title: CXCL12 promoter methylation and PD-L1 expression as prognostic biomarkers in prostate cancer patients.
abstract: 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.
  
  
  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.
authors.affiliation: Institute of Pathology, University Hospital Bonn, Bonn, Germany.
authors.forename: Diane
authors.initials: D
authors.lastname: Goltz
authors.affiliation: Institute of Pathology, University Hospital Bonn, Bonn, Germany.
authors.forename: Emily Eva
authors.initials: EE
authors.lastname: Holmes
authors.affiliation: Institute of Pathology, University Hospital Bonn, Bonn, Germany.
authors.forename: Heidrun
authors.initials: H
authors.lastname: Gevensleben
authors.affiliation: Weill Cornell Medicine of Cornell University, Department of Pathology and Laboratory Medicine, New York, NY, USA.|Weill Cornell Medicine of Cornell University, Englander Institute for Precision Medicine, New York, NY, USA.
authors.forename: Verena
authors.initials: V
authors.lastname: Sailer
authors.affiliation: Institute of Pathology, University Hospital Bonn, Bonn, Germany.
authors.forename: Jörn
authors.initials: J
authors.lastname: Dietrich
authors.affiliation: Institute of Pathology, University Hospital Bonn, Bonn, Germany.
authors.forename: Maria
authors.initials: M
authors.lastname: Jung
authors.affiliation: Institute of Pathology, University Hospital Bonn, Bonn, Germany.
authors.forename: Magda
authors.initials: M
authors.lastname: Röhler
authors.affiliation: Institute of Pathology, University Hospital Bonn, Bonn, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Meller
authors.affiliation: Department of Urology, University Hospital Bonn, Bonn, Germany.
authors.forename: Jörg
authors.initials: J
authors.lastname: Ellinger
authors.affiliation: Institute of Pathology, University Hospital Bonn, Bonn, Germany.
authors.forename: Glen
authors.initials: G
authors.lastname: Kristiansen
authors.affiliation: Institute of Pathology, University Hospital Bonn, Bonn, Germany.|Department of Otolaryngology, Head and Neck Surgery, University Hospital Bonn, Bonn, Germany.
authors.forename: Dimo
authors.initials: D
authors.lastname: Dietrich
mesh_terms: D060890:B7-H1 Antigen / Q000235:genetics*; D014408:Biomarkers, Tumor / Q000235:genetics*; D054377:Chemokine CXCL12 / Q000235:genetics*; D015331:Cohort Studies; D019175:DNA Methylation; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D015999:Multivariate Analysis; D060787:Neoplasm Grading; D017063:Outcome Assessment, Health Care / Q000379:methods / Q000706:statistics & numerical data; D011379:Prognosis; D011401:Promoter Regions, Genetic / Q000235:genetics*; D016016:Proportional Hazards Models; D011468:Prostatectomy / Q000379:methods; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000473:pathology / Q000601:surgery
chemical_list: D060890:B7-H1 Antigen; D014408:Biomarkers, Tumor; C423236:CD274 protein, human; C515255:CXCL12 protein, human; D054377:Chemokine CXCL12
keywords: CXCL12; DNA methylation; biomarker; prostate cancer