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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,
  7. Kana Wu3,
  8. Stephanie Smith-Warner3,5,
  9. Yanan Ma8,
  10. Jonathan A Nowak7,
  11. Fatemeh Momen-Heravi9,10,
  12. Libin Zhang11,
  13. Michaela Bowden12,
  14. Teppei Morikawa13,
  15. Annacarolina da Silva2,
  16. Molin Wang5,6,
  17. Andrew T Chan9,14,15,
  18. Charles S Fuchs9,16,17,18,
  19. Jeffrey A Meyerhardt12,
  20. Kimmie Ng12,
  21. Edward Giovannucci3,5,9,
  22. Shuji Ogino2,5,7,
  23. Xuehong Zhang9
  1. 1Department of Social Science and Public Health, School of Basic Medical Science, Jiujiang University, Jiujiang, PR China
  2. 2Department of Oncologic Pathology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA
  3. 3Department of Nutrition, Harvard TH Chan School of Public Health, Boston, MA, USA
  4. 4Department 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. 5Department of Epidemiology, Harvard TH Chan School of Public Health, Boston, MA, USA
  6. 6Department of Biostatistics, Harvard TH Chan School of Public Health, Boston, MA, USA
  7. 7Department of Pathology, Brigham and Women's Hospital, Division of MPe Molecular Pathological epidemiology, Boston, MA, USA
  8. 8Department of Biostatistics and Epidemiology, School of Public Health, China Medical University, Shenyang, PR China
  9. 9Department of Medicine, Brigham and Women's Hospital, Channing Division of Network Medicine, Boston, MA, USA
  10. 10Section of Oral and Diagnostic Sciences, Division of Periodontics, Columbia University College of Dental Medicine, New York, USA
  11. 11University of Massachusetts Boston, Institute for Community Inclusion, Boston, MA, USA
  12. 12Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA
  13. 13Department of Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
  14. 14Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
  15. 15Department of Medicine, Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
  16. 16Department of Medical Oncology, Yale Cancer Center, New Haven, CT, USA
  17. 17Department of Medicine, Yale School of Medicine, New Haven, CT, USA
  18. 18Department 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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  • 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.

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