Markers of the APC/β-Catenin Signaling Pathway as Potential Treatable, Preneoplastic Biomarkers of Risk for Colorectal Neoplasms

Abstract

Background: Malfunctioning of the adenomatous polyposis coli (APC)/b-catenin signaling pathway is both an early and common event in sporadic colorectal cancer. To assess the potential of APC/b-catenin signaling pathway markers as treatable, preneoplastic biomarkers of risk for colorectal neoplasms, we conducted a pilot colonoscopy-based case-control study (51 cases and 154 controls) of incident, sporadic colorectal adenoma.Methods: We evaluated APC, b-catenin, and E-cadherin expression in normal mucosa from the rectum and ascending and sigmoid colon using automated immunohistochemical and quantitative image analysis. Diet, lifestyle, and medical history were assessed with validated questionnaires.Results: In the normal rectal mucosa, the ratio of the proportion of APC expression in the upper 40% of crypts with total b-catenin expression (APC/b-catenin score) was 14.3% greater in controls than in cases [P ¼ 0.02; OR, 0.40; 95% confidence interval (CI), 0.14-1.14]. Compared with controls, in cases, APC expression was 3.2% lower, b-catenin expression was 3.0% higher, and E-cadherin expression was 0.7% lower; however, none of these differences were statistically significant. The APC/b-catenin score statistically significantly differed according to categories of plausible risk factors for colorectal cancer [e.g., it was 17.7% higher among those with 25(OH) vitamin D 3 concentrations ! 27 ng/mL].Conclusions: These preliminary data suggest that the combined expression of APC and b-catenin in the normal rectal mucosa may be associated with risk for incident, sporadic colorectal neoplasms, as well as with modifiable risk factors for colorectal neoplasms.Impact: Our results may help advance the development of treatable, preneoplastic biomarkers of risk for colorectal neoplasms. Cancer Epidemiol Biomarkers Prev; 21(6); 969-79. Ó2012 AACR.

A Randomized Clinical Trial of the Effects of Supplemental Calcium and Vitamin D3 on the APC/β-Catenin Pathway in the Normal Mucosa of Colorectal Adenoma Patients

“…During the adenoma-carcinoma sequence APC and E-cadherin expression markedly decrease (although the decrease in E-cadherin tends to occur in later stages) (25-27), and β-catenin expression appears to steadily increase and translocate from the membrane to the cytoplasm and eventually into the nucleus (25, 28). We previously proposed that the APC/β-catenin score may represent the potential of β-catenin to translocate to the nucleus and promote proliferative signaling (8). We found the APC/β-catenin score in the normal colorectal mucosa of sporadic colorectal adenoma patients to be statistically significantly lower than in the normal colorectal mucosa of healthy controls; and that ϕh APC and β-catenin expression and the APC/β-catenin score may be modifiable as suggested by their being associated with lifestyle and dietary risk factors for colorectal neoplasms (8).…”

“…We previously proposed that the APC/β-catenin score may represent the potential of β-catenin to translocate to the nucleus and promote proliferative signaling (8). We found the APC/β-catenin score in the normal colorectal mucosa of sporadic colorectal adenoma patients to be statistically significantly lower than in the normal colorectal mucosa of healthy controls; and that ϕh APC and β-catenin expression and the APC/β-catenin score may be modifiable as suggested by their being associated with lifestyle and dietary risk factors for colorectal neoplasms (8). …”

“…E-cadherin may also antagonize β-catenin nuclear expression by sequestering β-catenin to its cytoplasmic tail, linking E-cadherin to actin filaments and promoting cell adhesion and differentiation (5, 7). We reported that APC expression (especially the proportion of APC in the upper 40% of colorectal crypts (ϕh APC)), β-catenin expression, and the ϕh APC/β-catenin ratio (APC/β-catenin score) in normal colorectal mucosa may be valid, potentially modifiable, pre-neoplastic biomarkers of risk for colorectal neoplasms (8). …”

Effects of supplemental vitamin D and calcium on normal colon tissue and circulating biomarkers of risk for colorectal neoplasms

“…The methods and findings from this study are reported in detail elsewhere [56, 81, 85, 87, 88]. Briefly, persons being scheduled for an elective, outpatient colonoscopy were recruited to fill out questionnaires prior to the day of colonoscopy, undergo venipuncture upon arriving for their colonoscopy visit (i.e., fasting but before receiving any colonoscopy-related medications or procedures), and undergo procurement of biopsies of normal-appearing colorectal mucosa from the rectum (10 cm above the anus), mid-sigmoid colon, and proximal ascending colon during colonoscopy.…”

Molecular oncogenesis of craniopharyngioma: current and future strategies for the development of targeted therapies

“…Mutations in the b-catenin gene (CTNNB1) on chromosome 3 and aberrations in b-catenin expression have been well documented in multiple cancers, including colorectal 3,4,7,56,70,80 and hepatocellular 25,52,58 carcinomas, which prompted early studies in other solid tumors. CTNNB1 mutations were subsequently found in the Wnt subtype of medulloblastomas 42 and adamantinomatous craniopharyngiomas, 16,21,47,66,78 suggesting that, in addition to being clinically and histopathologically distinct, these subtypes also have distinct genetic origins.…”