Comprehensive metabolomic and epigenomic characterization of microsatellite stable BRAF-mutated colorectal cancer
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.
Authors
- Kimmo Palin (ORCID: https://orcid.org/0000-0002-4621-6128)
- Jan Böhm (ORCID: https://orcid.org/0000-0001-9664-588X)
- Anne Mattila (ORCID: https://orcid.org/0000-0001-6517-1765)
- Toni T. Seppälä (ORCID: https://orcid.org/0000-0002-4940-3498)
- Aurora Taira (ORCID: https://orcid.org/0000-0002-1179-8500)
- Lauri A. Aaltonen (ORCID: https://orcid.org/0000-0001-6839-4286)
- Laura Renkonen‐Sinisalo (ORCID: https://orcid.org/0000-0002-3122-5312)
- Anna Lepistö (ORCID: https://orcid.org/0000-0002-5866-4059)
- Claus L. Andersen (ORCID: https://orcid.org/0000-0002-7406-2103)
- Ari Ristimäki (ORCID: https://orcid.org/0000-0002-5373-9234)
- Janne Ravantti (ORCID: https://orcid.org/0000-0002-8578-7230)
- Kyösti Tahkola (ORCID: https://orcid.org/0000-0002-1626-5690)
- Jesper B. Bramsen (ORCID: https://orcid.org/0000-0002-2084-0336)
- Riku Katainen (ORCID: https://orcid.org/0000-0003-4575-4239)
- Jukka‐Pekka Mecklin (ORCID: https://orcid.org/0000-0003-4895-2249)
- Mervi Aavikko (ORCID: https://orcid.org/0000-0003-2583-0150)
- Niko Välimäki (ORCID: https://orcid.org/0000-0001-9200-9560)
- Selja Koskensalo (ORCID: https://orcid.org/0000-0001-6959-8715)
- Eevi Kaasinen (ORCID: https://orcid.org/0000-0002-1333-8049)
- Kristiina Rajamäki (ORCID: https://orcid.org/0000-0001-5151-1220)
Institutions
- University of Helsinki (FI)
- Tampere University (FI)
- Aarhus University (DK)
- Helsinki University Hospital (FI)
- Aarhus University Hospital (DK)
- Wihuri Research Institute (FI)
- Tampere University Hospital (FI)
- Tampere University (FI)
- Institute for Molecular Medicine Finland (FI)
- Central Finland Health Care District (FI)
- Hospital District of Helsinki and Uusimaa (FI)
- University of Jyväskylä (FI)
Publication Details
- Journal
- Oncogene
- Published
- 2025-03-18
- DOI
- https://doi.org/10.1038/s41388-025-03326-y
- Citations
- 2
- Primary Topic
- Vitamin C and Antioxidants Research
- Type
- article
- Field-Weighted Citation Impact
- 2.24
Funders
- Ida Montinin Säätiö
- Helsingin Yliopisto
- Helsingin ja Uudenmaan Sairaanhoitopiiri
- Mary och Georg C. Ehrnrooths Stiftelse
- Fondation pour la Recherche Médicale
- Biomedicum Helsinki-säätiö
- Jane ja Aatos Erkon Säätiö
- China Scholarship Council
- Emil Aaltosen Säätiö
- Orionin Tutkimussäätiö
- Syöpäsäätiö
- Biocenter Finland
- Helsinki Institute of Life Science, Helsingin Yliopisto