Calcium intake and colon cancer risk subtypes by tumor molecular characteristics

Na Na Keum*, 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

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

9 Scopus citations


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 (p heterogeneity = 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 (p heterogeneity = 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.

Original languageEnglish
Pages (from-to)637-649
Number of pages13
JournalCancer Causes and Control
Issue number6
StatePublished - 1 Jun 2019
Externally publishedYes


FundersFunder number
Bennett Family Fund
Chinese Scholarship Council
Dana-Farber Harvard Cancer Center
Mitsukoshi Health and Welfare Foundation
National Institutes of HealthR35 CA197735, K24 DK098311, R01 CA 169141, R01 CA137178, P01 CA87969, K07 CA190673, P01 CA55075, R03 CA176717, UM1 CA167552, R01 CA118553, R01 CA151993, P50 CA127003, UM1 CA186107
National Institutes of Health
American Cancer SocietyRSG NEC-130476
American Cancer Society
National Cancer InstituteK07CA188126
National Cancer Institute
Entertainment Industry Foundation
Dana-Farber Cancer Institute
Colorectal Cancer Alliance
Japan Society for the Promotion of ScienceJP2017-775
Japan Society for the Promotion of Science
National Natural Science Foundation of China81302491
National Natural Science Foundation of China
Dongguk University
Huazhong University of Science and Technology17-40-12-SONG
Huazhong University of Science and Technology
National Research Foundation of KoreaNRF-2018R1A4A1022589, NRF-2018R1C1B6008822
National Research Foundation of Korea


    • CIMP
    • Colon cancer
    • Colorectal cancer
    • Dietary calcium
    • MSI


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