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:

Association between C-reactive protein and risk of overall and 18 site-specific cancers in a Japanese case-cohort

British Journal of Cancer volume 126, pages 1481–1489 (2022)Cite this article

Subjects

Abstract

Background

Evidence of the association between chronic low-grade inflammation, as reflected by C-reactive protein (CRP) measurements, and cancer risk is equivocal. Specifically, few studies have examined this in uncommon cancers and Asian populations.

Methods

We utilised a case-cohort design consisting of multi-types of cancer (N = 3608), and a random subcohort (N = 4432) in a Japanese large population-based study, with a median follow-up time of 15.6 years, and measured baseline plasma CRP using high sensitivity assay. The hazard ratios (HRs) were estimated using weighted Cox proportional hazards methods.

Results

The multivariable-adjusted HR (95% confidence interval) for the top quartile of CRP was 1.28 (1.11‒1.48) (Ptrend < 0.001) for overall cancer compared to the bottom quartile of CRP. Among site-specific cancers, higher CRP levels were associated with an increased risk of colorectal, lung, breast, biliary tract, and kidney cancer, and leukaemia. These positive associations remained among participants after >3 years’ follow-up. Furthermore, subgroup analyses for overall cancer robustly showed a positive association with CRP levels, regardless of sex and obesity.

Conclusion

Our consistent findings suggested that chronic low-grade inflammation measured by CRP is associated with the risk of cancer.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

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

Fig. 1: Hazard ratios (HRs) for total and site-specific cancer according to tertiles of C-reactive protein (CRP) by sex.

Similar content being viewed by others

Data availability

For information on how to submit an application for gaining access to JPHC data or biospecimens, please follow the instructions at https://epi.ncc.go.jp/en/jphc/805/8155.html.

References

  1. Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global Cancer Statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021;71:209–49.

    Article  Google Scholar 

  2. Bray F, Jemal A, Grey N, Ferlay J, Forman D. Global cancer transitions according to the Human Development Index (2008–2030): a population-based study. Lancet Oncol. 2012;13:790–801.

    Article  Google Scholar 

  3. Imhof A, Froehlich M, Brenner H, Boeing H, Pepys MB, Koenig W. Effect of alcohol consumption on systemic markers of inflammation. Lancet. 2001;357:763–7.

    Article  CAS  Google Scholar 

  4. Calder PC, Ahluwalia N, Brouns F, Buetler T, Clement K, Cunningham K, et al. Dietary factors and low-grade inflammation in relation to overweight and obesity. Br J Nutr. 2011;106:S5–78.

    Article  CAS  Google Scholar 

  5. Egger G, Dixon J. Non-nutrient causes of low-grade, systemic inflammation: support for a ‘canary in the mineshaft’ view of obesity in chronic disease. Obes Rev. 2011;12:339–45.

    Article  CAS  Google Scholar 

  6. Balkwill F, Mantovani A. Inflammation and cancer: back to Virchow? Lancet. 2001;357:539–45.

    Article  CAS  Google Scholar 

  7. Coussens LM, Werb Z. Inflammation and cancer. Nature. 2002;420:860–7.

    Article  CAS  Google Scholar 

  8. Mantovani A, Allavena P, Sica A, Balkwill F. Cancer-related inflammation. Nature. 2008;454:436–44.

    Article  CAS  Google Scholar 

  9. McWilliam S, Riordan A. How to use: C-reactive protein. Arch Dis Child Educ Pr Ed. 2010;95:55–8.

    Article  CAS  Google Scholar 

  10. Pepys MB. C-Reactive protein fifty years on. Lancet. 1981;317:653–7.

    Article  Google Scholar 

  11. Heinrich PC, Castell JV, Andus T. Interleukin-6 and the acute phase response. Biochem J. 1990;265:621–36.

    Article  CAS  Google Scholar 

  12. Pepys MB, Hirschfield GM. C-reactive protein: a critical update. J Clin Invest. 2003;111:1805–12.

    Article  CAS  Google Scholar 

  13. Guo YZ, Pan L, Du CJ, Ren DQ, Xie XM. Association between C-reactive protein and risk of cancer: a meta-analysis of prospective cohort studies. Asian Pac J Cancer Prev. 2013;14:243–8.

    Article  Google Scholar 

  14. Choi J, Joseph L, Pilote L. Obesity and C-reactive protein in various populations: a systematic review and meta-analysis. Obes Rev. 2013;14:232–44.

    Article  CAS  Google Scholar 

  15. Bhaskaran K, Douglas I, Forbes H, dos-Santos-Silva I, Leon DA, Smeeth L. Body-mass index and risk of 22 specific cancers: a population-based cohort study of 5·24 million UK adults. Lancet. 2014;384:755–65.

    Article  Google Scholar 

  16. Collaboration” NRF. Trends in adult body-mass index in 200 countries from 1975 to 2014: a pooled analysis of 1698 population-based measurement studies with 19·2 million participants. Lancet. 2016;387:1377–96.

    Article  Google Scholar 

  17. Wang Y, Zhang Z, Wang J, Zhang X. Association between C-reactive protein level and subsequent risk of ovarian cancer: A meta-analysis of 13 cohorts in 1,852 ovarian cancer patients. Medicine. 2020;99:e18821.

    Article  Google Scholar 

  18. Zhou B, Shu B, Yang J, Liu J, Xi T, Xing Y. C-reactive protein, interleukin-6 and the risk of colorectal cancer: a meta-analysis. Cancer Causes Control. 2014;25:1397–405.

    Article  Google Scholar 

  19. Wang J, Lee IM, Tworoger SS, Buring JE, Ridker PM, Rosner B, et al. Plasma C-reactive protein and risk of breast cancer in two prospective studies and a meta-analysis. Cancer Epidemiol Biomark Prev. 2015;24:1199–206.

    Article  CAS  Google Scholar 

  20. Guo L, Liu S, Zhang S, Chen Q, Zhang M, Quan P, et al. C-reactive protein and risk of breast cancer: a systematic review and meta-analysis. Sci Rep. 2015;5:10508.

    Article  Google Scholar 

  21. Zhou B, Liu J, Wang ZM, Xi T. C-reactive protein, interleukin 6 and lung cancer risk: a meta-analysis. PLoS ONE. 2012;7:e43075.

    Article  CAS  Google Scholar 

  22. Tsugane S, Sawada N. The JPHC study: design and some findings on the typical Japanese diet. Jpn J Clin Oncol. 2014;44:777–82.

    Article  Google Scholar 

  23. Budhathoki S, Hidaka A, Yamaji T, Sawada N, Tanaka-Mizuno S, Kuchiba A, et al. Plasma 25-hydroxyvitamin D concentration and subsequent risk of total and site specific cancers in Japanese population: large case-cohort study within Japan Public Health Center-based Prospective Study cohort. BMJ 2018;360:k671.

    Article  Google Scholar 

  24. Kulathinal S, Karvanen J, Saarela O, Kuulasmaa K. Case-cohort design in practice—experiences from the MORGAM Project. Epidemiol Perspect Innov. 2007;4:15.

    Article  Google Scholar 

  25. Aleksandrova K, Boeing H, Nothlings U, Jenab M, Fedirko V, Kaaks R, et al. Inflammatory and metabolic biomarkers and risk of liver and biliary tract cancer. Hepatology. 2014;60:858–71.

    Article  CAS  Google Scholar 

  26. Valle JW, Kelley RK, Nervi B, Oh D-Y, Zhu AX. Biliary tract cancer. Lancet. 2021;397:428–44.

    Article  CAS  Google Scholar 

  27. Trichopoulos D, Psaltopoulou T, Orfanos P, Trichopoulou A, Boffetta P. Plasma C-reactive protein and risk of cancer: a prospective study from Greece. Cancer Epidemiol Biomark Prev. 2006;15:381–4.

    Article  CAS  Google Scholar 

  28. Gu Y, Shore RE, Arslan AA, Koenig KL, Liu M, Ibrahim S, et al. Circulating cytokines and risk of B-cell non-Hodgkin lymphoma: a prospective study. Cancer Causes Control. 2010;21:1323–33.

    Article  Google Scholar 

  29. Brasky TM, Kabat GC, Ho GYF, Thomson CA, Nicholson WK, Barrington WE, et al. C-reactive protein concentration and risk of selected obesity-related cancers in the Women’s Health Initiative. Cancer Causes Control. 2018;29:855–62.

    Article  Google Scholar 

  30. Naugler WE, Sakurai T, Kim S, Maeda S, Kim K, Elsharkawy AM, et al. Gender disparity in liver cancer due to sex differences in MyD88-dependent IL-6 production. Science. 2007;317:121–4.

    Article  CAS  Google Scholar 

  31. Castell JV, Gómez-Lechón MJ, David M, Hirano T, Kishimoto T, Heinrich PC. Recombinant human interleukin-6 (IL-6/BSF-2/HSF) regulates the synthesis of acute phase proteins in human hepatocytes. FEBS Lett. 1988;232:347–50.

    Article  CAS  Google Scholar 

  32. Hotamisligil GS. Inflammation and metabolic disorders. Nature. 2006;444:860–7.

    Article  CAS  Google Scholar 

  33. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144:646–74.

    Article  CAS  Google Scholar 

  34. Padala SA, Barsouk A, Thandra KC, Saginala K, Mohammed A, Vakiti A, et al. Epidemiology of renal cell carcinoma. World J Oncol. 2020;11:79–87.

    Article  Google Scholar 

  35. Haggar FA, Boushey RP. Colorectal cancer epidemiology: incidence, mortality, survival, and risk factors. Clin Colon Rectal Surg. 2009;22:191–7.

    Article  Google Scholar 

  36. Bade BC, Dela Cruz CS. Lung cancer 2020: epidemiology, etiology, and prevention. Clin Chest Med. 2020;41:1–24.

    Article  Google Scholar 

  37. Doll R, Hill AB. Smoking and carcinoma of the lung; preliminary report. Br Med J. 1950;2:739–48.

    Article  CAS  Google Scholar 

  38. Kaneko H, Anzai T, Nagai T, Anzai A, Takahashi T, Mano Y, et al. Human C-reactive protein exacerbates metabolic disorders in association with adipose tissue remodelling. Cardiovasc Res. 2011;91:546–55.

    Article  CAS  Google Scholar 

  39. Ockene IS, Matthews CE, Rifai N, Ridker PM, Reed G, Stanek E. Variability and classification accuracy of serial high-sensitivity C-reactive protein measurements in healthy adults. Clin Chem. 2001;47:444–50.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank the participants and all the staff members in this study. We are indebted to the Aomori, Iwate, Akita, Ibaraki, Niigata, Osaka, Kochi, Nagasaki, and Okinawa Cancer Registries for providing their incidence data. The Japan Public Health Center-based Prospective Study members are listed at the after site: http://epi.ncc.go.jp/en/jphc/781/7951.html.

Funding

This study was supported by the National Cancer Center Research and Development Fund (23-A-31 [toku], 26-A-2, and, 29-A-4), a Grant-in-Aid for Cancer Research from the Ministry of Health, Labour and Welfare of Japan (from 1989 to 2010), and the Practical Research for Innovative Cancer Control (JP16ck0106095 and JP19ck0106266) from the Japan Agency for Medical Research and Development. The funders had no role in study design, data collection, and analysis, decision to publish, or preparation of the study.

Author information

Authors and Affiliations

  1. Epidemiology and Prevention Group, Institute for Cancer Control, National Cancer Center, Tokyo, Japan

    Shiori Suzuki, Ryoko Katagiri, Taiki Yamaji, Norie Sawada, Takuya Imatoh, Hikaru Ihira, Manami Inoue, Shoichiro Tsugane & Motoki Iwasaki

  2. Division of Cancer Medicine, Jikei University School of Medicine, Tokyo, Japan

    Shiori Suzuki & Motoki Iwasaki

  3. National Institute of Health and Nutrition, National Institutes of Biomedical Innovation, Health and Nutrition, Tokyo, Japan

    Shoichiro Tsugane

  4. National Cancer Center, Tokyo, Japan

    N. Sawada, S. Tsugane, M. Iwasaki, M. Inoue, T. Yamaji, R. Katagiri, Y. Miyamoto, H. Ihira, S. K. Abe & S. Tanaka

  5. Iwate Prefectural Ninohe Public Health Center, Iwate, Japan

    T. Moriya

  6. Akita Prefectural Yokote Public Health Center, Akita, Japan

    T. Minamizono

  7. Nagano Prefectural Saku Public Health Center, Nagano, Japan

    Y. Shirai

  8. Okinawa Prefectural Chubu Public Health Center, Okinawa, Japan

    H. Kuniyoshi

  9. Ibaraki Prefectural Chuo Public Health Center, Ibaraki, Japan

    T. Yoshimi

  10. Niigata Prefectural Nagaoka Public Health Center, Niigata, Japan

    H. Sonoda

  11. Kochi Prefectural Chuo-higashi Public Health Center, Kochi, Japan

    T. Tagami

  12. Nagasaki Prefectural Kamigoto Public Health Center, Nagasaki, Japan

    T. Ando

  13. Okinawa Prefectural Miyako Public Health Center, Okinawa, Japan

    T. Kimura

  14. National Cerebral and Cardiovascular Center, Osaka, Japan

    Y. Kokubo

  15. University of Tsukuba, Ibaraki, Japan

    K. Yamagishi

  16. National Center for Global Health and Medicine, Tokyo, Japan

    T. Mizoue

  17. Niigata University, Niigata, Japan

    K. Nakamura

  18. Nara Women’s University, Nara, Japan

    R. Takachi

  19. Azabu University, Kanagawa, Japan

    J. Ishihara

  20. Osaka University, Osaka, Japan

    H. Iso & T. Kitamura

  21. Oita University, Oita, Japan

    I. Saito

  22. Kochi University, Kochi, Japan

    N. Yasuda

  23. Keio University, Tokyo, Japan

    M. Mimura

  24. Iwate Medical University, Iwate, Japan

    K. Sakata

  25. Saitama Medical University, Saitama, Japan

    M. Noda

  26. Yokohama City University, Kanagawa, Japan

    A. Goto

  27. Nagoya university, Aichi, Japan

    H. Yatsuya

Authors
  1. Shiori Suzuki
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ryoko Katagiri
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Taiki Yamaji
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Norie Sawada
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Takuya Imatoh
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Hikaru Ihira
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Manami Inoue
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Shoichiro Tsugane
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Motoki Iwasaki
    View author publications

    You can also search for this author in PubMed Google Scholar

Consortia

for the Japan Public Health Center-based Prospective Study Group

  • N. Sawada
  • , S. Tsugane
  • , M. Iwasaki
  • , M. Inoue
  • , T. Yamaji
  • , R. Katagiri
  • , Y. Miyamoto
  • , H. Ihira
  • , S. K. Abe
  • , S. Tanaka
  • , T. Moriya
  • , T. Minamizono
  • , Y. Shirai
  • , H. Kuniyoshi
  • , T. Yoshimi
  • , H. Sonoda
  • , T. Tagami
  • , T. Ando
  • , T. Kimura
  • , Y. Kokubo
  • , K. Yamagishi
  • , T. Mizoue
  • , K. Nakamura
  • , R. Takachi
  • , J. Ishihara
  • , H. Iso
  • , T. Kitamura
  • , I. Saito
  • , N. Yasuda
  • , M. Mimura
  • , K. Sakata
  • , M. Noda
  • , A. Goto
  •  & H. Yatsuya

Contributions

SS, RK and TY had full access to all the data in the study and took responsibility for the integrity of the data and the accuracy of the data analysis. Concept and design: SS, RK, TY and M Iwasaki. Acquisition, analysis, or interpretation of data: All authors. Statistical analysis: SS, RK and TY. Drafting of the manuscript: SS drafted the first manuscript with RK support. Critical revision of the manuscript for important intellectual content: All authors. Obtained funding: ST, M Iwasaki. Administrative, technical, or material support: TY, NS, ST and M Iwasaki. Supervision: TY, NS, M Inoue, ST and M Iwasaki.

Corresponding author

Correspondence to Ryoko Katagiri.

Ethics declarations

Ethics approval and consent to participate

All precedures complied with the Helsinki Declaration. The comprehensive study protocol, including this study, was approved by the Institutional Review Board of the National Cancer Center, Tokyo, Japan (Approval No.2011-044). Before initiating this study, all living participants who had provided blood were contacted by mail and given the opportunity to opt-out of participation. Additionally, information on the study was posted on the website of our center to provide participants with the opportunity to opt-out at any time. Respondents who refused to participate were excluded from this study and their withdrawal of consent was documented.

Consent to publish

This manuscript does not contain any individual person’s data in any form, thus, consent for publication was not required.

Competing interests

The authors declare no competing interests.

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

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Suzuki, S., Katagiri, R., Yamaji, T. et al. Association between C-reactive protein and risk of overall and 18 site-specific cancers in a Japanese case-cohort. Br J Cancer 126, 1481–1489 (2022). https://doi.org/10.1038/s41416-022-01715-8

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41416-022-01715-8

Search

Advanced search

Quick links