title: Impact of genetic polymorphisms on adenoma recurrence and toxicity in a COX2 inhibitor (celecoxib) trial: results from a pilot study.
abstract: OBJECTIVE
  Chemoprevention trials have shown that celecoxib reduces adenoma recurrence but can cause cardiovascular toxicity. In this pilot study, we evaluated associations between genetic variation in several candidate pathways (e.g. prostaglandin synthesis) and adenoma recurrence and cardiovascular and gastrointestinal toxicities.
  
  
  METHODS
  Genotyping analysis was carried out on 117 Israeli colorectal adenoma patients who participated in the Prevention of Colorectal Sporadic Adenomatous Polyps trial. Reassessment followed after 3 years on celecoxib and after 2 years from termination of treatment with celecoxib. Efficacy (absence of colorectal adenomas) was measured by colonoscopy at years 1, 3, and 5. Toxicities were assessed by investigators during celecoxib treatment and by self-report post-treatment. A linkage disequilibrium-based selection algorithm (r2≥0.90, MAF≥4%) identified 255 tagSNPs in 25 analyzed candidate genes. Genotyping was performed by using Illumina GoldenGate technology.
  
  
  RESULTS
  Multiple genetic variants were associated with adenoma recurrence and toxicity. Genetic variability in COX1, COX2, and ALOX12/15 genes played a role in adenoma recurrence, particularly among patients on placebo. More gene variants (especially variants in PGES, CRP, SRC, and GPX3) were associated with increased risk for cardiovascular toxicity and symptoms, compared with gastrointestinal toxicity and symptoms. The increased risk for cardiovascular toxicity/symptoms associated with the SRC gene variants (rs6017996, rs6018256, rs6018257) ranged from 6.61 (95% confidence interval 1.66-26.36, P<0.01) to 10.71 (95% confidence interval 1.96-58.60, P<0.01).
  
  
  CONCLUSIONS
  Genetic polymorphisms in multiple inflammation-related genes appear to interact with celecoxib on adenoma recurrence and its attendant toxicity, particularly cardiovascular toxicity/symptoms. Larger studies validating these pharmacogenetic relationships are needed.
authors.affiliation: Integrated Cancer Prevention Center, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel.|Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Sarah
authors.initials: S
authors.lastname: Kraus
authors.affiliation: National Center for Tumor Diseases (NCT) and German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Simone
authors.initials: S
authors.lastname: Hummler
authors.affiliation: Department of Surgery, Division of Public Health Sciences, Siteman Cancer Center, Washington University School of Medicine, St Louis, Missouri.
authors.forename: Adetunji T
authors.initials: AT
authors.lastname: Toriola
authors.affiliation: Fred Hutchinson Cancer Research Center, Seattle, Washington.|Department of Medicine, Channing Division of Network Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.|Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts.
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Poole
authors.affiliation: National Center for Tumor Diseases (NCT) and German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Dominique
authors.initials: D
authors.lastname: Scherer
authors.affiliation: National Center for Tumor Diseases (NCT) and German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Jana
authors.initials: J
authors.lastname: Kotzmann
authors.affiliation: Fred Hutchinson Cancer Research Center, Seattle, Washington.
authors.forename: Karen W
authors.initials: KW
authors.lastname: Makar
authors.affiliation: Integrated Cancer Prevention Center, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel.
authors.forename: Dina
authors.initials: D
authors.lastname: Kazanov
authors.affiliation: Integrated Cancer Prevention Center, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel.|Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Lior
authors.initials: L
authors.lastname: Galazan
authors.affiliation: Integrated Cancer Prevention Center, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel.|Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Inna
authors.initials: I
authors.lastname: Naumov
authors.affiliation: Fred Hutchinson Cancer Research Center, Seattle, Washington.
authors.forename: Anna E
authors.initials: AE
authors.lastname: Coghill
authors.affiliation: Translational Genomics Research Institute, Phoenix, Arizona, USA.
authors.forename: David
authors.initials: D
authors.lastname: Duggan
authors.affiliation: National Center for Tumor Diseases (NCT) and German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Biljana
authors.initials: B
authors.lastname: Gigic
authors.affiliation: Integrated Cancer Prevention Center, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel.|Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Nadir
authors.initials: N
authors.lastname: Arber
authors.affiliation: National Center for Tumor Diseases (NCT) and German Cancer Research Center (DKFZ), Heidelberg, Germany.|Fred Hutchinson Cancer Research Center, Seattle, Washington.
authors.forename: Cornelia M
authors.initials: CM
authors.lastname: Ulrich
mesh_terms: D000236:Adenoma / Q000188:drug therapy* / Q000235:genetics; D018256:Adenomatous Polyps / Q000188:drug therapy / Q000235:genetics; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002318:Cardiovascular Diseases / Q000139:chemically induced* / Q000235:genetics; D000068579:Celecoxib; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics; D052246:Cyclooxygenase 2 Inhibitors / Q000009:adverse effects* / Q000627:therapeutic use; D005260:Female; D005767:Gastrointestinal Diseases / Q000139:chemically induced* / Q000235:genetics; D014644:Genetic Variation; D006801:Humans; D007249:Inflammation / Q000139:chemically induced / Q000188:drug therapy / Q000235:genetics; D015810:Linkage Disequilibrium; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000235:genetics / Q000517:prevention & control; D010597:Pharmacogenetics; D010865:Pilot Projects; D020641:Polymorphism, Single Nucleotide; D011720:Pyrazoles / Q000009:adverse effects* / Q000627:therapeutic use; D013449:Sulfonamides / Q000009:adverse effects* / Q000627:therapeutic use
chemical_list: D052246:Cyclooxygenase 2 Inhibitors; D011720:Pyrazoles; D013449:Sulfonamides; D000068579:Celecoxib