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

Research output: Contribution to journalArticlepeer-review


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


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

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research


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