Abstract B53: Analysis of Wnt signaling as a determinant of racial disparities in colorectal cancer outcomes.
Authors: Miller Megan E. , Kunnavakkam Rangesh , Khramtsova Galina , Khramtsov Andrey , Sylvester Brooke , Huo Dezheng , Olopade Olufunmilayo I. , Goss Kathleen H. 
Published: August 2014

Purpose: While it is well-known that African American patients with colorectal cancer have worse survival outcomes than their Caucasian counterparts, the underlying mechanisms remain largely unidentified. We sought to determine whether differences exist in the molecular pathways which drive colorectal cancer between these two racial groups, with particular attention to genetic alterations and Wnt pathway activation. Although a majority of sporadic colorectal tumors have an APC mutation, the prognostic significance of β-catenin localization in colorectal cancer has yet to be determined definitively.

Experimental Design: We retrospectively examined 380 African American and Caucasian patients diagnosed with colorectal cancer at The University of Chicago Medical Center between 1992 and 2002. Tissue microarrays (TMAs) were constructed from the surgical pathology archive, and immunohistochemistry with β-catenin antibody (BD Biosciences) was performed. Two independent pathologists quantitatively analyzed the specimens for β-catenin localization; scoring was based on the intensity and percentage of positively stained cells in the nucleus, cytosol, and at the membrane. The tissues were previously analyzed for microsatellite instability (MSI) by genotyping the BAT25, BAT26, BAT40, D5S346, and BAXloci. Mutations in BRAF codon 600 and KRAS codons 12 and 13 were previously identified by direct sequencing. The molecular and immunohistochemical data were correlated with clinicopathological features, including age, race, gender, overall survival, anatomic location, AJCC stage, TNM stage, and receipt of chemotherapy. Statistical analyses were performed using Stata 11.0 (StataCorp).

Results: While there was no correlation between β-catenin localization and race, overall survival, anatomic location, or receipt of chemotherapy, tumor stage N1 was associated with higher cytosolic and nuclear scores than either N0 or N2 tumors (p = 0.01 and p = 0.001, respectively). Additionally, KRAS codon 13 mutation was significantly associated with low nuclear and cytosolic scores (p = 0.015 and p = 0.028). No association was found between β-catenin localization and KRAS codon 12 mutation, BRAF mutation, or MSI status. Importantly, after adjusting for demographic factors, pathologic factors, chemotherapy, molecular markers, and β-catenin localization, a significant difference in overall survival was demonstrated in African American vs. Caucasian patients, with an hazard ratio of 1.4 (95% CI 1.02-1.96, p = 0.036). The racial disparity was even greater in MSS/MSI-L tumors, with a 57% increased risk of death in African American patients compared to Caucasians (p = 0.011), even after controlling for prognostic factors.

Conclusion: Commonly used molecular markers, genetic alterations, and Wnt pathway status could not explain the significantly higher risk of death among African American patients with colorectal cancer in our cohort. Wnt pathway activation, as evidenced by high nuclear and cytosolic scores in N1 tumors, may be associated with early metastatic disease. KRAS codon 13 mutation was inversely related to Wnt pathway activation, suggesting that β-catenin localization has potential as a surrogate marker for this mutation if validated in larger studies. Overall, the results from this study highlight the need for additional targeted research to determine which biologic mechanisms are driving racial disparities in colorectal cancer outcomes.

Citation Format: Megan E. Miller, Rangesh Kunnavakkam, Galina Khramtsova, Andrey Khramtsov, Brooke Sylvester, Dezheng Huo, Olufunmilayo I. Olopade, Kathleen H. Goss. Analysis of Wnt signaling as a determinant of racial disparities in colorectal cancer outcomes. [abstract]. In: Proceedings of the Fifth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2012 Oct 27-30; San Diego, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2012;21(10 Suppl):Abstract nr B53.