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ß-Cateninand ras Oncogenes Detect Most Human Colorectal Cancer¹

Divisions of Diagnostic Molecular Oncology [B. Z., A. O., T. M.] and Surgical Oncology [B. Z., K. Y., Y. T., M. M., T. M.], Cancer Research Institute, Kanazawa University, Kanazawa 920-0934, Japan

Purpose and Study Design: Recent studies have shown that ß-catenin translocated into the cell nucleus functions like an oncogene. Accumulating evidence suggests that activation of the ß-catenin oncogenic signaling cascade along with its twin, the K-ras cascade, may exert syngeneic or synergistic effects on tumor development and progression. In the study reported here, we analyzed oncogenic ß-catenin activation on the basis of its nuclear accumulation (NA) and compared the results with those of mutational activation of K-ras in 74 patients with colorectal cancer to determine whether the two oncogene-mediated signaling cascades interact.

Results: We found two distinct patterns of ß-catenin activation, i.e., diffuse NA in 20 cases (27%) and selective NA at the tumor invasion front (NAinv) in 19 cases (26%). The presence of the NAinv pattern was significantly correlated with advanced Dukes’ stage tumor (P = 0.0005) and the presence of distant metastases (P = 0.0064). K-ras proto-oncogene was mutated in the tumors of 31 cases (42%). Activated ß-catenin or K-ras was detected in most (78%) colorectal cancers analyzed, although a weak inverse correlation was found between the activities of the two oncogenes in the tumors. Importantly, most (7 of 8) patients with tumor showing both K-ras activation and the NAinv pattern of ß-catenin activation were in Dukes’ stage C at surgery, and half of them developed distant metastases to the liver and lungs.

Conclusion: The results suggest that although oncogenic activation of ß-catenin and K-ras is independent in the process of clinical cancer development, combined analysis of the two major oncogenes can detect most colorectal cancers and identify a subset of patients with poorer outcomes. Consequently, activation of either or both of these oncogenes may serve as a genetic marker for molecular diagnosis.

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