title: Influence of Genetic Polymorphisms in Prostaglandin E2 Pathway (COX-2/HPGD/SLCO2A1/ABCC4) on the Risk for Colorectal Adenoma Development and Recurrence after Polypectomy.
abstract: OBJECTIVE
  Deregulation of prostaglandin E2 (PGE2) levels reported in colorectal carcinogenesis contributes to key steps of cancer development. Our aim was to evaluate the influence of the genetic variability in COX-2/HPGD/SLCO2A1/ABCC4 PGE2 pathway genes on the development and recurrence of colorectal adenomas.
  
  
  METHODS
  A case-control study was conducted gathering 480 unscreened individuals and 195 patients with personal history of adenomas. A total of 43 tagSNPs were characterized using the Sequenom platform or real-time PCR.
  
  
  RESULTS
  Ten tagSNPs were identified as susceptibility biomarkers for the development of adenomas. The top three most meaningful tagSNPs include the rs689466 in COX-2 (odds ratio (OR)=3.23; 95% confidence interval (CI): 1.52-6.86), rs6439448 in SLCO2A1 (OR=0.38; 95% CI: 0.22-0.65) and rs1751051 in ABCC4 genes (OR=2.75; 95% CI: 1.58-4.80). The best four-locus gene-gene interaction model included the rs1346271, rs1863642 and rs12500316 single nucleotide polymorphisms in HPGD and rs1678405 in ABCC4 genes and was associated with a 13-fold increased susceptibility (95% CI: 3.84-46.3, P<0.0001, cross-validation (CV) accuracy: 0.78 and CV consistency: 8/10). Interesting, in low-risk patients the ABCC4 rs9524821AA genotype was associated not only with a higher hazard ratio (HR=2.93; 95% CI: 1.07-8.03), but half of these patients had adenoma recurrence at 60 months, considerably higher than the 21% noticed in low-risk patients.
  
  
  CONCLUSIONS
  Genetic polymorphisms in COX-2/PGE2 pathway appear to contribute to the development of colorectal adenomas and influence the interval time to adenomas recurrence. The definition of risk models through the inclusion of genetic biomarkers might improve the adherence and optimization of current screening and surveillance guidelines for colorectal cancer prevention.
authors.affiliation: Molecular Oncology and Viral Pathology Group, IPO-Porto Research Center, Portuguese Oncology Institute of Porto, Porto, Portugal.|Abel Salazar Institute of Biomedical Sciences, University of Porto, Porto, Portugal.|Department of Research, Portuguese League Against Cancer, Porto, Portugal.
authors.forename: Carina
authors.initials: C
authors.lastname: Pereira
authors.affiliation: Molecular Oncology and Viral Pathology Group, IPO-Porto Research Center, Portuguese Oncology Institute of Porto, Porto, Portugal.
authors.forename: Sara
authors.initials: S
authors.lastname: Queirós
authors.affiliation: Department of Pathology, Portuguese Oncology Institute of Porto, Porto, Portugal.
authors.forename: Ana
authors.initials: A
authors.lastname: Galaghar
authors.affiliation: Molecular Oncology and Viral Pathology Group, IPO-Porto Research Center, Portuguese Oncology Institute of Porto, Porto, Portugal.|Virology Service, Portuguese Institute of Oncology, Porto, Portugal.
authors.forename: Hugo
authors.initials: H
authors.lastname: Sousa
authors.affiliation: Department of Gastroenterology, Centro Hospitalar do Porto, Porto, Portugal.
authors.forename: Ricardo
authors.initials: R
authors.lastname: Marcos-Pinto
authors.affiliation: Department of Gastroenterology, Portuguese Oncology Institute of Porto, Porto, Portugal.|Faculty of Medicine, Department of Physiology, University of Porto, Porto, Portugal.
authors.forename: Pedro
authors.initials: P
authors.lastname: Pimentel-Nunes
authors.affiliation: Department of Gastroenterology, Portuguese Oncology Institute of Porto, Porto, Portugal.
authors.forename: Catarina
authors.initials: C
authors.lastname: Brandão
authors.affiliation: Molecular Oncology and Viral Pathology Group, IPO-Porto Research Center, Portuguese Oncology Institute of Porto, Porto, Portugal.|Abel Salazar Institute of Biomedical Sciences, University of Porto, Porto, Portugal.|Department of Research, Portuguese League Against Cancer, Porto, Portugal.|Virology Service, Portuguese Institute of Oncology, Porto, Portugal.|CEBIMED, Faculty of Health Sciences of Fernando Pessoa University of Porto, Porto, Portugal.
authors.forename: Rui
authors.initials: R
authors.lastname: Medeiros
authors.affiliation: Department of Gastroenterology, Portuguese Oncology Institute of Porto, Porto, Portugal.|Faculty of Medicine, CINTESIS/Department of Biostatistics and Medical Informatics, University of Porto, Porto, Portugal.
authors.forename: Mário
authors.initials: M
authors.lastname: Dinis-Ribeiro