Purpose: African Americans (AA) are at high risk for Colorectal Cancer (CRC). Studies report a 30-60 % increase in CRC risk with physical inactivity, obesity and metabolic syndrome. Activation of the WNT/ β-catenin (CTNNB1) signaling pathway plays a critical role in colorectal carcinogenesis. Accumulating evidence also indicates a role of WNT-CTNNB1 signaling in obesity and metabolic diseases.
Aim: To examine the association between obesity, β-Catenin expression and colonic lesions in African Americans.
Methods: We reviewed the pathology records of 152 colorectal specimens from 2010-2012 (46 CRCs, 74 advanced adenoma and 32 normal colon tissues). Tissue Microarrays (TMA) were constructed from these samples. Immunohistochemistry (IHC) for CTNNB1 (β-catenin; clone β-Catenin-1) was performed on the constructed TMAs. The IHC results were evaluated by 2 pathologists and the nuclear intensity staining was scored from 0-4. BMI, sex, age, location of the lesion and other demographic data were obtained.
Results: Positive nuclear staining in normal, advanced adenoma and CRC was 0%, 24% and 41%, respectively (P <0.001). CRC was associated with positive status for nuclear CTNNB1 intensity (adjusted OR: 3.40, 95%CI=1.42%-8.15%, P=0.006 for positive nuclear staining) compared to non-CRC samples (Normal or advanced adenoma). Nuclear staining percentage has a good diagnostic ability for CRC (AUC: 0.63, 95%CI=0.55%- 0.71%). Overweight and obese patients (BMI>25) did not show a significant (p=0.3) expression of positive status for nuclear CTNNB1 (17% positive in normal weight vs. 27% positive in overweight/obese). The association between nuclear intensity and CRC was not different between normal and overweight patients (P for interaction = 0.6). The positive nuclear CTNNB1status in CRC stage III and IV (35% of all CRC) was not different from stage I and II (50%. vs. 36%, respectively, P = 0.4).
Conclusion: In our study, advanced adenoma and CRC were associated with activation of β-catenin in physically fit, overweight and obese patients. Thus, participation of the obesity and WNT pathway seem to be independent in African American patients. WNT/β-catenin signaling pathway has a potential to be used as an effector in colon carcinogenic transformation. Whether or not BMI is a modifier of this pathway needs to be investigated further.