Calcium intake and risk of colorectal cancer according to expression status of calcium-sensing receptor (CASR)

Wanshui Yang, Li Liu, Yohei Masugi, Zhi Rong Qian, Reiko Nishihara, Na Na Keum, Kana Wu, Stephanie Smith-Warner, Yanan Ma, Jonathan A. Nowak, Fatemeh Momen-Heravi, Libin Zhang, Michaela Bowden, Teppei Morikawa, Annacarolina da Silva, Molin Wang, Andrew T. Chan, Charles S. Fuchs, Jeffrey A. Meyerhardt, Kimmie NgEdward Giovannucci, Shuji Ogino, Xuehong Zhang

Research output: Contribution to journalArticle

17 Citations (Scopus)


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.

Original languageEnglish
Publication statusAccepted/In press - 2017 Jul 4
Externally publishedYes


  • calcium
  • Calcium-sensing receptor
  • Cancer epidemiology
  • Cancer prevention
  • Cohort study
  • Colon cancer
  • Diet
  • Etiologic heterogeneity
  • Molecular pathological epidemiology
  • Rectal cancer
  • Tumor microenvironment

ASJC Scopus subject areas

  • Gastroenterology

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    Yang, W., Liu, L., Masugi, Y., Qian, Z. R., Nishihara, R., Keum, N. N., Wu, K., Smith-Warner, S., Ma, Y., Nowak, J. A., Momen-Heravi, F., Zhang, L., Bowden, M., Morikawa, T., Silva, A. D., Wang, M., Chan, A. T., Fuchs, C. S., Meyerhardt, J. A., ... Zhang, X. (Accepted/In press). Calcium intake and risk of colorectal cancer according to expression status of calcium-sensing receptor (CASR). Gut.