title: Genetic polymorphisms in key hypoxia-regulated downstream molecules and phenotypic correlation in prostate cancer.
abstract: BACKGROUND
  In this study we sought if, in their quest to handle hypoxia, prostate tumors express target hypoxia-associated molecules and their correlation with putative functional genetic polymorphisms.
  
  
  METHODS
  Representative areas of prostate carcinoma (n = 51) and of nodular prostate hyperplasia (n = 20) were analysed for hypoxia-inducible factor 1 alpha (HIF-1α), carbonic anhydrase IX (CAIX), lysyl oxidase (LOX) and vascular endothelial growth factor (VEGFR2) immunohistochemistry expression using a tissue microarray. DNA was isolated from peripheral blood and used to genotype functional polymorphisms at the corresponding genes (HIF1A +1772 C > T, rs11549465; CA9 + 201 A > G; rs2071676; LOX +473 G > A, rs1800449; KDR - 604 T > C, rs2071559).
  
  
  RESULTS
  Immunohistochemistry analyses disclosed predominance of positive CAIX and VEGFR2 expression in epithelial cells of prostate carcinomas compared to nodular prostate hyperplasia (P = 0.043 and P = 0.035, respectively). In addition, the VEGFR2 expression score in prostate epithelial cells was higher in organ-confined and extra prostatic carcinoma compared to nodular prostate hyperplasia (P = 0.031 and P = 0.004, respectively). Notably, for LOX protein the immunoreactivity score was significantly higher in organ-confined carcinomas compared to nodular prostate hyperplasia (P = 0.015). The genotype-phenotype analyses showed higher LOX staining intensity for carriers of the homozygous LOX +473 G-allele (P = 0.011). Still, carriers of the KDR-604 T-allele were more prone to have higher VEGFR2 expression in prostate epithelial cells (P < 0.006).
  
  
  CONCLUSIONS
  Protein expression of hypoxia markers (VEGFR2, CAIX and LOX) on prostate epithelial cells was different between malignant and benign prostate disease. Two genetic polymorphisms (LOX +473 G > A and KDR-604 T > C) were correlated with protein level, accounting for a potential gene-environment effect in the activation of hypoxia-driven pathways in prostate carcinoma. Further research in larger series is warranted to validate present findings.
authors.affiliation: Department of Urology, Porto Hospital Centre - St. António Hospital, Largo Prof. Abel Salazar, 4000-001, Porto, Portugal. avfraga@gmail.com.|Center for Urological Research, Department of Urology, Porto Hospital Centre - St. António Hospital, Porto, Portugal. avfraga@gmail.com.|ICBAS, Abel Salazar Biomedical Sciences Institute, University of Porto, Porto, Portugal. avfraga@gmail.com.
authors.forename: Avelino
authors.initials: A
authors.lastname: Fraga
authors.affiliation: Center for Urological Research, Department of Urology, Porto Hospital Centre - St. António Hospital, Porto, Portugal.|Molecular Oncology Group - CI, Portuguese Institute of Oncology, Porto, Portugal.|Genetics Laboratory, Faculty of Medicine, University of Lisbon, Lisbon, Portugal.
authors.forename: Ricardo
authors.initials: R
authors.lastname: Ribeiro
authors.affiliation: Department of Pathology, Porto Hospital Centre - St. António Hospital, Porto, Portugal.
authors.forename: André
authors.initials: A
authors.lastname: Coelho
authors.affiliation: Department of Pathology, Porto Hospital Centre - St. António Hospital, Porto, Portugal.
authors.forename: José Ramon
authors.initials: JR
authors.lastname: Vizcaíno
authors.affiliation: Department of Pathology and Oncology, Faculty of Medicine, University of Porto, Porto, Portugal.
authors.forename: Helena
authors.initials: H
authors.lastname: Coutinho
authors.affiliation: Department of Pathology and Oncology, Faculty of Medicine, University of Porto, Porto, Portugal.|Institute of Pathology and Molecular Immunology of University of Porto (IPATIMUP), Porto, Portugal.
authors.forename: José Manuel
authors.initials: JM
authors.lastname: Lopes
authors.affiliation: Department of Urology, Porto Hospital Centre - St. António Hospital, Largo Prof. Abel Salazar, 4000-001, Porto, Portugal.|Center for Urological Research, Department of Urology, Porto Hospital Centre - St. António Hospital, Porto, Portugal.
authors.forename: Paulo
authors.initials: P
authors.lastname: Príncipe
authors.affiliation: Department of Urology, Porto Military Hospital, Porto, Portugal.
authors.forename: Carlos
authors.initials: C
authors.lastname: Lobato
authors.affiliation: ICBAS, Abel Salazar Biomedical Sciences Institute, University of Porto, Porto, Portugal.
authors.forename: Carlos
authors.initials: C
authors.lastname: Lopes
authors.affiliation: ICBAS, Abel Salazar Biomedical Sciences Institute, University of Porto, Porto, Portugal.|Molecular Oncology Group - CI, Portuguese Institute of Oncology, Porto, Portugal.
authors.forename: Rui
authors.initials: R
authors.lastname: Medeiros
mesh_terms: D000368:Aged; D000071231:Carbonic Anhydrase IX / Q000096:biosynthesis; D015687:Cell Hypoxia / Q000235:genetics; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000096:biosynthesis; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D011110:Polymorphism, Genetic; D011470:Prostatic Hyperplasia / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D008249:Protein-Lysine 6-Oxidase / Q000096:biosynthesis; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis
chemical_list: D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D042461:Vascular Endothelial Growth Factor A; D008249:Protein-Lysine 6-Oxidase; D000071231:Carbonic Anhydrase IX
keywords: Genetic polymorphism; Hypoxia; Hypoxia-inducible factor 1; Prostate cancer