title: Intestinal PTGS2 mRNA levels, PTGS2 gene polymorphisms, and colorectal carcinogenesis.
abstract: OBJECTIVE
  Inflammation is a major risk factor for development of colorectal cancer (CRC). Prostaglandin synthase cyclooxygenase-2 (COX-2) encoded by the PTGS2 gene is the rate limiting enzyme in prostaglandin synthesis and therefore plays a distinct role as regulator of inflammation.
  
  
  METHODS
  PTGS2 mRNA levels were determined in intestinal tissues from 85 intestinal adenoma cases, 115 CRC cases, and 17 healthy controls. The functional PTGS2 polymorphisms A-1195G (rs689466), G-765C (rs20417), T8473C (rs5275) were assessed in 200 CRC cases, 991 adenoma cases and 399 controls from the Norwegian KAM cohort.
  
  
  RESULTS
  PTGS2 mRNA levels were higher in mild/moderate adenoma tissue compared to morphologically normal tissue from the same individual (P<0.0001) and (P<0.035) and compared to mucosa from healthy individuals (P<0.0039) and (P<0.0027), respectively. In CRC patients, PTGS2 mRNA levels were 8-9 times higher both in morphologically normal tissue and in cancer tissue, compared to healthy individuals (P<0.0001). PTGS2 A-1195G variant allele carriers were at reduced risk of CRC (odds ratio (OR) = 0.52, 95% confidence interval (95% CI): 0.28-0.99, P = 0.047). Homozygous carriers of the haplotype encompassing the A-1195G and G-765C wild type alleles and the T8473C variant allele (PTGS2 AGC) were at increased risk of CRC as compared to homozygous carriers of the PTGS2 AGT (A-1195G, G-765C, T8473C) haplotype (OR = 5.37, 95% CI: 1.40-20.5, P = 0.014). No association between the investigated polymorphisms and PTGS2 mRNA levels could be detected.
  
  
  CONCLUSIONS
  High intestinal PTGS2 mRNA level is an early event in colorectal cancer development as it occurs already in mild/moderate dysplasia. PTGS2 polymorphisms that have been associated with altered PTGS2 mRNA levels/COX-2 activity in some studies, although not the present study, were associated with colorectal cancer risk. Thus, both PTGS2 polymorphisms and PTGS2 mRNA levels may provide information regarding CRC risk.
authors.affiliation: Department of Cellular and Molecular Medicine, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Lotte K
authors.initials: LK
authors.lastname: Vogel
authors.affiliation: Department of Environmental and Health Studies, Telemark University College, Telemark, Norway.
authors.forename: Mona
authors.initials: M
authors.lastname: Sæbø
authors.affiliation: Department of Environmental and Health Studies, Telemark University College, Telemark, Norway; Department of Laboratory Medicine, Telemark Hospital, Skien, Norway.
authors.forename: Helle
authors.initials: H
authors.lastname: Høyer
authors.affiliation: National Food Institute, Technical University of Denmark, Søborg, Denmark.
authors.forename: Tine Iskov
authors.initials: TI
authors.lastname: Kopp
authors.affiliation: National Research Centre for the Working Environment, Copenhagen, Denmark.
authors.forename: Ulla
authors.initials: U
authors.lastname: Vogel
authors.affiliation: Department of Cellular and Molecular Medicine, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Sine
authors.initials: S
authors.lastname: Godiksen
authors.affiliation: Department of Cellular and Molecular Medicine, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Franz B
authors.initials: FB
authors.lastname: Frenzel
authors.affiliation: Department of Genetics, Oslo University Hospital, Oslo, Norway.
authors.forename: Julian
authors.initials: J
authors.lastname: Hamfjord
authors.affiliation: Department of Genetics, Oslo University Hospital, Oslo, Norway; Department of Pathology, Oslo University Hospital, Oslo, Norway.
authors.forename: Inger Marie
authors.initials: IM
authors.lastname: Bowitz-Lothe
authors.affiliation: Department of Gastrointestinal and Pediatric Surgery, Oslo University Hospital, Oslo, Norway; Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
authors.forename: Egil
authors.initials: E
authors.lastname: Johnson
authors.affiliation: Department of Environmental and Health Studies, Telemark University College, Telemark, Norway; Department of Genetics, Oslo University Hospital, Oslo, Norway.
authors.forename: Elin H
authors.initials: EH
authors.lastname: Kure
authors.affiliation: Organ Center, Hospital of Southern Jutland, Aabenraa, Denmark; Institute of Regional Health Research, University of Southern Denmark, Odense, Denmark; Medical Department, Regional Hospital Viborg, Viborg, Denmark.
authors.forename: Vibeke
authors.initials: V
authors.lastname: Andersen
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000236:Adenoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000368:Aged; D000483:Alleles; D063646:Carcinogenesis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D016022:Case-Control Studies; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D051546:Cyclooxygenase 2 / Q000235:genetics* / Q000378:metabolism; D005260:Female; D005838:Genotype; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism*; D007422:Intestines / Q000473:pathology; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism
chemical_list: D012333:RNA, Messenger; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human