title: Cathepsin B expression and survival in colon cancer: implications for molecular detection of neoplasia.
abstract: OBJECTIVE
  Proteases play a critical role in tumorigenesis and are upregulated in colorectal cancer and neoplastic polyps. In animal models, cathepsin B (CTSB)-activatable imaging agents show high enzyme activity within intestinal tumors.
  
  
  METHODS
  We conducted a prospective cohort study of 558 men and women with colon cancer with tumors that were accessible for immunohistochemical assessment. We used Cox proportional hazards models, stratified by stage, to compute colon cancer-specific and overall mortality according to tumoral expression of CTSB.
  
  
  RESULTS
  Among 558 participants, 457 (82%) had tumors that expressed CTSB (CTSB positive) and 101 (18%) had tumors that did not express CTSB (CTSB negative). CTSB expression was not associated with disease stage (P = 0.19). After a median follow-up of 11.6 years, there were 254 total and 155 colon cancer-specific deaths. Compared with participants with CTSB-negative tumors, participants with CTSB-positive tumors experienced a multivariate hazard ratio for colon cancer-specific mortality of 1.99 (95% confidence interval, 1.19-3.34) and overall mortality of 1.71 (95% confidence interval, 1.16-2.50). CTSB expression was independently associated with KRAS (P = 0.01) and BRAF mutation (P = 0.04), but not microsatellite instability status, CpG island methylator phenotype status, PIK3CA mutation, LINE-1 methylation, TP53 expression, or PTGS2 (cyclooxygenase-2) expression. Among 123 individuals with adenomas, 91% expressed CTSB.
  
  
  CONCLUSIONS
  As assessed by immunohistochemistry, CTSB is expressed in the vast majority of colon cancers, independent of stage, and is significantly associated with higher risk of colon cancer-specific and overall mortality.
  
  
  CONCLUSIONS
  These results support the potential of CTSB a target for image detection of neoplastic lesions in humans.
authors.affiliation: Gastrointestinal Unit, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA. achan@partners.org
authors.forename: Andrew T
authors.initials: AT
authors.lastname: Chan
authors.forename: Yoshifumi
authors.initials: Y
authors.lastname: Baba
authors.forename: Kaori
authors.initials: K
authors.lastname: Shima
authors.forename: Katsuhiko
authors.initials: K
authors.lastname: Nosho
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Chung
authors.forename: Kenneth E
authors.initials: KE
authors.lastname: Hung
authors.forename: Umar
authors.initials: U
authors.lastname: Mahmood
authors.forename: Karen
authors.initials: K
authors.lastname: Madden
authors.forename: Kirtland
authors.initials: K
authors.lastname: Poss
authors.forename: Audrey
authors.initials: A
authors.lastname: Ranieri
authors.forename: Daniel
authors.initials: D
authors.lastname: Shue
authors.forename: Raju
authors.initials: R
authors.lastname: Kucherlapati
authors.forename: Charles S
authors.initials: CS
authors.lastname: Fuchs
authors.forename: Shuji
authors.initials: S
authors.lastname: Ogino
mesh_terms: D014408:Biomarkers, Tumor / Q000032:analysis* / Q000378:metabolism; D002401:Cathepsin B / Q000096:biosynthesis*; D015331:Cohort Studies; D003110:Colonic Neoplasms / Q000378:metabolism* / Q000401:mortality* / Q000473:pathology; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D008297:Male; D009367:Neoplasm Staging
chemical_list: D014408:Biomarkers, Tumor; D002401:Cathepsin B