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.

Genomic landscape of carcinogen-induced and genetically induced mouse skin squamous cell carcinoma

“…In addition, we identified a recurrent amplification of region 17qB1 (30%) containing Crisp3 (Fig. 3d,e), a gene expressed in a subset of prostate cancers with poor prognosis 46 , and Pgk2, which expresses an enzyme of the glycolytic pathway. Overall, these data indicate that whole-chromosome amplifications and focal CNAs are likely to influence the progression of DMBA-induced tumors by affecting regions harboring well-established and putative oncogenes.…”

In�silico analysis identifies CRISP3 as a potential peripheral blood biomarker for multiple myeloma: From data modeling to validation with RT-PCR

“…Although it is generally accepted that IgH translocation occurs frequently either in malignant MM or MGUS (4), little is known about the exact mechanism of MM development. The transcriptional factors Oct2 and B-cell-specific coactivator OBF-1 may activate the expression of IgH by directly binding to the consensus ATGCAAAT octamer, which also exists on the CRISP3 gene (6,27). Previous studies have indicated that the gene expression of CRISP3 was markedly up regulated in prostate carcinoma and closely associated with neoplastic epithelium (27,28).…”

“…Previous studies have indicated that the gene expression of CRISP3 was markedly up regulated in prostate carcinoma and closely associated with neoplastic epithelium (27,28). Additionally, CRISP3, together with Transcription regulator ERG and Phosphatase and tensin homolog, defined a molecular subtype of poorest clinical outcomes (27,28), suggesting that CRISP3 is a potential biomarker for prostate cancer. In addition, CRISP3 expression has been demonstrated to be altered in chronic pancreatitis and oral squamous cell carcinoma (29,30).…”

“…The transcriptional factors Oct2 and B-cell-specific coactivator OBF-1 may activate the expression of IgH by directly binding to the consensus ATGCAAAT octamer, which also exists on the CRISP3 gene (6,27). Previous studies have indicated that the gene expression of CRISP3 was markedly up regulated in prostate carcinoma and closely associated with neoplastic epithelium (27,28). Additionally, CRISP3, together with Transcription regulator ERG and Phosphatase and tensin homolog, defined a molecular subtype of poorest clinical outcomes (27,28), suggesting that CRISP3 is a potential biomarker for prostate cancer.…”

Trends in Gene Expression Profiling for Prostate Cancer Risk Assessment: A Systematic Review

“…After literature screening, 12 reviews [7,8,9,10,11,12,13,14,15,16,17,18] and 137 research papers [19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70,71,72,73,74,75,76,77,78,79,80,81,82,83,84,85,86,87,88,89,90,91,92,93,94,95,96,97,98,99,100,101,102...…”