Association of CTNNB1 (β-Catenin) Alterations, Body Mass Index, and Physical Activity With Survival in Patients With Colorectal Cancer

Abstract

Context Alterations of WNT-CTNNB1 (β-catenin) signaling play roles in colorectal carcinogenesis and metabolic diseases. Objective To test the hypothesis that CTNNB1 activation in colorectal cancer might modify prognostic associations of body mass index (BMI) and post-diagnosis physical activity. Design We utilized molecular pathological epidemiology (MPE, or molecular pathologic epidemiology) design, investigating interactive effects of tumor and lifestyle factors on tumor behavior. We evaluated CTNNB1 (HGNC ID: 2514) localization by immunohistochemistry in 955 colon and rectal cancers. Cox proportional hazards model was used to compute mortality hazard ratio (HR), adjusting for covariates, including microsatellite instability (MSI), CpG island methylator phenotype (CIMP), LINE-1 methylation, KRAS, BRAF, PIK3CA, and TP53 (p53). Setting Two U.S. nationwide prospective cohort studies, the Nurses’ Health Study and the Health Professional Follow-up Study. Results In obese patients (BMI ≥30 kg/m2), nuclear CTNNB1 positivity was associated with significantly better cancer-specific survival [adjusted HR=0.24; 95% confidence interval (CI), 0.12-0.49; 5-year survival, 0.85 vs. 0.78 for nuclear CTNNB1-positive vs. negative patients] and overall survival (adjusted HR=0.56; 95% CI, 0.35-0.90; 5-year survival, 0.77 vs. 0.74 for nuclear CTNNB1-positive vs. negative patients), while CTNNB1 status was not associated with prognosis among nonobese patients (Pinteraction=0.0003 and 0.034 for cancer-specific and overall survival, respectively). Among nuclear CTNNB1-negative stage I-III patients, post-diagnosis physical activity was associated with better cancer-specific survival [adjusted HR=0.33; 95% CI, 0.13-0.81; ≥18 vs. <18 MET (metabolic equivalent task) hours/week; 5-year survival, 0.97 vs. 0.89] while physical activity was not associated with survival among nuclear CTNNB1-positive stage I-III patients (Pinteraction=0.046). Conclusions This MPE study showed that CTNNB1 activation was associated with better cancer-specific and overall survival only among obese patients. Post-diagnosis physical activity was associated with better cancer-specific survival only among nuclear CTNNB1-negative patients. Our novel MPE data support a role of interactions between tumor and host factors influencing tumor aggressiveness.

PDLIM1 Stabilizes the E-Cadherin/β-Catenin Complex to Prevent Epithelial–Mesenchymal Transition and Metastatic Potential of Colorectal Cancer Cells

“…Given the roles of PDLIM1 in colorectal cancer invasion and metastasis, these findings implicated PDLIM1 as a marker for tumor aggressiveness and a predictor for colorectal cancer patients' survival. Our tissue microarray results also confirmed that low expressions of either E-cadherin or membrane b-catenin were indicators of poor prognosis for colorectal cancer patients, which is compatible with the results of previous studies (22,25). Unlike tumors such as breast cancer where metastasis might take decades to acquire the function for colonization (17), malignant progression and most metastatic traits in colorectal cancer are acquired during progression to the invasive carcinoma stage in the primary site (26).…”

Associations of the Transforming Growth Factor β/Smad Pathway, Body Mass Index, and Physical Activity With Breast Cancer Outcomes: Results From the Shanghai Breast Cancer Study

“…Given the intrinsic gene-environment interaction between TGF-β and obesity (20,21), we conducted stratified analysis in this study showing that the association between nuclear pSmad2 expression and breast cancer outcome is modified by BMI, with the association predominantly seen among patients who have lower BMI. A similar host-tumor interaction in β-catenin expression and cancer survival was previously shown in a colon cancer study (35).…”

Establishment of the Cancer Prevention Study II Nutrition Cohort Colorectal Tissue Repository

“…The methods used to establish this repository are described in detail to motivate and inform future collections of tissue materials in other epidemiologic studies. With tissue samples accrued thus far from 882 participants diagnosed with colon or rectal cancer, the CPS-II colorectal tissue repository is on par with or larger than other tissue collections from comparable prospective cohort studies, including the Nurses' Health Study and Health Professionals Follow-up Study (21)(22)(23), European Prospective Investigation into Cancer and Nutrition (EPIC) (24), the Iowa Women's Health Study (8,25), the Melbourne Collaborative Cohort Study (6,26), the Netherlands Cohort Study (6), and the Northern Sweden Health and Disease Study (27).…”