title: Association of CTNNB1 (beta-catenin) alterations, body mass index, and physical activity with survival in patients with colorectal cancer.
abstract: BACKGROUND
  Alterations of the WNT signaling pathway and cadherin-associated protein β 1 (CTNNB1 or β-catenin) have been implicated in colorectal carcinogenesis and metabolic diseases.
  
  
  OBJECTIVE
  To test the hypothesis that CTNNB1 activation in colorectal cancer modifies prognostic associations of body mass index (BMI) and level of postdiagnosis physical activity.
  
  
  METHODS
  Two US prospective cohort studies (Nurses' Health Study and the Health Professionals Follow-up Study) were used to evaluate CTNNB1 localization by immunohistochemistry in 955 patients with stage I, II, III, or IV colon and rectal cancer from 1980 through 2004. A Cox proportional hazards model was used to compute the hazard ratio (HR) for mortality, adjusting for clinical and tumor features, including microsatellite instability, CpG island methylator phenotype, level of long interspersed nucleotide element 1 methylation, mutations in KRAS, BRAF, or PIK3CA, and tumor protein p53.
  
  
  METHODS
  Colorectal cancer-specific mortality and overall mortality through June 30, 2009.
  
  
  RESULTS
  In obese patients (BMI ≥30), positive status for nuclear CTNNB1 was associated with significantly better colorectal cancer-specific survival (adjusted HR, 0.24 [95% confidence interval {CI}, 0.12-0.49], P <.001 for interaction; 5-year survival: 0.85 for patients with positive nuclear CTNNB1 status vs 0.78 for those with negative status) and overall survival (adjusted HR, 0.56 [95% CI, 0.35-0.90], P = .03 for interaction; 5-year survival: 0.77 for patients with positive nuclear CTNNB1 status vs 0.74 for those with negative status), while CTNNB1 status was not associated with prognosis among nonobese patients (BMI <30). Among patients with negative status for nuclear CTNNB1 and cancer in stages I, II, or III, postdiagnosis physical activity was associated with better colorectal cancer-specific survival (adjusted HR, 0.33 [95% CI, 0.13-0.81], P = .05 for interaction; 5-year survival: 0.97 for ≥18 vs 0.89 for <18 metabolic equivalent task hours/week), while postdiagnosis physical activity was not associated with colorectal cancer-specific survival among patients with positive status for nuclear CTNNB1 (adjusted HR, 1.07 [95% CI, 0.50-2.30]).
  
  
  CONCLUSIONS
  Among obese patients only, activation of CTNNB1 was associated with better colorectal cancer-specific survival and overall survival. Postdiagnosis physical activity was associated with better colorectal cancer-specific survival only among patients with negative status for nuclear CTNNB1. These molecular pathological epidemiology findings suggest that the effects of alterations in the WNT-CTNNB1 pathway on outcome are modified by BMI and physical activity.
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Brigham and Women's Hospital, Harvard Medical School, 450 Brookline Ave, Boston, MA 02215, USA.
authors.forename: Teppei
authors.initials: T
authors.lastname: Morikawa
authors.forename: Aya
authors.initials: A
authors.lastname: Kuchiba
authors.forename: Mai
authors.initials: M
authors.lastname: Yamauchi
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Meyerhardt
authors.forename: Kaori
authors.initials: K
authors.lastname: Shima
authors.forename: Katsuhiko
authors.initials: K
authors.lastname: Nosho
authors.forename: Andrew T
authors.initials: AT
authors.lastname: Chan
authors.forename: Edward
authors.initials: E
authors.lastname: Giovannucci
authors.forename: Charles S
authors.initials: CS
authors.lastname: Fuchs
authors.forename: Shuji
authors.initials: S
authors.lastname: Ogino
mesh_terms: D000368:Aged; D015992:Body Mass Index; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000401:mortality* / Q000503:physiopathology; D018899:CpG Islands / Q000235:genetics; D015444:Exercise; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008019:Life Style; D008297:Male; D053842:Microsatellite Instability; D008875:Middle Aged; D009765:Obesity; D011379:Prognosis; D011446:Prospective Studies; D016019:Survival Analysis; D051153:Wnt Proteins / Q000378:metabolism; D051176:beta Catenin / Q000378:metabolism*
chemical_list: C495270:CTNNB1 protein, human; D051153:Wnt Proteins; D051176:beta Catenin