Comprehensive landscape of DNA methylation in colorectal cancer

Abstract

Colorectal cancer (CRC) is already the second leading cause of cancer deaths worldwide, being the third most commonly diagnosed malignancy in developed countries. CRC typically arises as a consequence of the accumulation of genetic and epigenetic alterations in colonic epithelial cells. Particularly, aberrant DNA methylation, are recognized as common molecular feature in human colorectal tumors. However, nowadays, we know relatively little related to the cause and consequence of DNA methylation in CRC. Therefore, we hypothesized that DNA methylation landscape could provide crucial information in the management of CRC, which may be affected by potential epigenetic drivers, such as vitamin D, since several epidemiological studies have suggested a protective role. This approach could also elucidate what potential pathways are involved in colorectal carcinogenesis, and identify key CRC risk factors. In addition, the reversible nature of epigenetic changes may enable us to identify potential DNA methylation drivers, including some bioactive food components, to reverse them and further decrease the risk of CRC.

Therefore, the aims of this thesis were i) to evaluate the association between global DNA methylation (through long interspersed nuclear element 1 (LINE1)) and survival rates in patients with CRC, ii) to investigate the association between serum 25-hydroxyvitamin D (25(OH)D) and DNA methylation in the CRC context (both epigenome-wide association study and specific promoter methylation), and finally, iii) to analyze the global DNA methylation landscape of visceral adipose tissue from patients with CRC, and its relationship with the risk of CRC.Our results showed that i) CRC patients treated with neoadjuvant therapy, and had low LINE1 methylation levels in tumor area, had worse disease-free and overall survival rates than those with normal or high LINE1 methylation levels (p=0.004 and p=0.0049, respectively).