Early mutational events and clonal dynamics in normal crypts: implications for colorectal tumorigenesis.

Colorectal cancer has widely been described by the classic adenoma-carcinoma sequence, where sequential mutations in APC, KRAS, and TP53 drive the transition from normal epithelium to carcinoma. However, recent high-resolution genomic analyses have expanded this framework by revealing the presence of multiple driver mutations within morphologically normal colonic crypts. In this review, we summarize the emerging landscape of several somatic driver mutations in normal crypts, highlighting genes that were reported to be under positive selection, such as FBXW7, STAG2, AXIN2, PIK3CA, ERBB2, and ERBB3, and discuss their known functions in both normal epithelium and colorectal cancer. We also postulate the functional consequences of these mutations in the overall priming of colonic crypts to potential tumorigenesis. Despite their presence, the frequencies of these mutations in both normal epithelial and colorectal cancers are low, and most of them do not progress to malignancy. We therefore discuss the intrinsic and extrinsic factors that dictate the fate of these crypts. Together, these findings underscore that tumor-initiating events in colorectal cancer may occur much earlier than previously recognized. A deeper understanding of these early driver events may help to better inform strategies for early detection, risk stratification, and prevention before these morphologically normal crypts transform into neoplasia.