Carcinogenesis is also associated with mutations in tumor suppressor genes such as those encoding SMAD2 and SMAD4, which are effectors of TGF-β signaling. Because TGF-β signaling normally inhibits the cell cycle, loss of these genes may allow unrestrained cell growth. The tumor suppressor gene TP53 is mutated in 70% to 80% of colon cancers but is uncommonly affected in adenomas, suggesting that TP53 mutations also occur at later stages of tumor progression. Loss of function of TP53 and other tumor suppressor genes is often caused by chromosomal deletions, dem- onstrating the chromosomal instability that is a hallmark of the APC/β-catenin pathway. Alternatively, tumor suppressor genes may be silenced by methylation of CpG-rich zones, or CpG islands, within the 5′ region that frequently includes the promoter and transcriptional start site of some genes. Telomerase expression also increases as lesions become more advanced.