The first evidence of histone modification in CRC was discovered in 2005  and since then, other studies suggested that histone alterations can lead to
a dysregulation of oncogenic pathways. For example, oncogenic RAS pathways can affect histone covalent modifications to regulare the expression of target genes like Cyclin D1 or E-cadherin .
Disruption of epigenetic regulation in CRC, particularly aberrant histone methylation mediated by histone methyltransferases (HMTs) and
demethylases (HDMs), correlate with poorer survival rates in mCRC. DNA methylation and histone acetylation have been already addressed for drug design and several DNA methyltransferases and histone deacetylases inhibitors are FDA-approved anti-cancer drugs (e.g., azacitidine, decitabine, vorinostat, romidepsin and belinostat). Indeed, epigenetics provides promising new targets for anticancer therapy. Numerous phase I/II trial are now enrolling patients to test the safety and efficacy of drugs targeting histone modifiers in solid tumors, including CRC .
Initial results of current clinical trials will probably guide the future clinical development of new histone methylation modifiers and different therapeutic indications .
Herein, we aimed to highlight the molecular differences between CRC harboring pathological mutations in genes involved in histone modification
(KMT family) versus wild-type tumors. We also investigated whether an association existed between histone modification and well-known molecular and clinical CRC features, such as KRAS, MSI, BRAF status, sidedness, gender, age.
Our findings provide the first exploratory data on KMT genes mutations and their association with clinical and molecular features in CRC, in a large population of patients with extensive genetic testing.
Further investigations are warranted to elucidate the association between MSI-H and histone modifications, potentially leading to a better understanding of epigenetic alterations in CRC and to the identification of novel targets to improve therapeutic options for CRC patients.Download Publication