Identification of potential biomarkers to differentially diagnose solid pseudopapillary tumors and pancreatic malignancies via a gene regulatory network

Abstract

BackgroundSolid pseudopapillary neoplasms (SPN) are pancreatic tumors with low malignant potential and good prognosis. However, differential diagnosis between SPN and pancreatic malignancies including pancreatic neuroendocrine tumor (PanNET) and ductal adenocarcinoma (PDAC) is difficult. This study tried to identify candidate biomarkers for the distinction between SPN and the two malignant pancreatic tumors by examining the gene regulatory network of SPN.MethodsThe gene regulatory network for SPN was constructed by a co-expression model. Genes that have been reported to be correlated with SPN were used as the clues to hunt more SPN-related genes in the network according to a shortest path approach. By means of the K-nearest neighbor algorithm (KNN) classifier evaluated by the jackknife test, sets of genes to distinguish SPN and malignant pancreatic tumors were determined.ResultsWe took a new strategy to identify candidate biomarkers for differentiating SPN from the two malignant pancreatic tumors PanNET and PDAC by analyzing shortest paths among SPN-related genes in the gene regulatory network. 43 new SPN-relevant genes were discovered, among which, we found hsa-miR-194 and hsa-miR-7 along with 7 transcription factors (TFs) such as SOX11, SMAD3 and SOX4 etc. could correctly differentiate SPN from PanNET, while hsa-miR-204 and 4 TFs such as SOX9, TCF7 and PPARD etc. were demonstrated as the potential markers for SPN versus PDAC. 14 genes were demonstrated to serve as the candidate biomarkers for distinguishing SPN from PanNET and PDAC when considering them as malignant pancreatic tumors together.ConclusionThis study provides new candidate genes related to SPN and the potential biomarkers to differentiate SPN from PanNET and PDAC, which may help to diagnose patients with SPN in clinical setting. Furthermore, candidate biomarkers such as SOX11 and hsa-miR-204 which could cause cell proliferation but inhibit invasion or metastasis may be of importance in understanding the molecular mechanism of pancreatic oncogenesis and could be possible therapeutic targets for malignant pancreatic tumors.Electronic supplementary materialThe online version of this article (doi:10.1186/s12967-015-0718-3) contains supplementary material, which is available to authorized users.

Immunocytochemistry for SOX‐11 and TFE3 as diagnostic markers for solid pseudopapillary neoplasms of the pancreas in FNA biopsies

“…Nuclear immunoreactivity for TFE3 ( Table 2) was seen in 9 of the 13 SPN EUS-FNA samples and in none of the control cases; this resulted in a sensitivity of 69.2%, a specificity of 100%, a PPV of 1, and an NPV of 0.765. Six of the 13 cases (46.2%) exhibited moderate nuclear expression (21), 3 of the 13 cases (23.1%) exhibited weak nuclear staining (11), and 4 of the 13 cases (30.8%) were negative (0). Aberrant nuclear and cytoplasmic staining for b-catenin (Table 2) was present in all 13 of the SPN EUS-FNA samples and in 1 of the 13 control cases.…”

“…Tumors showing nuclear staining that was readily apparent at a low-power magnification (a 43 objective) were scored as strongly positive (31), and those showing nuclear staining that was readily apparent at an intermediate magnification (a 103 objective) were scored as moderately positive (21). The tumors that showed weak nuclear staining in at least 5% of the tumor nuclei that was apparent only at a high magnification (20-403 objectives) were scored as weakly positive (11). Tumors that exhibited no staining or showed weak staining (11) in less than 5% of the tumor nuclei were scored as negative (0).…”

“…The tumors that showed weak nuclear staining in at least 5% of the tumor nuclei that was apparent only at a high magnification (20-403 objectives) were scored as weakly positive (11). Tumors that exhibited no staining or showed weak staining (11) in less than 5% of the tumor nuclei were scored as negative (0). b-Catenin immunoreactivity was scored as either positive or negative.…”

“…SOX‐11 gene mutations have also been previously associated with malignancies such as mantle cell lymphoma and gliomas . More recently, SOX‐11 messenger RNA has shown to be consistently increased in SPNs by RNA microarray analysis …”

“…9,10 More recently, SOX-11 messenger RNA has shown to be consistently increased in SPNs by RNA microarray analysis. 11 TFE3 is a member of the microphthalmia family of transcription factors (ie, the MiT family), which are considered oncogenes. TFE3 specifically has been implicated in the biogenesis of lysosomes and autophagosomes and in the clearance of cellular debris, and it is also associated with alveolar soft part sarcoma and translocationassociated renal cell carcinoma.…”