Colorectal cancer (CRC) is the second leading cause for cancer-related deaths worldwide (GLOBOCAN, 2020) and its global incidence is on the rise. CRC is a complex disease characterized by the accumulation of genetic and epigenetic alterations in colonic epithelial cells. Elucidating the molecular and cellular mechanisms involved in CRC pathogenesis may lead to better prevention, diagnosis, prognosis, and more effective targeted therapies. Recently, due to the opportunity to chemically reverse the epigenetic changes, epigenetic therapies are emerging as promising treatment options.
The TET protein family dioxygenases (TET1-3) oxidize 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC), and subsequently to other oxidized forms of 5mC, in an active process that supports DNA demethylation and helps maintain epigenomic stability (Figure 1).
Emerging evidence indicates that TET1 is a tumorigenic driver in CRC and TET2 mutations have been identified in CRC by next generation sequencing approaches. In addition, CRCs frequently show loss of 5hmC but only a subset of these cancers has low TET1 expression, possibly involving other mechanisms, such as TET2 defects. These observations point to an important role of TET2 in CRC. However, whether TET2 defects contribute to CRC pathogenesis, or represent a bystander event, remains to be established.
This project aimed to investigate the role of TET2 in colorectal tumorigenesis with a multidisciplinary approach and an innovative technology, and to lay the groundwork for future translational studies. Specifically, the main objectives of this project were: 1) to investigate the functional consequences of TET2 defects in CRC, and 2) to determine the clinical significance of TET2 defects in human CRCs.
The findings made in the timeframe of TETCOLON project provided new knowledge on the molecular mechanisms and pathways implicated in the pathogenesis of CRC and they will likely be relevant for the clinical management of CRC patients.
