Clinico-pathological significance of the molecular alterations of the SPOP gene in prostate cancer

• Published in: European journal of cancer (1990) Vol. 50; no. 17; pp. 2994 - 3002
• Main Authors: García-Flores, María, Casanova-Salas, Irene, Rubio-Briones, José, Calatrava, Ana, Domínguez-Escrig, José, Rubio, Luis, Ramírez-Backhaus, Miguel, Fernández-Serra, Antonio, García-Casado, Zaida, López-Guerrero, José Antonio
• Format: Journal Article
• Language: English
• Published: Kidlington Elsevier Ltd 01.11.2014; Elsevier
• Subjects: Adult; Aged; Biological and medical sciences; Biomarker; Biotype; Disease Progression; Down-Regulation; Genetic Markers - genetics; Hematology, Oncology and Palliative Medicine; Humans; Kaplan-Meier Estimate; Male; Medical sciences; Middle Aged; Multiple tumors. Solid tumors. Tumors in childhood (general aspects); Mutation - genetics; Neoplasm Grading; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; Pharmacology. Drug treatments; Prognosis; Prostate cancer; Prostatic Neoplasms - genetics; Prostatic Neoplasms - pathology; Repressor Proteins - genetics; Repressor Proteins - metabolism; RNA, Neoplasm - analysis; Speckle-type POZ protein (SPOP); Tumors; Biotype; Biomarker; Prognosis; Prostate cancer; Speckle-type POZ protein (SPOP); Urinary system disease; Prostate disease; Biological marker; Malignant tumor; Protein; Cancerology; Gene; Genetics; Male genital diseases; Cancer
• ISSN: 0959-8049; 1879-0852
• DOI: 10.1016/j.ejca.2014.08.009

Abstract Aims 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. Patients and 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.