Comprehensive metabolomic and epigenomic characterization of microsatellite stable BRAF-mutated colorectal cancer

Aurora Taira ^1,2, Mervi Aavikko ^1,2,3, Riku Katainen ^1,2,3

¹Medicum/Department of Medical and Clinical Genetics, University of Helsinki, Helsinki, 00014, Finland.
²Applied Tumor Genomics Research Program, Research Programs Unit, University of Helsinki, Helsinki, 00014, Finland.
³Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, Helsinki, Finland.
⁴Molecular and Integrative Biosciences Research Programme, Faculty of Biological and Environmental Sciences, University of Helsinki, FI-00014, Helsinki, Finland.
⁵Department of Pathology, HUSLAB, HUS Diagnostic Center, University of Helsinki and Helsinki University Hospital, Helsinki, 00014, Finland.
⁶Department of Surgery, Helsinki University Central Hospital, Hospital District of Helsinki and Uusimaa, Helsinki, 00290, Finland.
⁷Department of Gastroenterology and Alimentary Tract Surgery, Tampere University Hospital and TAYS Cancer Centre, 33520, Tampere, Finland.
⁸Faculty of Medicine and Health Technology, Tampere University, Tampere, 33100, Finland.
⁹iCAN Digital Precision Cancer Medicine Flagship, University of Helsinki, Helsinki, 00014, Finland.
¹⁰Department of Surgery, The Wellbeing Services of Central Finland, Hoitajatie 1, 40620, Jyväskylä, Finland.
¹¹The HUCH Gastrointestinal Clinic, Helsinki University Central Hospital, Helsinki, 00280, Finland.
¹²Department of Education and Research, The Wellbeing Services of Central Finland, Hoitajatie 1, 40620, Jyväskylä, Finland.
¹³Department of Sport and Health Sciences, University of Jyväskylä, 40014, Jyväskylä, Finland.
¹⁴Department of Pathology, The Wellbeing Services of Central Finland, Hoitajatie 1, 40620, Jyväskylä, Finland.
¹⁵Department of Molecular Medicine, Aarhus University Hospital, DK-8200, Aarhus, Denmark.
¹⁶Department of Clinical Medicine, Aarhus University, DK-8200, Aarhus, Denmark.
¹⁷Medicum/Department of Medical and Clinical Genetics, University of Helsinki, Helsinki, 00014, Finland. lauri.aaltonen@helsinki.fi.
¹⁸Applied Tumor Genomics Research Program, Research Programs Unit, University of Helsinki, Helsinki, 00014, Finland. lauri.aaltonen@helsinki.fi.
¹⁹iCAN Digital Precision Cancer Medicine Flagship, University of Helsinki, Helsinki, 00014, Finland. lauri.aaltonen@helsinki.fi.

⁰Medicum/Department of Medical and Clinical Genetics, University of Helsinki, Helsinki, 00014, Finland.

Oncogene +

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March 19, 2025

View abstract on PubMed

Summary

BRAF mutations in colorectal cancer are linked to low vitamin C levels, potentially causing DNA hypermethylation. This discovery offers new insights into cancer development and treatment strategies.

Area Of Science

Oncology
Epigenetics
Molecular Biology

Background

BRAF V600E mutations drive colorectal cancer (CRC) via MAPK/ERK pathway activation.
BRAF-mutated CRC often exhibits microsatellite instability and high DNA methylation, but the link is unclear.
Microsatellite stable (MSS) BRAF-mutated CRC presents a survival challenge, necessitating mechanistic understanding.

Purpose Of The Study

To investigate the link between BRAF mutations and DNA hypermethylation in MSS colorectal cancer.
To characterize the metabolomic, epigenetic, and transcriptomic profiles of BRAF-mutated MSS CRC.
To explore the potential role of vitamin C in the observed hypermethylation.

Main Methods

Analysis of metabolomic, epigenetic, and transcriptomic data from 39 MSS BRAF-mutated CRC tumors.
Assessment of vitamin C levels and its metabolites within tumor tissues.
Gene expression analysis of vitamin C-related genes and DNA methyltransferases (TET enzymes).

Main Results

BRAF-mutated tumors showed significantly lower levels of vitamin C and its metabolites.
Gene expression data indicated dysregulated vitamin C antioxidant activity.
Low vitamin C levels and reduced expression of the vitamin C transporter SLC23A1 correlated with increased DNA methylation.

Conclusions

Reduced vitamin C levels may impair TET DNA demethylase activity, contributing to hypermethylation in BRAF-mutated CRC.
This study proposes a novel mechanism linking BRAF mutations, vitamin C metabolism, and DNA methylation.
Findings suggest vitamin C's role in BRAF-mutated colorectal cancer genesis warrants further investigation.