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Original article
Calcium intake and risk of colorectal cancer according to expression status of calcium-sensing receptor (CASR)
  1. Wanshui Yang1,
  2. Li Liu2,3,4,
  3. Yohei Masugi2,
  4. Zhi Rong Qian2,
  5. Reiko Nishihara2,3,5,6,7,
  6. NaNa Keum3,8,
  7. Kana Wu3,
  8. Stephanie Smith-Warner3,5,
  9. Yanan Ma9,
  10. Jonathan A Nowak7,
  11. Fatemeh Momen-Heravi10,11,
  12. Libin Zhang12,
  13. Michaela Bowden13,
  14. Teppei Morikawa14,
  15. Annacarolina da Silva2,
  16. Molin Wang5,6,
  17. Andrew T Chan10,15,16,
  18. Charles S Fuchs10,17,18,19,
  19. Jeffrey A Meyerhardt13,
  20. Kimmie Ng13,
  21. Edward Giovannucci3,5,10,
  22. Shuji Ogino2,5,7,
  23. Xuehong Zhang10
  1. 1 Department of Social Science and Public Health, School of Basic Medical Science, Jiujiang University, Jiujiang, PR China
  2. 2 Department of Oncologic Pathology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA
  3. 3 Department of Nutrition, Harvard TH Chan School of Public Health, Boston, MA, USA
  4. 4 Department of Epidemiology and Biostatistics, and the Ministry of Education Key Lab of Environment and Health, School of Public Health, Huazhong University of Science and Technology, Wuhan, PR China
  5. 5 Department of Epidemiology, Harvard TH Chan School of Public Health, Boston, MA, USA
  6. 6 Department of Biostatistics, Harvard TH Chan School of Public Health, Boston, MA, USA
  7. 7 Department of Pathology, Brigham and Women’s Hospital, Division of MPe Molecular Pathological epidemiology, Boston, MA, USA
  8. 8 Department of Food Science and Biotechnology, Dongguk University, Goyang, South Korea
  9. 9 Department of Biostatistics and Epidemiology, School of Public Health, China Medical University, Shenyang, PR China
  10. 10 Department of Medicine, Brigham and Women’s Hospital, Channing Division of Network Medicine, Boston, MA, USA
  11. 11 Section of Oral and Diagnostic Sciences, Division of Periodontics, Columbia University College of Dental Medicine, New York, USA
  12. 12 University of Massachusetts Boston, Institute for Community Inclusion, Boston, MA, USA
  13. 13 Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA
  14. 14 Department of Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
  15. 15 Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
  16. 16 Department of Medicine, Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
  17. 17 Department of Medical Oncology, Yale Cancer Center, New Haven, CT, USA
  18. 18 Department of Medicine, Yale School of Medicine, New Haven, CT, USA
  19. 19 Department of Medical Oncology, Smilow Cancer Hospital, New Haven, CT, USA
  1. Correspondence to Dr Shuji Ogino; shuji_ogino{at} and Dr Xuehong Zhang; poxue{at}


Objective Although evidence suggests an inverse association between calcium intake and the risk of colorectal cancer, the mechanisms remain unclear. The calcium-sensing receptor (CASR) is expressed abundantly in normal colonic epithelium and may influence carcinogenesis. We hypothesized that calcium intake might be associated with lower risk of CASR-positive, but not CASR-negative, colorectal cancer.

Design We assessed tumour CASR protein expression using immunohistochemistry in 779 incident colon and rectal cancer cases that developed among 136 249 individuals in the Nurses’ Health Study and Health Professionals Follow-Up Study. Duplication method Cox proportional hazards regression analysis was used to assess associations of calcium intake with incidence of colorectal adenocarcinoma subtypes by CASR status.

Results Total calcium intake was inversely associated with the risk of developing colorectal cancer (ptrend=0.01, comparing ≥1200 vs <600 mg/day: multivariable HR=0.75, 95% CI 0.60 to 0.95). For the same comparison, higher total calcium intake was associated with a lower risk of CASR-positive tumours (ptrend=0.003, multivariable HR=0.67, 95% CI 0.51 to 0.86) but not with CASR-negative tumours (ptrend=0.67, multivariable HR=1.15, 95% CI 0.75 to 1.78; pheterogeneity=0.06 between the CASR subtypes). The stronger inverse associations of calcium intake with CASR-positive but not CASR-negative tumours generally appeared consistent regardless of sex, tumour location and source of calcium.

Conclusions Our molecular pathological epidemiology data suggest a causal relationship between higher calcium intake and lower colorectal cancer risk, and a potential role of CASR in mediating antineoplastic effect of calcium.

  • calcium
  • calcium-sensing receptor
  • cancer epidemiology
  • cancer prevention
  • cohort study
  • colon cancer
  • diet
  • etiologic heterogeneity
  • molecular pathological epidemiology
  • rectal cancer
  • tumor microenvironment.

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  • EG, SO and XZ contributed equally.

  • WY, LL and YM contributed equally.

  • Contributors XZ, ELG and SO conceived and designed the study; YoM and ZRQ performed experiments; WY, LL and YM analysed and interpreted the data; WY and XZ wrote the paper. All authors commented and approved the final manuscript.

  • Competing interests None declared.

  • Patient consent Obtained.

  • Ethics approval Institutional review boards of the Brigham and Women’s Hospital and Harvard TH Chan School of Public Health.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Correction notice This article has been corrected since it published Online First. The affiliations for NaNa Keum have been corrected.