Cancer Causes & Control

, Volume 30, Issue 6, pp 637–649 | Cite as

Calcium intake and colon cancer risk subtypes by tumor molecular characteristics

  • NaNa KeumEmail author
  • Li Liu
  • Tsuyoshi Hamada
  • Zhi Rong Qian
  • Jonathan A. Nowak
  • Yin Cao
  • Annacarolina da Silva
  • Keisuke Kosumi
  • Mingyang Song
  • Daniel Nevo
  • Molin Wang
  • Andrew T. Chan
  • Jeffrey A. Meyerhardt
  • Charles S. Fuchs
  • Kana Wu
  • Shuji Ogino
  • Reiko Nishihara
  • Xuehong Zhang
Original Paper



A preventive potential of high calcium intake against colorectal cancer has been indicated for distal colon cancer, which is inversely associated with high-level CpG island methylator phenotype (CIMP), high-level microsatellite instability (MSI), and BRAF and PIK3CA mutations. In addition, BRAF mutation is strongly inversely correlated with KRAS mutation. We hypothesized that the association between calcium intake and colon cancer risk might vary by these molecular features.


We prospectively followed 88,506 women from the Nurses’ Health Study and 47,733 men from the Health Professionals Follow-up Study for up to 30 years. Duplication-method Cox proportional cause-specific hazards regression was used to estimate multivariable hazard ratios (HRs), and 95% confidence intervals (95% CIs) for the associations between calcium intake and the risk of colon cancer subtypes. By Bonferroni correction, the α-level was adjusted to 0.01.


Based on 853 colon cancer cases, the inverse association between dietary calcium intake and colon cancer risk differed by CIMP status (pheterogeneity = 0.01). Per each 300 mg/day increase in intake, multivariable HRs were 0.84 (95% CI 0.76–0.94) for CIMP-negative/low and 1.12 (95% CI 0.93–1.34) for CIMP-high. Similar differential associations were suggested for MSI subtypes (pheterogeneity = 0.02), with the corresponding HR being 0.86 (95% CI 0.77–0.95) for non-MSI-high and 1.10 (95% CI 0.92–1.32) for MSI-high. No differential associations were observed by BRAF, KRAS, or PIK3CA mutations.


The inverse association between dietary calcium intake and colon cancer risk may be specific to CIMP-negative/low and possibly non-MSI-high subtypes.


Dietary calcium Colorectal cancer Colon cancer MSI CIMP 



Body mass index


Calcium sensing receptor


CpG island methylator phenotype


Food frequency questionnaire


Microsatellite instability


Nurses’ Health Study


Health Professionals Follow-up Study



The authors would like to thank the participants and staff of the Health Professionals Follow-up Study and Nurses’ Health Study for their valuable contributions. NK, LL, and TH—conceived of the project, performed the statistical analysis, wrote the paper, and had primary responsibility for all parts of the manuscript; and all authors—reviewed and interpreted the data, and read and approved the final manuscript.


This work was supported by the U.S. National Institutes of Health (NIH) Grants (P01 CA87969 to M.J. Stampfer; UM1 CA186107 to M.J. Stampfer; P01 CA55075 to W.C. Willett; UM1 CA167552 to W.C. Willett; P50 CA127003 to C.S.F.; R01 CA118553 to C.S.F.; R01 CA 169141 to C.S.F.; R01 CA137178 to A.T.C.; K24 DK098311 to A.T.C.; R35 CA197735 to S.O.; R01 CA151993 to S.O.; K07 CA190673 to R.N.; R03 CA176717, and K07 CA188126 to X.Z.); Nodal Award from the Dana-Farber Harvard Cancer Center (to S.O.); by the American Cancer Society Research Scholar Grant (RSG NEC-130476 to X.Z.); and by grants from the Project P Fund, The Friends of the Dana-Farber Cancer Institute, Bennett Family Fund, and the Entertainment Industry Foundation through National Colorectal Cancer Research Alliance. N.K. was supported by grants from the National Research Foundation of Korea (NRF-2018R1C1B6008822; NRF-2018R1A4A1022589) and the Dongguk University Research Grant of 2017. T.H. was supported by a fellowship grant from the Mitsukoshi Health and Welfare Foundation. K.K. was supported by the Overseas Research Fellowship grant from the Japan Society for the Promotion of Science (JP2017-775). L.L. is supported by the grant from National Natural Science Foundation of China No. 81302491, a scholarship grant from the Chinese Scholarship Council and a fellowship grant from the Huazhong University of Science and Technology. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. The funders had no role in study design, data collection, and analysis, decision to publish, or preparation of the manuscript. M.S. was supported by the 2017 AACR-AstraZeneca Fellowship in Immuno-oncology Research (17-40-12-SONG).

Compliance with ethical standards

Conflict of interest

The authors had no conflicts of interest to declare related to the study.

Supplementary material

10552_2019_1165_MOESM1_ESM.docx (155 kb)
Supplementary material 1 (DOCX 155 kb)


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Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • NaNa Keum
    • 1
    • 2
    Email author
  • Li Liu
    • 1
    • 3
    • 4
  • Tsuyoshi Hamada
    • 3
  • Zhi Rong Qian
    • 3
  • Jonathan A. Nowak
    • 5
  • Yin Cao
    • 6
  • Annacarolina da Silva
    • 3
  • Keisuke Kosumi
    • 3
  • Mingyang Song
    • 1
    • 7
    • 8
  • Daniel Nevo
    • 9
    • 10
  • Molin Wang
    • 9
    • 10
  • Andrew T. Chan
    • 7
    • 8
    • 11
  • Jeffrey A. Meyerhardt
    • 3
  • Charles S. Fuchs
    • 12
    • 13
    • 14
  • Kana Wu
    • 1
  • Shuji Ogino
    • 1
    • 3
    • 5
    • 10
    • 15
  • Reiko Nishihara
    • 1
    • 3
    • 5
    • 9
    • 10
  • Xuehong Zhang
    • 11
  1. 1.Department of NutritionHarvard T.H. Chan School of Public HealthBostonUSA
  2. 2.Department of Food Science and BiotechnologyDongguk UniversityGoyangSouth Korea
  3. 3.Department of Oncologic PathologyDana-Farber Cancer Institute and Harvard Medical SchoolBostonUSA
  4. 4.Department of Epidemiology and Biostatistics, and the Ministry of Education Key Lab of Environment and Health, School of Public HealthHuazhong University of Science and TechnologyWuhanPeople’s Republic of China
  5. 5.Program in MPE Molecular Pathological Epidemiology, Department of PathologyBrigham and Women’s Hospital and Harvard Medical SchoolBostonUSA
  6. 6.Division of Public Health Sciences, Department of SurgeryWashington University School of MedicineSt. LouisUSA
  7. 7.Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical SchoolBostonUSA
  8. 8.Division of GastroenterologyMassachusetts General HospitalBostonUSA
  9. 9.Department of BiostatisticsHarvard T.H. Chan School of Public HealthBostonUSA
  10. 10.Department of EpidemiologyHarvard T.H. Chan School of Public HealthBostonUSA
  11. 11.Channing Division of Network Medicine, Department of MedicineBrigham and Women’s Hospital and Harvard Medical SchoolBostonUSA
  12. 12.Yale Cancer CenterNew HavenUSA
  13. 13.Department of MedicineYale School of MedicineNew HavenUSA
  14. 14.Smilow Cancer HospitalNew HavenUSA
  15. 15.Broad Institute of MIT and HarvardCambridgeUSA

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