title: Cysteine- rich secretory protein 3 (CRISP3), ERG and PTEN define a molecular subtype of prostate cancer with implication to patients' prognosis.
abstract: Cysteine- rich secretory protein 3 (CRISP3) prognostic significance in prostate cancer (PCA) has generated mixed result. Herein, we investigated and independently validated CRISP3 expression in relation to ERG and PTEN genomic aberrations and clinical outcome. CRISP3 protein expression was examined by immunohistochemistry using a cohort of patients with localized PCA (n = 215) and castration resistant PCA (CRPC) (n = 46). The Memorial Sloan Kettering (MSKCC) and Swedish cohorts were used for prognostic validation. Results showed, CRISP3 protein intensity to be significantly associated with neoplastic epithelium, being highest in CRPC vs. benign prostate tissue (p < 0.0001), but was not related to Gleason score (GS). CRISP3 mRNA was significantly associated with higher GS (p = 0.022 in MSKCC, p = 1.1e-4 in Swedish). Significant association between CRISP3 expression and clinical outcome was documented at the mRNA but not the protein expression levels. CRISP3 mRNA expression was related to biochemical recurrence in the MSKCC (p = 0.038) and lethal disease in the Swedish cohort (p = 0.0086) and retained its prognostic value in the subgroup of patients with GS 6 & 7. Furthermore, CRISP3 protein and mRNA expression was significantly associated with positive ERG status and with PTEN deletions. Functional biology analysis documented phenylalanine metabolism as the most significant pathway governing high CRISP3 and ERG expression in this subtype of PCA. In conclusion, the combined status of CRISP3, ERG and PTEN define a molecular subtype of PCA with poorest and lethal outcome. Assessing their combined value may be of added value in stratifying patients into different prognostic groups and identify those with poorest clinical outcome.
authors.forename: Samir
authors.initials: S
authors.lastname: Al Bashir
authors.forename: Mohammed
authors.initials: M
authors.lastname: Alshalalfa
authors.forename: Samar A
authors.initials: SA
authors.lastname: Hegazy
authors.forename: Michael
authors.initials: M
authors.lastname: Dolph
authors.forename: Bryan
authors.initials: B
authors.lastname: Donnelly
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Calgary and Calgary Laboratory Services, Calgary, AB, Canada. tarek.bismar@cls.ab.ca.
authors.forename: Tarek A
authors.initials: TA
authors.lastname: Bismar
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000096:biosynthesis* / Q000235:genetics; D045744:Cell Line, Tumor; D015331:Cohort Studies; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D051059:PTEN Phosphohydrolase / Q000096:biosynthesis* / Q000235:genetics; D011379:Prognosis; D011471:Prostatic Neoplasms / Q000145:classification* / Q000378:metabolism*; D012471:Salivary Proteins and Peptides / Q000096:biosynthesis* / Q000235:genetics; D029589:Seminal Plasma Proteins / Q000096:biosynthesis* / Q000235:genetics; D046888:Tissue Array Analysis; D015534:Trans-Activators / Q000096:biosynthesis* / Q000235:genetics; D000071230:Transcriptional Regulator ERG
chemical_list: D014408:Biomarkers, Tumor; C489926:CRISP3 protein, human; C072312:ERG protein, human; D012471:Salivary Proteins and Peptides; D029589:Seminal Plasma Proteins; D015534:Trans-Activators; D000071230:Transcriptional Regulator ERG; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human