffuse / Q000401:mortality / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D050053:TRPM Cation Channels / Q000032:analysis / Q000096:biosynthesis* / Q000276:immunology; D015854:Up-Regulation
chemical_list: D014408:Biomarkers, Tumor; D050053:TRPM Cation Channels; C437888:TRPM4 protein, human
keywords: TRPM4; diffuse large B cell lymphoma; immunohistochemistry; prognosis