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Epidemiology

Vitamin C intake and colorectal cancer survival according to KRAS and BRAF mutation: a prospective study in two US cohorts

British Journal of Cancer volume 129, pages 1793–1800 (2023)Cite this article

Subjects

Abstract

Background

The associations of vitamin C intake with colorectal cancer (CRC) survival according to tumour KRAS or BRAF mutation status remain unclear.

Methods

We used the inverse probability weighted multivariable Cox proportional hazards regression model to calculate the hazard ratio (HR) of mortality, and spline analysis to evaluate the dose–response relationship in the Nurses’ Health Study and Health Professionals Follow-up Study. We also assessed SLC2A1 mRNA expression according to KRAS or BRAF mutation in the TCGA database.

Results

During an average of 12.0 years of follow-up, we documented 2,096 CRC cases, of which 703 cases had KRAS and BRAF mutation data. The association between total vitamin C intake and CRC-specific mortality suggestively differed according to KRAS or BRAF mutation status (Pinteraction = 0.04), with the multivariable HR (95% CI) per 400 mg/day increase in vitamin C intake for CRC-specific mortality of 1.07 (0.87–1.32, Ptrend = 0.52) in cases with both wild type and 0.74 (0.55–1.00, Ptrend < 0.05) in cases with either KRAS or BRAF mutant type. TCGA analysis showed a higher mRNA SLC2A1 expression in KRAS or BRAF-mutated tumours than in wild-type tumours (P = 0.02).

Conclusion

Our findings support the laboratory evidence for a potential benefit of vitamin C for CRC patients with KRAS or BRAF mutated tumours.

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Fig. 1: Dose–response relationship between post-diagnostic vitamin C intake and mortality.
Fig. 2: SLC2A1 mRNA expression according to KRAS/BRAF mutation status in stage I–III colorectal tumours in the TCGA (n = 460)*.

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Data availability

Study data is not publicly available due to proprietary restrictions but is available upon request.

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Acknowledgements

We would like to acknowledge the contribution to this study from central cancer registries supported through the Centres for Disease Control and Prevention’s National Programme of Cancer Registries (NPCR) and/or the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) Programme. Central registries may also be supported by state agencies, universities, and cancer centres. Participating central cancer registries include the following: Alabama, Alaska, Arizona, Arkansas, California, Colorado, Connecticut, Delaware, Florida, Georgia, Hawaii, Idaho, Indiana, Iowa, Kentucky, Louisiana, Massachusetts, Maine, Maryland, Michigan, Mississippi, Montana, Nebraska, Nevada, New Hampshire, New Jersey, New Mexico, New York, North Carolina, North Dakota, Ohio, Oklahoma, Oregon, Pennsylvania, Puerto Rico, Rhode Island, Seattle SEER Registry, South Carolina, Tennessee, Texas, Utah, Virginia, West Virginia, Wyoming. The authors assume full responsibility for analyses and interpretation of these data. The content is solely the responsibility of the authors and does not necessarily represent the official views of NIH. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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Author notes

  1. These authors contributed equally: Shuji Ogino, Mingyang Song.

Authors and Affiliations

  1. Department of Pathology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China

    Shanshan Shi

  2. Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA

    Shanshan Shi, Kai Wang, Tomotaka Ugai, Edward L. Giovannucci, Shuji Ogino & Mingyang Song

  3. Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women’s Hospital, and Harvard Medical School, Boston, MA, USA

    Tomotaka Ugai, Jonathan A. Nowak & Shuji Ogino

  4. Broad Institute of MIT and Harvard, Cambridge, MA, USA

    Marios Giannakis, Andrew T. Chan & Shuji Ogino

  5. Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA

    Marios Giannakis, Jules Cazaubiel & Jeffrey A. Meyerhardt

  6. Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA

    Marios Giannakis

  7. Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA

    Andrew T. Chan & Mingyang Song

  8. Division of Gastroenterology, Massachusetts General Hospital, Boston, MA, USA

    Andrew T. Chan & Mingyang Song

  9. Channing Division of Network Medicine, Department of Medicine, Brigham and Women’s Hospital, and Harvard Medical School, Boston, MA, USA

    Andrew T. Chan

  10. Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA

    Edward L. Giovannucci & Mingyang Song

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SS and MS have full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. All authors reviewed and approved the final paper.

Corresponding author

Correspondence to Mingyang Song.

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Competing interests

This study was not funded by any commercial entities. No other conflicts of interest exist. The authors declare that they have no conflicts of interest.

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The study protocol was approved by the institutional review boards of Brigham and Women’s Hospital (1999P011117) and those of participating state cancer registries as needed.

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All patients provided written informed consent.

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Shi, S., Wang, K., Ugai, T. et al. Vitamin C intake and colorectal cancer survival according to KRAS and BRAF mutation: a prospective study in two US cohorts. Br J Cancer 129, 1793–1800 (2023). https://doi.org/10.1038/s41416-023-02452-2

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