A 26-year-old man with a family history of colon carcinoma undergoes a surveillance colonoscopy. It reveals hundreds of polyps in the colon and two focal 0.5-cm ulcerated areas. A biopsy specimen from an ulcer reveals irregularly shaped glands that have penetrated into the muscular layer. Which of the following molecular events is believed to occur very early in the evolution of his colonic disease process?

The patient has a classic history of familial adenomatous polyposis with numerous adenomatous polyps and malignant transformation. The earliest event in the APC - adenocarcinoma sequence is the loss of APC gene function. This prevents the destruction of b-catenin in the cytoplasm, which translocate to the nucleus and coactivates transcription of several genes. The APC b-catenin sequence is a component of the WNT signaling pathway. RAS activation occurs after the malignant transformation sequence is initiated by the APC (gatekeeper) gene. Loss of cell cycle G1 arrest occurs with p53 loss late in the sequence. Mutations in mismatch repair genes give rise to hereditary nonpolyposis colon cancer syndrome from loss of ability to repair DNA damage. The BCL2 gene is not involved in the transition from adenoma to carcinoma.