title: SPINK1 expression in relation to PTEN and ERG in matched primary and lymph node metastatic prostate cancer: Implications for biomarker development.
abstract: BACKGROUND
  SPINK1, ERG, and PTEN are proposed prognostic biomarkers in prostate cancer (PCA). However, their relations and patterns of expression in primary and metastatic lymph node (LN) PCAs are not fully explored.
  
  
  METHODS
  A tissue microarray of matched primary PCA and LN metastasis was constructed from 36 patients. SPINK1, ERG, and PTEN expression statuses were assessed by immunohistochemistry and correlated with each other.
  
  
  RESULTS
  SPINK1 and ERG were expressed in 25% and 42.7% of primary PCA cases, respectively. PTEN loss of any degree was observed in 91.7% of primary PCA cases, with 54.2% showing complete loss. In primary PCA, 12.5% of the cases showed SPINK1+/ERG-phenotype, 16.7% showed SPINK1+/ERG+phenotype, 25.0% showed SPINK1-/ERG+phenotype, and 45.8% showed SPINK1-/ERG-phenotype. All PCAs with expression of either SPINK1 or ERG also exhibited PTEN loss, whereas PCA without PTEN loss (2 cases) expressed neither SPINK1 nor ERG. In primary PCA, evaluation of combined ERG and SPINK1 status, but not SPINK1 individually, was associated with a significant difference in proportion of Gleason patterns (P = 0.013), with the SPINK1+/ERG+and SPINK1-/ERG-phenotypes represented more in Gleason pattern>7 PCAs. In LN metastases, the overall SPINK1 protein expression frequency was significantly lower (6.5% of cases) compared with primary PCA (P = 0.03). Only 16.7% of cases with positive SPINK1 expression in primary PCA maintained expression in LN metastases. The down-regulated SPINK1 expression in LN was primarily because of a reduction in the SPINK1+/ERG+PCA subpopulation to 3.5% of cases (P = 0.16 compared with primary PCA). The frequencies of ERG expression and PTEN loss were relatively stable in primary PCA and LN metastases.
  
  
  CONCLUSIONS
  SPINK1 expression is dynamically regulated with up-regulation in primary sites of nodal metastatic PCA and down-regulation in LN metastases. The increased SPINK1 expression in primary site of nodal metastatic PCA is secondary to an increased frequency of SPINK1+/ERG+tumors. In primary PCAs, the SPINK1+/ERG+phenotype is associated with higher Gleason grade, suggesting that this phenotype may mark a more aggressive PCA subpopulation with higher risk of LN metastases.
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Calgary and Calgary Laboratory Services, Calgary, Alberta, Canada.
authors.forename: Kuo-Cheng
authors.initials: KC
authors.lastname: Huang
authors.affiliation: Division of Anatomic Pathology, Hôpital du Sacré-Coeur de Montréal, Montreal, Quebec, Canada.
authors.forename: Louis R
authors.initials: LR
authors.lastname: Bégin
authors.affiliation: Department of Urology, Vattikuti Urology Institute, Henry Ford Health System, Detroit, MI.
authors.forename: Nallasivam
authors.initials: N
authors.lastname: Palanisamy
authors.affiliation: Department of Urology, University of Calgary, Calgary, Alberta, Canada; The Prostate Cancer Center, Calgary, Alberta, Canada.
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, Alberta, Canada; The Prostate Cancer Center, Calgary, Alberta, Canada; Departments of Oncology, Biochemistry and Molecular Biology, Calgary, Alberta, Canada; Southern Alberta Cancer Institute and Tom Baker Cancer Center, Calgary, Alberta, Canada. Electronic address: tabismar@ucalgary.ca.
authors.forename: Tarek A
authors.initials: TA
authors.lastname: Bismar
mesh_terms: D000368:Aged; D014408:Biomarkers, Tumor / Q000096:biosynthesis; D002352:Carrier Proteins / Q000096:biosynthesis*; D006801:Humans; D007150:Immunohistochemistry; D008198:Lymph Nodes / Q000473:pathology; D008207:Lymphatic Metastasis; D008297:Male; D008875:Middle Aged; D060787:Neoplasm Grading; D051059:PTEN Phosphohydrolase / Q000096:biosynthesis*; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000473:pathology; D012307:Risk Factors; D000071230:Transcriptional Regulator ERG / Q000096:biosynthesis; D014359:Trypsin Inhibitor, Kazal Pancreatic
chemical_list: D014408:Biomarkers, Tumor; D002352:Carrier Proteins; C072312:ERG protein, human; C486642:SPINK1 protein, human; D000071230:Transcriptional Regulator ERG; D014359:Trypsin Inhibitor, Kazal Pancreatic; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human
keywords: Biomarkers; ERG; High-risk primary localized prostate cancer; PTEN; Prostate cancer; SPINK1; lymph node metastasis