2025

Taira, Aurora; Aavikko, Mervi; Katainen, Riku; Kaasinen, Eevi; Välimäki, Niko; Ravantti, Janne; Ristimäki, Ari; Seppälä, Toni T.; Renkonen-Sinisalo, Laura; Lepistö, Anna; Tahkola, Kyösti; Mattila, Anne; Koskensalo, Selja; Mecklin, Jukka-Pekka; Böhm, Jan; Bramsen, Jesper Bertram; Andersen, Claus Lindbjerg; Palin, Kimmo; Rajamäki, Kristiina; Aaltonen, Lauri A.

Oncogenic codon V600E mutations of the BRAF gene affect 10-15% of colorectal cancers, resulting in activation of the MAPK/ERK signaling pathway and increased cell proliferation and survival. BRAF-mutated colorectal tumors are often microsatellite unstable and characterized by high DNA methylation levels. However, the mechanistic link between BRAF mutations and hypermethylation remains controversial. Understanding this link, particularly in microsatellite stable tumors is of great interest as these often show poor survival. We characterized the metabolomic, epigenetic and transcriptomic patterns of altogether 39 microsatellite stable BRAF-mutated colorectal cancers. Metabolomic analysis of tumor tissue showed low levels of vitamin C and its metabolites in BRAF-mutated tumors. Gene expression analysis indicated dysregulation of vitamin C antioxidant activity in these lesions. As vitamin C is an important cofactor for the activity of TET DNA demethylase enzymes, low vitamin C levels could directly contribute to the high methylation levels in these tumors by decreasing enzymatic TET activity. Vitamin C transporter gene SLC23A1 expression, as well as vitamin C metabolite levels, were inversely correlated with DNA methylation levels. This work proposes a new mechanistic link between BRAF mutations and hypermethylation, inspiring further work on the role of vitamin C in the genesis of BRAF-mutated colorectal cancer.