title: Metachronous cancer development in patients with sporadic colorectal adenomas-multivariate risk model with independent and combined value of hTERT and survivin.
abstract: OBJECTIVE
  Accurate, long-term risk predictors for colorectal cancer development in patients with sporadic adenomas are lacking. We sought to validate biomarkers predictive of metachronous colorectal cancer (mCRC) in patients with sporadic colorectal adenomas, using 374 consecutive patients from a large defined population.
  
  
  METHODS
  Risk evaluation was performed for patient and adenoma risk factors (morphometric longest nuclear axis and immunohistochemical markers survivin, human telomerase reverse transcriptase (hTERT), beta-catenin, p16INK4a, p21CIP1, and cyclin D1). Diagnostic accuracy was assessed by receiver-operating characteristics curve analysis, and uni- and multivariate survival analysis was performed.
  
  
  RESULTS
  Of the 374 patients, 26 (7%) developed mCRC with a median of 5.6 years (range 2-19) from index adenoma. Independent risk factors included age greater than or equal to 60 years, proximal location, multiplicity (greater than or equal to three adenomas), and high-grade neoplasia, with high-grade intraepithelial neoplasia and proximal location as the strongest on multivariate analysis (hazard ratio [HR] of 4.1 and 5.2, respectively; both p< 0.05). The molecular markers hTERT (HR 11.3, 95% confidence interval [CI] 3.9-33.1; p < 0.001) and survivin (HR 7.0, 95% CI 2.4-20.5; p < 0.001) were independent predictors for mCRC, and proximal location (4 of 16 = 25% with mCRC) was the only clinical one. The value of hTERT and survivin were retained in the validation set. Survivin and hTERT together yielded high mCRC risk when both were positive (15 of 51 = 29%; HR 14.3, 5.6-36.5), modest with one positive (survivin 4 of 90 = 4.4%; hTERT 4 of 60 = 6.7%), and no risk with both negative (0 of 144 = 0%).
  
  
  CONCLUSIONS
  hTERT and survivin are the best risk predictors for long-term, mCRC development in patients with sporadic colorectal adenomas.
authors.affiliation: Department of Pathology, Stavanger University Hospital, P.O. Box 8100, 4068 Stavanger, Norway.
authors.forename: Kjetil
authors.initials: K
authors.lastname: Søreide
authors.forename: Einar
authors.initials: E
authors.lastname: Gudlaugsson
authors.forename: Ivar
authors.initials: I
authors.lastname: Skaland
authors.forename: Emiel A M
authors.initials: EA
authors.lastname: Janssen
authors.forename: Bianca
authors.initials: B
authors.lastname: Van Diermen
authors.forename: Hartwig
authors.initials: H
authors.lastname: Körner
authors.forename: Jan P A
authors.initials: JP
authors.lastname: Baak
mesh_terms: D011125:Adenomatous Polyposis Coli / Q000453:epidemiology / Q000378:metabolism / Q000473:pathology*; D000368:Aged; D014408:Biomarkers, Tumor / Q000378:metabolism; D003113:Colonoscopy; D015179:Colorectal Neoplasms / Q000453:epidemiology / Q000378:metabolism / Q000473:pathology*; D016001:Confidence Intervals; D003937:Diagnosis, Differential; D018450:Disease Progression; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007150:Immunohistochemistry; D051034:Inhibitor of Apoptosis Proteins; D008297:Male; D008869:Microtubule-Associated Proteins / Q000378:metabolism*; D008875:Middle Aged; D009017:Morbidity; D009363:Neoplasm Proteins / Q000378:metabolism*; D016609:Neoplasms, Second Primary / Q000453:epidemiology / Q000378:metabolism / Q000473:pathology*; D009664:Norway / Q000453:epidemiology; D011379:Prognosis; D012372:ROC Curve; D012189:Retrospective Studies; D012307:Risk Factors; D000077022:Survivin; D019098:Telomerase / Q000378:metabolism*; D013997:Time Factors
chemical_list: C107489:BIRC5 protein, human; D014408:Biomarkers, Tumor; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; D009363:Neoplasm Proteins; D000077022:Survivin; C509186:TERT protein, human; D019098:Telomerase