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J Cancer Res Clin Oncol. 2018 Sep;144(9):1665-1683. doi: 10.1007/s00432-018-2685-6. Epub 2018 Jun 12.

Association between pathologic factors and ERG expression in prostate cancer: finding pivotal networking.

Author information

1
Department of Urology, CHA Bundang Medical Center, CHA University College of Medicine, Seongnam, South Korea.
2
Department of Urology, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 03722, South Korea.
3
Department of Urology, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 03722, South Korea. youngd74@yuhs.ac.
4
Department of Pathology, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 03722, South Korea. CHO1988@yuhs.ac.

Abstract

PURPOSE:

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.

METHODS:

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.

RESULTS:

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).

CONCLUSIONS:

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.

KEYWORDS:

ERG (ETS-related gene); ETS (erythroblast transformation-specific) gene fusions; Next-generation sequencing; Prostate cancer; TMPRSS2 (transmembrane protease serine 2 gene)

PMID:
29948147
DOI:
10.1007/s00432-018-2685-6
[Indexed for MEDLINE]

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