Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

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.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

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)*.

Similar content being viewed by others

Data availability

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

References

  1. Sebolt-Leopold JS, Herrera R. Targeting the mitogen-activated protein kinase cascade to treat cancer. Nat Rev Cancer. 2004;4:937–47.

    Article  CAS  PubMed  Google Scholar 

  2. Karapetis CS, Khambata-Ford S, Jonker DJ, O’Callaghan CJ, Tu D, Tebbutt NC, et al. K-ras mutations and benefit from cetuximab in advanced colorectal cancer. N Engl J Med. 2008;359:1757–65.

    Article  CAS  PubMed  Google Scholar 

  3. Di Nicolantonio F, Martini M, Molinari F, Sartore-Bianchi A, Arena S, Saletti P, et al. Wild-type BRAF is required for response to panitumumab or cetuximab in metastatic colorectal cancer. J Clin Oncol. 2008;26:5705–12.

    Article  PubMed  Google Scholar 

  4. Granger M, Eck P. Dietary vitamin c in human health. Adv Food Nutr Res. 2018;83:281–310.

    Article  PubMed  Google Scholar 

  5. Kuiper C, Vissers MC. Ascorbate as a co-factor for fe- and 2-oxoglutarate dependent dioxygenases: physiological activity in tumor growth and progression. Front Oncol. 2014;4:359.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Di Tano M, Raucci F, Vernieri C, Caffa I, Buono R, Fanti M, et al. Synergistic effect of fasting-mimicking diet and vitamin C against KRAS mutated cancers. Nat Commun. 2020;11:2332.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Mikkelsen SU, Gillberg L, Lykkesfeldt J, Gronbaek K. The role of vitamin C in epigenetic cancer therapy. Free Radic Biol Med. 2021;170:179–93.

    Article  CAS  PubMed  Google Scholar 

  8. Cenigaonandia-Campillo A, Serna-Blasco R, Gomez-Ocabo L, Solanes-Casado S, Banos-Herraiz N, Puerto-Nevado LD, et al. Vitamin C activates pyruvate dehydrogenase (PDH) targeting the mitochondrial tricarboxylic acid (TCA) cycle in hypoxic KRAS mutant colon cancer. Theranostics. 2021;11:3595–606.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Mueckler M, Thorens B. The SLC2 (GLUT) family of membrane transporters. Mol Asp Med. 2013;34:121–38.

    Article  CAS  Google Scholar 

  10. Yun J, Mullarky E, Lu C, Bosch KN, Kavalier A, Rivera K, et al. Vitamin C selectively kills KRAS and BRAF mutant colorectal cancer cells by targeting GAPDH. Science. 2015;350:1391–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Rimm EB, Giovannucci EL, Willett WC, Colditz GA, Ascherio A, Rosner B, et al. Prospective study of alcohol consumption and risk of coronary disease in men. Lancet. 1991;338:464–8.

    Article  CAS  PubMed  Google Scholar 

  12. Colditz GA, Manson JE, Hankinson SE. The Nurses’ Health Study: 20-year contribution to the understanding of health among women. J Women’s Health. 1997;6:49–62.

    Article  CAS  Google Scholar 

  13. Amin MB, Greene FL, Edge SB, Compton CC, Gershenwald JE, Brookland RK, et al. The Eighth Edition AJCC Cancer Staging Manual: Continuing to build a bridge from a population-based to a more “personalized” approach to cancer staging. CA Cancer J Clin. 2017;67:93–9.

    Article  PubMed  Google Scholar 

  14. Rich-Edwards JW, Corsano KA, Stampfer MJ. Test of the National Death Index and Equifax Nationwide Death Search. Am J Epidemiol. 1994;140:1016–9.

    Article  CAS  PubMed  Google Scholar 

  15. Stampfer MJ, Willett WC, Speizer FE, Dysert DC, Lipnick R, Rosner B, et al. Test of the National Death Index. Am J Epidemiol. 1984;119:837–9.

    Article  CAS  PubMed  Google Scholar 

  16. Cadeau C, Farvid MS, Rosner BA, Willett WC, Eliassen AH. Dietary and Supplemental Vitamin C intake and risk of breast cancer: results from the nurses’ health studies. J Nutr. 2022;152:835–43.

    Article  PubMed  Google Scholar 

  17. WC W. Reproducibility and validity of food frequency questionnaires. In: Nutritional epidemiology. 3rd edn. New York:Oxford University Press;2012.

  18. Yuan C, Spiegelman D, Rimm EB, Rosner BA, Stampfer MJ, Barnett JB, et al. Validity of a dietary questionnaire assessed by comparison with multiple weighed dietary records or 24-hour recalls. Am J Epidemiol. 2017;185:570–84.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Willett W, Stampfer MJ. Total energy intake: implications for epidemiologic analyses. Am J Epidemiol. 1986;124:17–27.

    Article  CAS  PubMed  Google Scholar 

  20. Shan Z, Li Y, Baden MY, Bhupathiraju SN, Wang DD, Sun Q, et al. Association between healthy eating patterns and risk of cardiovascular disease. JAMA Intern Med. 2020;180:1090–100.

    Article  PubMed  Google Scholar 

  21. Song M, Zhang X, Meyerhardt JA, Giovannucci EL, Ogino S, Fuchs CS, et al. Marine omega-3 polyunsaturated fatty acid intake and survival after colorectal cancer diagnosis. Gut. 2017;66:1790–6.

    Article  CAS  PubMed  Google Scholar 

  22. Song M, Wu K, Meyerhardt JA, Ogino S, Wang M, Fuchs CS, et al. Fiber intake and survival after colorectal cancer diagnosis. JAMA Oncol. 2018;4:71–9.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Rimm EB, Giovannucci EL, Stampfer MJ, Colditz GA, Litin LB, Willett WC. Reproducibility and validity of an expanded self-administered semiquantitative food frequency questionnaire among male health professionals. Am J Epidemiol. 1992;135:1114–26.

    Article  CAS  PubMed  Google Scholar 

  24. Feskanich D, Rimm EB, Giovannucci EL, Colditz GA, Stampfer MJ, Litin LB, et al. Reproducibility and validity of food intake measurements from a semiquantitative food frequency questionnaire. J Am Diet Assoc. 1993;93:790–6.

    Article  CAS  PubMed  Google Scholar 

  25. Imamura Y, Lochhead P, Yamauchi M, Kuchiba A, Qian ZR, Liao X, et al. Analyses of clinicopathological, molecular, and prognostic associations of KRAS codon 61 and codon 146 mutations in colorectal cancer: cohort study and literature review. Mol Cancer. 2014;13:135.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Xie J, Liu C. Adjusted Kaplan-Meier estimator and log-rank test with inverse probability of treatment weighting for survival data. Stat Med. 2005;24:3089–110.

    Article  PubMed  Google Scholar 

  27. Cain KC, Harlow SD, Little RJ, Nan B, Yosef M, Taffe JR, et al. Bias due to left truncation and left censoring in longitudinal studies of developmental and disease processes. Am J Epidemiol. 2011;173:1078–84.

    Article  PubMed  PubMed Central  Google Scholar 

  28. Durrleman S, Simon R. Flexible regression models with cubic splines. Stat Med. 1989;8:551–61.

    Article  CAS  PubMed  Google Scholar 

  29. Liu L, Nevo D, Nishihara R, Cao Y, Song M, Twombly TS, et al. Utility of inverse probability weighting in molecular pathological epidemiology. Eur J Epidemiol. 2018;33:381–92.

    Article  PubMed  Google Scholar 

  30. Aune D, Keum N, Giovannucci E, Fadnes LT, Boffetta P, Greenwood DC, et al. Dietary intake and blood concentrations of antioxidants and the risk of cardiovascular disease, total cancer, and all-cause mortality: a systematic review and dose-response meta-analysis of prospective studies. Am J Clin Nutr. 2018;108:1069–91.

    Article  PubMed  PubMed Central  Google Scholar 

  31. Chen J, Qin F, Li Y, Mo S, Deng K, Huang Y, et al. High-dose vitamin C tends to kill colorectal cancer with high MALAT1 expression. J Oncol. 2020;2020:2621308.

    Article  PubMed  PubMed Central  Google Scholar 

  32. Nakanishi K, Hiramoto K, Ooi K. High-dose vitamin C exerts its anti-cancer effects in a xenograft model of colon cancer by suppressing angiogenesis. Biol Pharm Bull. 2021;44:884–7.

    Article  CAS  PubMed  Google Scholar 

  33. Brandt KE, Falls KC, Schoenfeld JD, Rodman SN, Gu Z, Zhan F, et al. Augmentation of intracellular iron using iron sucrose enhances the toxicity of pharmacological ascorbate in colon cancer cells. Redox Biol. 2018;14:82–87.

    Article  CAS  PubMed  Google Scholar 

  34. van‘t Erve I, Wesdorp NJ, Medina JE, Ferreira L, Leal A, Huiskens J, et al. KRAS A146 mutations are associated with distinct clinical behavior in patients with colorectal liver metastases. JCO Precis Oncol. 2021;5:1758–67.

  35. Hutton JE, Wang X, Zimmerman LJ, Slebos RJ, Trenary IA, Young JD, et al. Oncogenic KRAS and BRAF drive metabolic reprogramming in colorectal cancer. Mol Cell Proteom. 2016;15:2924–38.

    Article  CAS  Google Scholar 

  36. Serna-Blasco R, Sanz-Alvarez M, Aguilera O, Garcia-Foncillas J. Targeting the RAS-dependent chemoresistance: the Warburg connection. Semin Cancer Biol. 2019;54:80–90.

    Article  CAS  PubMed  Google Scholar 

  37. Aguilera O, Munoz-Sagastibelza M, Torrejon B, Borrero-Palacios A, Del Puerto-Nevado L, Martinez-Useros J, et al. Vitamin C uncouples the Warburg metabolic switch in KRAS mutant colon cancer. Oncotarget. 2016;7:47954–65.

    Article  PubMed  PubMed Central  Google Scholar 

  38. Magri A, Germano G, Lorenzato A, Lamba S, Chila R, Montone M, et al. High-dose vitamin C enhances cancer immunotherapy. Sci Transl Med. 2020;12:1–12.

  39. Wang F, He MM, Xiao J, Zhang YQ, Yuan XL, Fang WJ, et al. A randomized, open-label, multicenter, phase 3 study of high-dose vitamin C plus FOLFOX +/- bevacizumab versus FOLFOX +/- bevacizumab in unresectable untreated metastatic colorectal cancer (VITALITY Study). Clin Cancer Res. 2022;28:4232–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Dachs GU, Gandhi J, Wohlrab C, Carr AC, Morrin HR, Pullar JM, et al. Vitamin C administration by intravenous infusion increases tumor ascorbate content in patients with colon cancer: a clinical intervention study. Front Oncol. 2020;10:600715.

    Article  PubMed  Google Scholar 

  41. Lykkesfeldt J. On the effect of vitamin C intake on human health: how to (mis)interprete the clinical evidence. Redox Biol. 2020;34:101532.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Levine M, Wang Y, Padayatty SJ, Morrow J. A new recommended dietary allowance of vitamin C for healthy young women. Proc Natl Acad Sci USA. 2001;98:9842–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Jacob RA, Sotoudeh G. Vitamin C function and status in chronic disease. Nutr Clin Care. 2002;5:66–74.

    Article  PubMed  Google Scholar 

  44. Saygili EI, Konukoglu D, Papila C, Akcay T. Levels of plasma vitamin E, vitamin C, TBARS, and cholesterol in male patients with colorectal tumors. Biochem (Mosc). 2003;68:325–8.

    Article  CAS  Google Scholar 

  45. Sharma Y, Miller M, Shahi R, Doyle A, Horwood C, Hakendorf P, et al. Vitamin C deficiency in Australian hospitalised patients: an observational study. Intern Med J. 2019;49:189–96.

    Article  CAS  PubMed  Google Scholar 

  46. Monsen ER. Dietary reference intakes for the antioxidant nutrients: vitamin C, vitamin E, selenium, and carotenoids. J Am Diet Assoc. 2000;100:637–40.

    Article  CAS  PubMed  Google Scholar 

  47. Hoffer LJ, Robitaille L, Zakarian R, Melnychuk D, Kavan P, Agulnik J, et al. High-dose intravenous vitamin C combined with cytotoxic chemotherapy in patients with advanced cancer: a phase I-II clinical trial. PLoS ONE. 2015;10:e0120228.

    Article  PubMed  PubMed Central  Google Scholar 

  48. Wang P, Giovannucci EL. Are exposure-disease relationships assessed in cohorts of health professionals generalizable?: a comparative analysis based on WCRF/AICR systematic literature reviews. Cancer Causes Control. 2023;34:39–45.

    Article  CAS  PubMed  Google Scholar 

Download references

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.

Author information

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

Authors
  1. Shanshan Shi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kai Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Tomotaka Ugai
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Marios Giannakis
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jules Cazaubiel
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Andrew T. Chan
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Edward L. Giovannucci
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Jonathan A. Nowak
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Jeffrey A. Meyerhardt
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Shuji Ogino
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Mingyang Song
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

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.

Ethics declarations

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.

Ethics approval and consent to participate

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.

Consent for publication

All patients provided written informed consent.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

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

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41416-023-02452-2

This article is cited by

Search

Advanced search

Quick links