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; NaNa 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 Ng; Edward Giovannucci; Shuji Ogino; Xuehong Zhang

doi:10.1136/gutjnl-2017-314163

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

Gut. 2018 Aug;67(8):1475-1483. doi: 10.1136/gutjnl-2017-314163. Epub 2017 Jul 4.

Authors

Wanshui Yang^#¹, Li Liu^#^{2

3

4}, Yohei Masugi^#², Zhi Rong Qian², Reiko Nishihara^{2

3

5

6

7}, NaNa Keum^{3

8}, Kana Wu³, Stephanie Smith-Warner^{3

5}, Yanan Ma⁹, Jonathan A Nowak⁷, Fatemeh Momen-Heravi^{10

11}, Libin Zhang¹², Michaela Bowden¹³, Teppei Morikawa¹⁴, Annacarolina da Silva², Molin Wang^{5

6}, Andrew T Chan^{10

15

16}, Charles S Fuchs^{10

17

18

19}, Jeffrey A Meyerhardt¹³, Kimmie Ng¹³, Edward Giovannucci^#^{3

5

10}, Shuji Ogino^#^{2

5

7}, Xuehong Zhang^#¹⁰

Affiliations

¹ Department of Social Science and Public Health, School of Basic Medical Science, Jiujiang University, Jiujiang, PR China.
² Department of Oncologic Pathology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA.
³ Department of Nutrition, Harvard TH Chan School of Public Health, Boston, MA, USA.
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 Department of Epidemiology, Harvard TH Chan School of Public Health, Boston, MA, USA.
⁶ Department of Biostatistics, Harvard TH Chan School of Public Health, Boston, MA, USA.
⁷ Department of Pathology, Brigham and Women's Hospital, Division of MPe Molecular Pathological epidemiology, Boston, MA, USA.
⁸ Department of Food Science and Biotechnology, Dongguk University, Goyang, South Korea.
⁹ Department of Biostatistics and Epidemiology, School of Public Health, China Medical University, Shenyang, PR China.
¹⁰ Department of Medicine, Brigham and Women's Hospital, Channing Division of Network Medicine, Boston, MA, USA.
¹¹ Section of Oral and Diagnostic Sciences, Division of Periodontics, Columbia University College of Dental Medicine, New York, USA.
¹² University of Massachusetts Boston, Institute for Community Inclusion, Boston, MA, USA.
¹³ Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA.
¹⁴ Department of Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
¹⁵ Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
¹⁶ Department of Medicine, Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
¹⁷ Department of Medical Oncology, Yale Cancer Center, New Haven, CT, USA.
¹⁸ Department of Medicine, Yale School of Medicine, New Haven, CT, USA.
¹⁹ Department of Medical Oncology, Smilow Cancer Hospital, New Haven, CT, USA.

^# Contributed equally.

Abstract

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 (p_trend=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 (p_trend=0.003, multivariable HR=0.67, 95% CI 0.51 to 0.86) but not with CASR-negative tumours (p_trend=0.67, multivariable HR=1.15, 95% CI 0.75 to 1.78; p_{heterogeneity}=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.

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

MeSH terms

Adult
Aged
Calcium, Dietary / administration & dosage*
Cohort Studies
Colorectal Neoplasms / diagnosis
Colorectal Neoplasms / epidemiology*
Colorectal Neoplasms / metabolism*
Diet*
Female
Humans
Incidence
Male
Middle Aged
Receptors, Calcium-Sensing / metabolism*
Risk Factors

Substances

Calcium, Dietary
Receptors, Calcium-Sensing

Abstract

MeSH terms

Substances

Grants and funding