Abstract
The etiology of colorectal cancer (CRC) has been informed from both a molecular biology perspective, which concerns the study of the nature, timing, and consequences of mutations in driver genes, and epidemiology, which focuses on identifying risk factors for cancer. For the most part, these fields have developed independently, and it is thus important to consider them in a more integrated manner. The molecular mutational perspective has stressed the importance of mutations due to replication of adult stem cells, and the molecular fingerprint of most CRCs does not suggest the importance of direct carcinogens. Epidemiology has identified numerous modifiable risk factors that account for most CRCs, most of which are not direct mutagens. The distribution of CRCs across the large bowel is not uniform, which is possibly caused by regional differences in the microbiota. Some risk factors are likely to act through or interact with the microbiota. The mutational perspective informs when risk factors may begin to operate in life and when they may cease to operate. Evidence from the mutational model and epidemiology supports that CRC risk factors begin early in life and may contribute to the risk of early-onset CRC. Later in carcinogenesis, there may be a "point of no return" when sufficient mutations have accumulated, and some risk factors do not affect cancer risk. This period may be at least 5-15 years for some risk factors. A more precise knowledge of timing of risk factor to cancer is required to inform preventive efforts.