Colorectal cancer is associated with the presence of cancer driver mutations in normal colon

While somatic mutations in colorectal cancer (CRC) are well characterized, little is known about the accumulation of cancer mutations in the normal colon prior to cancer. Here we have developed and applied an ultra-sensitive, single-molecule mutational test based on CRISPR-DS technology, which enables mutation detection at extremely low frequency (<0.001) in normal colon from patients with and without CRC. We found oncogenic KRAS mutations in the normal colon of about one third of patients with CRC but in none of the patients without CRC. Patients with CRC also carried more TP53 mutations than patients without cancer, and these mutations were more pathogenic and formed larger clones, especially in patients with early onset CRC. Most mutations in normal colon were different from the driver mutations in tumors suggesting that the occurrence of independent clones with pathogenic KRAS and TP53 mutations is a common event in the colon of individuals that develop CRC. SIGNIFICANCEOur results suggest a prevalent process of somatic mutation and evolution in the normal colon of patients with CRC, which can be detected by ultra-sensitive sequencing of driver genes and potentially employed clinically for CRC risk prediction.