In silico analyses reveal common cellular pathways affected by loss of heterozygosity (LOH) events in the lymphomagenesis of Non-Hodgkin's lymphoma (NHL).

Carlos Aya-Bonilla,Maher K Gandhi,Rod Lea,Larisa M Haupt,Emily Camilleri,Lyn R Griffiths

doi:10.1186/1471-2164-15-390

Abstract

BackgroundThe analysis of cellular networks and pathways involved in oncogenesis has increased our knowledge about the pathogenic mechanisms that underlie tumour biology and has unmasked new molecular targets that may lead to the design of better anti-cancer therapies. Recently, using a high resolution loss of heterozygosity (LOH) analysis, we identified a number of potential tumour suppressor genes (TSGs) within common LOH regions across cases suffering from two of the most common forms of Non-Hodgkin’s lymphoma (NHL), Follicular Lymphoma (FL) and Diffuse Large B-cell Lymphoma (DLBCL). From these studies LOH of the protein tyrosine phosphatase receptor type J (PTPRJ) gene was identified as a common event in the lymphomagenesis of these B-cell lymphomas. The present study aimed to determine the cellular pathways affected by the inactivation of these TSGs including PTPRJ in FL and DLBCL tumourigenesis.ResultsPathway analytical approaches identified that candidate TSGs located within common LOH regions participate within cellular pathways, which may play a crucial role in FL and DLBCL lymphomagenesis (i.e., metabolic pathways). These analyses also identified genes within the interactome of PTPRJ (i.e. PTPN11 and B2M) that when inactivated in NHL may play an important role in tumourigenesis. We also detected genes that are differentially expressed in cases with and without LOH of PTPRJ, such as NFATC3 (nuclear factor of activated T-cells, cytoplasmic, calcineurin-dependent 3). Moreover, upregulation of the VEGF, MAPK and ERBB signalling pathways was also observed in NHL cases with LOH of PTPRJ, indicating that LOH-driving events causing inactivation of PTPRJ, apart from possibly inducing a constitutive activation of these pathways by reduction or abrogation of its dephosphorylation activity, may also induce upregulation of these pathways when inactivated. This finding implicates these pathways in the lymphomagenesis and progression of FL and DLBCL.ConclusionsThe evidence obtained in this research supports findings suggesting that FL and DLBCL share common pathogenic mechanisms. Also, it indicates that PTPRJ can play a crucial role in the pathogenesis of these B-cell tumours and suggests that activation of PTPRJ might be an interesting novel chemotherapeutic target for the treatment of these B-cell tumours.Electronic supplementary materialThe online version of this article (doi: 10.1186/1471-2164-15-390) contains supplementary material, which is available to authorized users.

Highlights

The analysis of cellular networks and pathways involved in oncogenesis has increased our knowledge about the pathogenic mechanisms that underlie tumour biology and has unmasked new molecular targets that may lead to the design of better anti-cancer therapies
Since the role of phosphatase receptor type J (PTPRJ) in normal and malignant B-cell differentiation is poorly understood, we used pathway and genomic analyses to identify cellular pathways that may be altered by the inactivation of PTPRJ in order to provide a better understanding of the role of PTPRJ in the lymphomagenesis of Follicular Lymphoma (FL) and Diffuse Large B-cell Lymphoma (DLBCL). These analyses identified metabolic pathways as one of the most enriched and affected pathways resulting from the inactivation of candidate tumour suppressor genes (TSGs), indicating that these cellular pathways might play an important role in FL and DLBCL tumourigenesis
Candidate tumour suppressor genes (TSGs) targeted by loss of heterozygosity (LOH) events participate within common cellular networks that may orchestrate Non-Hodgkin’s lymphoma (NHL) lymphomagenesis In order to determine whether the candidate tumour suppressor genes (TSGs) located within common LOH regions across DLBCL and FL cases interact and participate within common cellular networks, a global interactome of a total of 262 genes affected by LOH events [8], was created using the VisANT (v. 4.06) platform (Figure 1)

Summary

Introduction

The analysis of cellular networks and pathways involved in oncogenesis has increased our knowledge about the pathogenic mechanisms that underlie tumour biology and has unmasked new molecular targets that may lead to the design of better anti-cancer therapies. Using a high resolution loss of heterozygosity (LOH) analysis, we identified a number of potential tumour suppressor genes (TSGs) within common LOH regions across cases suffering from two of the most common forms of Non-Hodgkin’s lymphoma (NHL), Follicular Lymphoma (FL) and Diffuse Large B-cell Lymphoma (DLBCL). From these studies LOH of the protein tyrosine phosphatase receptor type J (PTPRJ) gene was identified as a common event in the lymphomagenesis of these B-cell lymphomas. The high genetic variability observed within NHL subtypes, has limited the understanding of the pathology of these NHL subtypes, as well as the discovery of new molecular targets for therapeutic development

Methods

Results

Conclusion