The classic adenoma-carcinoma sequence accounts for up to 80% of sporadic cancers and typically includes mutation of APC early in the neoplastic process (Fig. 17.49). Both copies of the APC gene must be functionally inactivated, either by mutation or by epigenetic events, for adenomas to develop. The APC protein normally binds to and promotes degradation of β-catenin, a component of the Wnt signal- ing pathway (Chapter 7). With loss of APC function, β-catenin accumulates and translocates to the nucleus, where it forms a complex with the DNA-binding factor TCF and activates the transcription of genes, including MYC and cyclin D1, that promote proliferation. The critical role of β-catenin in this pathway is demonstrated by the fact that many colon cancers without APC mutations harbor β-catenin mutations that prevent APC-dependent degradation, thereby allowing β-catenin to accumulate and activate Wnt signaling. Additional mutations accu- mulate including activating mutations in KRAS that promote growth and prevent apoptosis.