Grant: CIHR Fellowship

It is now widely recognized that while cancer is a genetic disorder, epigenetics plays a significant role in cancer progression. Epigenetics describes a set of modifications that are placed on DNA and can alter the message of the DNA sequence. Colorectal cancer (CRC) is the fourth leading cause of cancer mortality worldwide, and arises as the result of genetic and epigenetic abnormalities within the cells of the intestine. While it has been thought for some time that the initiating events of CRC are genetic abnormalities of intestinal stem cells, a growing body of evidence suggests that epigenetic alterations precede and may cooperate with these genetic changes. One of these epigenetic changes is termed DNA methylation, in which the DNA message is abnormally silenced. This proposal directly tests some of the DNA methylation observations that were detected in primary human cancers by use of an innovative reporter. This fluorescence signal allows us for the first time to visualize cells that have undergone the earliest genetic changes in the path to cancer. These intestinal cells will be isolated and analyzed for their DNA methylation status, and we will then evaluate which of these changes are important for cancer progression. In summary, we aim to identify those DNA methylation changes that are essential for the earliest stages of CRC. We anticipate that the findings from this study will have a lasting impact on the understanding of colorectal cancer initiation, will inform new biomarkers of early colorectal cancer and identify new therapeutic vulnerabilities. As these epigenetic DNA modifications are reversible, we have the potential to manipulate them with drugs for the ultimate goal of tumour suppression.