beta-Catenin and ras oncogenes detect most human colorectal cancer

• Published in: Clinical cancer research Vol. 9; no. 8; pp. 3073 - 3079
• Main Authors: Zhang, Bin, Ougolkov, Andrei, Yamashita, Kaname, Takahashi, Yutaka, Mai, Masayoshi, Minamoto, Toshinari
• Format: Journal Article
• Language: English
• Published: United States 01.08.2003
• Subjects: Adult; Aged; Aged, 80 and over; beta Catenin; Biomarkers, Tumor; Cell Nucleus - metabolism; Codon; Colorectal Neoplasms - diagnosis; Colorectal Neoplasms - genetics; Colorectal Neoplasms - metabolism; Cytoskeletal Proteins - biosynthesis; Cytoskeletal Proteins - genetics; Cytoskeletal Proteins - metabolism; Female; Genes, ras - genetics; Humans; Male; Middle Aged; Mutation; Polymorphism, Restriction Fragment Length; ras Proteins - biosynthesis; Signal Transduction; Trans-Activators - biosynthesis; Trans-Activators - genetics; Trans-Activators - metabolism
• ISSN: 1078-0432

PURPOSE AND STUDY DESIGN: Recent studies have shown that beta-catenin translocated into the cell nucleus functions like an oncogene. Accumulating evidence suggests that activation of the beta-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 beta-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. We found two distinct patterns of beta-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 beta-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 beta-catenin activation were in Dukes' stage C at surgery, and half of them developed distant metastases to the liver and lungs. The results suggest that although oncogenic activation of beta-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.