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Gene-expression analysis of gleason grade 3 tumor glands embedded in low- and high-risk prostate cancer

  • The Gleason score (GS) of prostate cancer on diagnostic biopsies is an important parameter for therapeutic decision-making. Biopsy GS under-estimates the actual GS at radical prostatectomy in a significant number of patients due to samplingartifact. The aim of this study was to identify markers that are differentially expressed in Gleason grade 3 (GG3) tumor glands embedded in GS 4 + 3 = 7 and GS 3 + 3 = 6 prostate cancer using laser capture microdissection and RNA sequencing. GG3 tumor glands embedded in nine GS 3 + 3 = 6 and nine GS 4 + 3 = 7 prostate cancers were isolated by laser capture microdissection of frozen radical prostatectomy specimens. After RNA amplification and RNA sequencing, differentially expressed genes in both GG3 components were identified by a 2log fold change > 1.0 and p-value < 0.05. We applied immunohistochemistry on a tissue micro-array representing 481 radical prostatectomy samples for further validation on protein level. A total of 501 genes were up-regulated and 421 down-regulated in GG3 glands embedded in GS 4 + 3 = 7 as compared to GS 3 + 3 = 6 prostate cancer. We selected HELLS, ZIC2 and ZIC5 genes for further validation. ZIC5 mRNA was up-regulated 17 fold (p = 8.4E–07), ZIC2 8 fold (p = 1.3E–05) and HELLS 2 fold (p = 0.006) in GG3 glands derived from GS 4 + 3 = 7. HELLS expression of ≥ 1% occurred in 10% GS < 7, 17% GS 7 and 43% GS >7 prostate cancer (p < 0.001). Using a cut-off of ≥ 1%, protein expression of ZIC5 was present in 28% GS < 7, 43% GS 7 and 57% GS > 7 cancer (p < 0.001). ZIC2 was neither associated with GS nor outcome in our validation set. HELLS was independently predictive for biochemical-recurrence after radical prostatectomy (HR 2.3; CI 1.5–3.6; p < 0.01). In conclusion, HELLS and ZIC5 might be promising candidate markers for selection of biopsy GS 6 prostate cancer being at risk for up-grading at prostatectomy.

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Metadaten
URN:urn:nbn:de:kobv:526-opus4-6573
Publisher DOI:https://doi.org/10.18632/oncotarget.9344
Author:A. Marije Hoogland, René BöttcherORCiD, Esther VerhoefORCiD, Guido JensterORCiD, Geert J.L.H. van LeendersORCiD
ISSN:1949-2553
Parent Title (English):Oncotarget
Document Type:Article
Language:English
Year of Publication:2016
Volume:7
Issue:25
First Page:37846
Last Page:37856
Faculties an central facilities:Fachbereich Ingenieur- und Naturwissenschaften
Publishing Institution:Technische Hochschule Wildau
Tag:RNA sequencing; immunohistochemistry; laser capture microdissection; prostate cancer
Source:Hoogland A. Marije, Böttcher R., Verhoef E., Jenster G., Leenders G. J.L.H. van Gene-expression analysis of gleason grade 3 tumor glands embedded in low- and high-risk prostate cancer. Oncotarget. 2016; 7: 37846-37856. Retrieved from https://www.oncotarget.com/article/9344/text/
Dewey Decimal Classification:6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 616 Krankheiten
Licence (German):Creative Commons - CC BY 3.0 - Namensnennung 3.0 Unported
Release Date:2016/07/15
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