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.
Highlights
Prostate cancer (PCA) remains a major cancer in the western countries and ranks as the second leading cause of cancer related deaths among men [1]
In high grade intraepithelial neoplasia (HGPIN), mean Cysteine- rich secretory protein 3 (CRISP3) protein expression was comparable to prostate cancer (PCA) (1.65 ± 0.56) (p = 0.84) and still significantly higher than benign prostate tissue (P < 0.0001)
CRISP3 protein expression in association to Gleason score, surgical margin, pathological stage and PSA biochemical relapse To investigate the association of CRISP3 protein expression in relation to Gleason score, we grouped samples based on Gleason score sum of individual tissue microarray (TMA) cores
Summary
Prostate cancer (PCA) remains a major cancer in the western countries and ranks as the second leading cause of cancer related deaths among men [1]. Several genomic studies have implemented methods to mark specific genomic alterations associated with disease progression and Cysteine- rich secretory protein 3 (CRISP3) is a member of large family of cysteine- rich secretory proteins that are expressed in vertebrates, insects, plants, fungi, and yeast [2,3,4,5,6]. ERG gene rearrangement is the most abundant genomic aberrations in prostate cancer that accounts for around 50% of clinically localized disease. Several studies have implicated ERG gene rearrangements with increased rate of PTEN deletion. The presence of both ERG and PTEN aberration has been suggested to signify a distinct molecular subtype of PCA.
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