Association between pathologic factors and ERG expression in prostate cancer: finding pivotal networking
To evaluate associations between pathologic factors and erythroblast transformation-specific (ETS)-related gene (ERG) expression in prostate cancer patients. Using next-generation sequencing, we identified target genes and regulatory networks.
ERG expression in 60 radical prostatectomies was compared with pathological findings by association rule mining with the Apriori algorithm. Whole-exome and RNA sequencing were performed on three formalin-fixed, paraffin-embedded ERG-positive and negative prostate cancer samples. A network diagram identifying dominant altered genes was constructed using Cytoscape open-source bioinformatics platform and GeneMania plugin.
Pathologic conditions positive for perineural invasion, apical margins, and Gleason score 3 + 4 = 7 were significantly more likely to be ERG-positive than other pathologic conditions (p = 0.0008), suggesting an association between ERG positivity, perineural invasion, apical margins, and Gleason score 3 + 4 = 7 (Firth’s logistic regression: OR 42.565, 95% CI 1.670–1084.847, p = 0.0232). Results of whole-exome and RNA sequencing identified 97 somatic mutations containing common mutated genes. Regulatory network analysis identified NOTCH1, MEF2C, STAT3, LCK, CACNA2D3, PCSK7, MEF2A, PDZD2, TAB1, and ASGR1 as pivotal genes. NOTCH1 appears to function as a hub, because it had the highest node degree and betweenness. NOTCH1 staining was found 8 of 60 specimens (13%), with a significant association between ERG and NOTCH1 positivity (p = 0.001).
Evaluating the association between ERG expression and pathologic factors, and identifying the regulatory network and pivotal hub may help to understand the clinical significance of ERG-positive prostate cancer.
KeywordsProstate cancer ETS (erythroblast transformation-specific) gene fusions TMPRSS2 (transmembrane protease serine 2 gene) ERG (ETS-related gene) Next-generation sequencing
This study was supported by a grant from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health and Welfare, Republic of Korea (Grant number: HI13C2163) and by the Mid-Career Researcher Program through a National Research Foundation of Korea grant (No. 2016R1A2B4011115; CNH).
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
This study was approved by the Institutional Review Board of Severance Hospital (4-2013-0857). All procedures performed in this study were in accordance with the ethical standards of the institutional research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
Written informed consent given by participants was exempted, because the study design was retrospective, and information was anonymized and de-identified prior to analysis.
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