CXCL12 promoter methylation and PD-L1 expression as prognostic biomarkers in prostate cancer patients
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Diane Goltz1,*, Emily Eva Holmes1,*, Heidrun Gevensleben1, Verena Sailer2,3, Jörn Dietrich1, Maria Jung1, Magda Röhler1, Sebastian Meller1, Jörg Ellinger4, Glen Kristiansen1,#, Dimo Dietrich1,5,#
1Institute of Pathology, University Hospital Bonn, Bonn, Germany
2Weill Cornell Medicine of Cornell University, Department of Pathology and Laboratory Medicine, New York, NY, USA
3Weill Cornell Medicine of Cornell University, Englander Institute for Precision Medicine, New York, NY, USA
4Department of Urology, University Hospital Bonn, Bonn, Germany
5Department of Otolaryngology, Head and Neck Surgery, University Hospital Bonn, Bonn, Germany
*These authors have contributed equally to this work
#These authors are joint senior authors on this work
Dimo Dietrich, email: firstname.lastname@example.org
Keywords: CXCL12, DNA methylation, prostate cancer, biomarker
Received: December 25, 2015 Accepted: June 26, 2016 Published: July 22, 2016
Background: The CXCR4/CXCL12 axis plays a central role in systemic metastasis of prostate carcinoma (PCa), thereby representing a promising target for future therapies. Recent data suggest that the CXCR4/CXCL12 axis is functionally linked to the PD-1/PD-L1 immune checkpoint. We evaluated the prognostic value of aberrant CXCL12 DNA methylation with respect to PD-L1 expression in primary PCa.
Results: CXCL12 methylation showed a consistent significant correlation with Gleason grading groups in both cohorts (p < 0.001 for training and p = 0.034 for testing cohort). Short BCR-free survival was significantly associated with aberrant CXCL12 methylation in both cohorts and served as an independent prognostic factor in the testing cohort (hazard ratio = 1.92 [95%CI: 1.12–3.27], p = 0.049). Concomitant aberrant CXCL12 methylation and high PD-L1 expression was significantly associated with shorter BCR-free survival (p = 0.005). In comparative analysis, the CXCL12 methylation assay was able to provide approximately equivalent results in biopsy and prostatectomy specimens.
Materials and Methods: CXCL12 methylation was determined by means of a methylation specific quantitative PCR analysis in a radical prostatectomy patient cohort (n = 247, training cohort). Data published by The Cancer Genome Atlas served as a testing cohort (n = 498). CXCL12 methylation results were correlated to clinicopathological parameters including biochemical recurrence (BCR)-free survival.
Conclusions: CXCL12 methylation is a powerful prognostic biomarker for BCR in PCa patients after radical prostatectomy. Further studies need to ascertain if CXCL12 methylation may aid in planning active surveillance strategies.
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