Epigenetic and genetic features of colon cancer From preclinical models to patient study

Recent developments in surgical techniques and advances in systemic therapies for colon cancer improved survival. However colon cancer remains a major cause of cancer related deaths. Therefore predicting prognosis and selecting the right patients for treatment is important to prevent therapy associated side effects and reduce health care costs.
In part one of this thesis, we describe the transcriptional based molecular subtypes of colon cancer, in particular, consensus molecular subtypes (CMS). We argued that molecular subtypes could be of additional value to predict therapy response. Furthermore, we showed that CMSs are recapitulated in cell lines and mouse models, independent of stromal content. To concluded this part, the role of CFTR expression in colon cancer and its potential to predict prognosis was described.
In the second part of this thesis, we explored DNA methylation in colon cancer. We performed a systematic review of literature to identify DNA methylation based biomarkers for diagnostic, prognostic and predictive purposes in colorectal cancer. Moreover, a validation study was performed, showing that WNT target genes AXIN2 and DKK1 predict poor prognosis in stage II colon cancer. Next we performed a proof of concept patient study, where we treated colon cancer patients pre-operatively with the demethylating agents decitabine. This treatment resulted in a limited decrease of LINE1 methylation without an effect on WNT target methylation. In a systematic review was showed that both biological changes and survival benefit is observed in individual patients, but overall response is limited.
In conclusion, this thesis shows the potential applications of CMS and the presence of CMS in preclinical models. This could open avenues for development of novel subtype specific therapies. DNA methylation e.g. methylation of WNT target genes AXIN2 and DKK1 could potentially predict prognosis in stage II colon cancer.