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

Suet K Loo; Ewe S Ch'ng; Md Salzihan Md Salleh; Alison H Banham; Lars M Pedersen; Michael B Møller; Tina M Green; Kah K Wong

doi:10.1111/his.13204

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

Histopathology. 2017 Jul;71(1):98-111. doi: 10.1111/his.13204. Epub 2017 Apr 27.

Authors

Suet K Loo¹, Ewe S Ch'ng², Md Salzihan Md Salleh³, Alison H Banham⁴, Lars M Pedersen⁵, Michael B Møller⁶, Tina M Green⁶, Kah K Wong¹

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.

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.

Keywords: TRPM4; diffuse large B cell lymphoma; immunohistochemistry; prognosis.

MeSH terms

Adult
Aged
B-Lymphocytes / immunology
B-Lymphocytes / pathology*
Biomarkers, Tumor / analysis*
Disease-Free Survival
Female
Humans
Kaplan-Meier Estimate
Lymphocyte Activation / immunology
Lymphoma, Large B-Cell, Diffuse / mortality
Lymphoma, Large B-Cell, Diffuse / pathology*
Male
Middle Aged
Prognosis
TRPM Cation Channels / analysis
TRPM Cation Channels / biosynthesis*
TRPM Cation Channels / immunology
Up-Regulation

Substances

Biomarkers, Tumor
TRPM Cation Channels
TRPM4 protein, human