title: Clinico-pathological significance of the molecular alterations of the SPOP gene in prostate cancer.
abstract: OBJECTIVE
  Speckle-type POZ protein (SPOP) is an E3 ubiquitin ligase adaptor recently described to be mutated in prostate cancer (PCa). Hence, studying the gene expression profile and the presence of SPOP mutations in PCa and understanding its clinico-pathological significance as prognostic and therapeutic biomarker are important to further understand its role in PCa development.
  
  
  METHODS
  A cohort of 265 paraffin-embedded PCa samples from patients with more than 5 years of follow-up and treated with radical prostatectomy were collected at our institution for SPOP evaluation. RT-qPCR analysis was performed for expression studies while mutations were assessed by next generation sequencing. Relationship with prognosis was analysed using log-rank analysis and multivariable Cox regression.
  
  
  RESULTS
  SPOP was found to be strongly down-regulated in PCa (median=0.24; range=0.04-9.98) and its expression was associated with both, biochemical (p=0.003) and clinical progression free survival (p=0.023), the very low SPOP expression levels being associated to the worst prognosis. Multivariate analysis demonstrated that low levels of SPOP independently predicted a worse prognosis for both, biochemical (Hazard ratio (HR)=0.5; confidence interval (CI) 95% [0.4-0.9], p=0.011) and clinical progression (HR=0.6; IC 95% [0.4-1], p=0.046). SPOP mutations were found in 10% of TMPRSS2-ERG (T2E)-negative cases. Log-rank tests showed that mutations were significantly associated with biochemical progression free survival (BPFS) (p=0.009) and also were significant in the multivariable analysis (HR=3.4; IC 95% [1.5-7.6], p=0.004).
  
  
  CONCLUSIONS
  The present study demonstrates that prognosis varies depending on SPOP expression and mutational status, hence, defining a new biotype of PCa associated with a worse prognosis.
authors.affiliation: Laboratory of Molecular Biology, Fundación Instituto Valenciano de Oncología, Valencia, Spain.
authors.forename: María
authors.initials: M
authors.lastname: García-Flores
authors.affiliation: Laboratory of Molecular Biology, Fundación Instituto Valenciano de Oncología, Valencia, Spain.
authors.forename: Irene
authors.initials: I
authors.lastname: Casanova-Salas
authors.affiliation: Service of Urology, Fundación Instituto Valenciano de Oncología, Valencia, Spain.
authors.forename: José
authors.initials: J
authors.lastname: Rubio-Briones
authors.affiliation: Department of Pathology, Fundación Instituto Valenciano de Oncología, Valencia, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Calatrava
authors.affiliation: Service of Urology, Fundación Instituto Valenciano de Oncología, Valencia, Spain.
authors.forename: José
authors.initials: J
authors.lastname: Domínguez-Escrig
authors.affiliation: Laboratory of Molecular Biology, Fundación Instituto Valenciano de Oncología, Valencia, Spain.
authors.forename: Luis
authors.initials: L
authors.lastname: Rubio
authors.affiliation: Service of Urology, Fundación Instituto Valenciano de Oncología, Valencia, Spain.
authors.forename: Miguel
authors.initials: M
authors.lastname: Ramírez-Backhaus
authors.affiliation: Laboratory of Molecular Biology, Fundación Instituto Valenciano de Oncología, Valencia, Spain.
authors.forename: Antonio
authors.initials: A
authors.lastname: Fernández-Serra
authors.affiliation: Laboratory of Molecular Biology, Fundación Instituto Valenciano de Oncología, Valencia, Spain.
authors.forename: Zaida
authors.initials: Z
authors.lastname: García-Casado
authors.affiliation: Laboratory of Molecular Biology, Fundación Instituto Valenciano de Oncología, Valencia, Spain. Electronic address: jalopez@fivo.org.
authors.forename: José Antonio
authors.initials: JA
authors.lastname: López-Guerrero
mesh_terms: D000328:Adult; D000368:Aged; D018450:Disease Progression; D015536:Down-Regulation; D005819:Genetic Markers / Q000235:genetics; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D060787:Neoplasm Grading; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D011379:Prognosis; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000473:pathology; D012334:RNA, Neoplasm / Q000032:analysis; D012097:Repressor Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D005819:Genetic Markers; D009687:Nuclear Proteins; D012334:RNA, Neoplasm; D012097:Repressor Proteins; C509761:SPOP protein, human
keywords: Biomarker; Biotype; Prognosis; Prostate cancer; Speckle-type POZ protein (SPOP)