Aims Prostate cancer (PrCa) is the most frequently diagnosed non-cutaneous cancer in men. Without clear pathological indicators of disease trajectory at diagnosis, management of PrCa is challenging, given its wide-ranging manifestation from indolent to highly aggressive disease. This study examines the role in PrCa of the Pygopus (PYGO)2 chromatin effector protein as a risk stratification marker in PrCa.
Methods RNA expression was performed in PrCa cell lines using Northern and RT-PCR analyses. Protein levels were assessed using immunoblot and immunofluorescence. Immunohistochemistry was performed on tissue microarrays constructed from radical prostatectomies with 5-year patient follow-up data including Gleason score tumour staging, margin and lymph node involvement and prostate serum antigen (PSA) levels. Biochemical recurrence (BR) was defined as a postoperative PSA level of >0.2 nL. Univariate and multivariate analyses were performed using SAS and Kaplan-Meier curves using graphPad (Prism).
Results In vitro depletion of PYGO2 by RNAi in both androgen receptor positive and negative PrCa cell lines attenuated growth and reduced Ki67 and 47S rRNA expression, while PYGO2 protein was localised to the nuclei of tumours as determined by immunohistochemistry. High expression levels of PYGO2 in tumours (n=156) were correlated with BR identified as PSA progression, after 7-year follow-up independent of other traditional risk factors. Most importantly, high PYGO2 levels in intermediate grade tumours suggested increased risk of recurrence over those with negative or weak expression.
Conclusion Our data suggest that elevated PYGO2 expression in primary prostate adenocarcinoma is a potential risk factor for BR.
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Handling editor Runjan Chetty.
Contributors KRK: wrote manuscript, designed and conducted investigation, collected data, acquired funding and supervised project. PP: statistical analysis, wrote and edited parts of manuscript (ms). JT: provided patient data, contributed to ms. SAoki: conducted experiments, wrote parts of ms. SAnwar: marked specimens for sampling and confirmed diagnoses. EF: constructed microarrays. PA: conducted experiments, collected data. KV: optimized IHC protocols. LG: scored specimens. SC: statistical analysis. ZH: conducted experiments and collected data. PG-A: collected data. AS: scored specimens, edited ms. CP: study design, acquired funding, wrote and edited parts of ms.
Funding This work was funded by the Avalon Motorcycle Ride for Dad, the CIHR and RDC, NL. We thank Marjan Afrousian, Ines Gai, Cynthia Curtis, Khisal Quereshi, Kweku Dankwa and Dan Fontaine for assistance.
Competing interests None declared.
Ethics approval Memorial University HREA 2012.133.
Provenance and peer review Not commissioned; externally peer reviewed.
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