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Calcium intake and colon cancer risk subtypes by tumor molecular characteristics

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Abstract

Background

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.

Methods

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.

Results

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.

Conclusion

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

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Abbreviations

BMI:

Body mass index

CASR:

Calcium sensing receptor

CIMP:

CpG island methylator phenotype

FFQ:

Food frequency questionnaire

MSI:

Microsatellite instability

NHS:

Nurses’ Health Study

HPFS:

Health Professionals Follow-up Study

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Acknowledgments

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.

Funding

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).

Author information

Author notes

  1. NaNa Keum, Li Liu, and Tsuyoshi Hamada have contributed equally as co-first authors.

  2. Reiko Nishihara, and Xuehong Zhang have contributed equally as co-last authors.

Authors and Affiliations

  1. Department of Nutrition, Harvard T.H. Chan School of Public Health, Building 2, 3rd Floor, 665 Huntington Avenue, Boston, MA, 02115, USA

    NaNa Keum, Li Liu, Mingyang Song, Kana Wu, Shuji Ogino & Reiko Nishihara

  2. Department of Food Science and Biotechnology, Dongguk University, Goyang, South Korea

    NaNa Keum

  3. Department of Oncologic Pathology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA

    Li Liu, Tsuyoshi Hamada, Zhi Rong Qian, Annacarolina da Silva, Keisuke Kosumi, Jeffrey A. Meyerhardt, Shuji Ogino & Reiko Nishihara

  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, Hubei, People’s Republic of China

    Li Liu

  5. Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA

    Jonathan A. Nowak, Shuji Ogino & Reiko Nishihara

  6. Division of Public Health Sciences, Department of Surgery, Washington University School of Medicine, St. Louis, MO, USA

    Yin Cao

  7. Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA

    Mingyang Song & Andrew T. Chan

  8. Division of Gastroenterology, Massachusetts General Hospital, Boston, MA, USA

    Mingyang Song & Andrew T. Chan

  9. Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA

    Daniel Nevo, Molin Wang & Reiko Nishihara

  10. Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA

    Daniel Nevo, Molin Wang, Shuji Ogino & Reiko Nishihara

  11. Channing Division of Network Medicine, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA

    Andrew T. Chan & Xuehong Zhang

  12. Yale Cancer Center, New Haven, CT, USA

    Charles S. Fuchs

  13. Department of Medicine, Yale School of Medicine, New Haven, CT, USA

    Charles S. Fuchs

  14. Smilow Cancer Hospital, New Haven, CT, USA

    Charles S. Fuchs

  15. Broad Institute of MIT and Harvard, Cambridge, MA, USA

    Shuji Ogino

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  1. NaNa Keum
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  2. Li Liu
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Correspondence to NaNa Keum.

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Use of standardized official symbols: We use HUGO (Human Genome Organisation)—approved official symbols for genes and gene products, including BRAF, CASR, KRAS, and PIK3CA; all of which are described at www.genenames.org. The official symbols are italicized, to differentiate from nonitalicized colloquial names that are used along with the official symbols. This format enables readers to familiarize the official symbols for genes and gene products together with common colloquial names.

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Keum, N., Liu, L., Hamada, T. et al. Calcium intake and colon cancer risk subtypes by tumor molecular characteristics. Cancer Causes Control 30, 637–649 (2019). https://doi.org/10.1007/s10552-019-01165-3

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