TRPM4 expression is associated with activated B cell subtype and poor survival in diffuse large B cell lymphoma

Loo SK 1 , Ch'ng ES 2 , Md Salleh MS 3 , Banham AH 4 , Pedersen LM 5 , Møller MB 6 Show all authors , Green TM 6 , Wong KK 1

Affiliations 

  • 1 Department of Immunology, School of Medical Sciences, Universiti Sains Malaysia, Kelantan, Malaysia
  • 2 Advanced Medical and Dental Institute, Universiti Sains Malaysia, Bertam, Malaysia
  • 3 Department of Pathology, School of Medical Sciences, Universiti Sains Malaysia, Kelantan, Malaysia
  • 4 Nuffield Division of Clinical Laboratory Sciences, Radcliffe Department of Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK
  • 5 Department of Haematology, Herlev University Hospital, Copenhagen, Denmark
  • 6 Department of Pathology, Odense University Hospital, Odense, Denmark
Histopathology, 2017 Jul;71(1):98-111.
PMID: 28248435 DOI: 10.1111/his.13204

Abstract

AIMS: 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.

METHODS AND 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.

* Title and MeSH Headings from MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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