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

Abstract

Background: 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. 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.

Results: Pathway 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.

Conclusions: The 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.

Figure 1

Global interactome of genes commonly affected by LOH across NHL patients. An initial list containing 262 genes was used; however, only those with more than one interaction are shown. A total of 1270 nodes belonging to 68 pathways were mapped, which indicates the high level of interaction among the genes targeted by LOH-driving events in NHL tumours. The genes with labels correspond to the questioned LOH genes.

Figure 2

Interactome of PTPRJ indicates that the inactivation of PTPRJ may affect cellular networks and that these networks are not only altered by inactivation of PTPRJ . PTPRJ gene network showing A) all the known genes that interact with PTPRJ and B) only those genes that were also found to be inactivated in NHL cases. Two levels of interaction were used to filter the interactions. Interestingly, we found that the gene PTPN11, which was also found inactivated in NHL cases, shares some target genes with PTPRJ; moreover, B2M has an indirect interaction with PTPRJ (red arrows).

Figure 3

Genes and pathways affected by LOH of PTPRJ . A) Heatmap of genes differentially expressed between cases with retention (RET) and LOH calls. B) DNA polymerase (HSA03030), TP53 signaling pathway (HSA04115) and Proteasome (HSA03050) were identified as the most enriched gene sets in cases with retention of PTPRJ. C) In cases with LOH, the gene sets VEGF signaling pathway (HSA04370), Melanoma (HSA05218), ERBB signaling pathway (HSA04012), Calcium signaling pathway (HSA04020), FC Epsilon RI signaling pathway (HSA04664) and MAPK signaling pathway (HSA04010) were the most enriched. Despite an FDR (false discovery rate) of 1 for all the enrichments, the results from this gene-set enrichment analysis were analysed based on the P values instead of the FDR scores. The high FDR values obtained in this analysis may be due to the low population size. The lists of all gene sets from this analysis are provided in Additional file 3 and Additional file 4.

Figure 4

Identification of genes located within the common LOH regions in NHL cases whose expression is affected by the LOH status of PTPRJ. A) Comparison of the differentially expressed genes between NHL cases with retention and LOH of PTPRJ (red circle) and genes located within the common LOH regions in NHL cases (blue circle) discovered that NFATC3 gene in addition to being inactivated in NHL subtypes, B) is upregulated in cases with LOH of PTPRJ. NFATC3 mean fluorescence intensity values were obtained from an Illumina Sentrix Human-6 (v2.0) Expression Beadchip [7].