Vitamin D status after colorectal cancer diagnosis and patient survival according to immune response to tumour

Tsuyoshi Hamada, Li Liu, Jonathan A. Nowak, Kosuke Mima, Yin Cao, Kimmie Ng, Tyler S. Twombly, Mingyang Song, Seungyoun Jung, Ruoxu Dou, Yohei Masugi, Keisuke Kosumi, Yan Shi, Annacarolina da Silva, Mancang Gu, Wanwan Li, Na Na Keum, Kana Wu, Katsuhiko Nosho, Kentaro InamuraJeffrey A. Meyerhardt, Daniel Nevo, Molin Wang, Marios Giannakis, Andrew T. Chan, Edward L. Giovannucci, Charles S. Fuchs, Reiko Nishihara, Xuehong Zhang, Shuji Ogino*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

21 Scopus citations


Background: High-level plasma 25-hydroxyvitamin D [25(OH)D] has been associated with lower colorectal cancer incidence and mortality. Considering evidence indicating immunomodulatory effects of vitamin D, we hypothesised that survival benefits from high systemic vitamin D level might be stronger for colorectal carcinoma with lower immune response to tumour. Methods: Using 869 colon and rectal cancer cases within the Nurses' Health Study and Health Professionals Follow-up Study, we assessed the prognostic association of postdiagnosis 25(OH)D score [derived from diet and lifestyle variables to predict plasma 25(OH)D level] in strata of levels of histopathologic lymphocytic reaction. The Cox proportional hazards regression model was adjusted for potential confounders, including microsatellite instability, CpG island methylator phenotype, LINE-1 methylation, PTGS2 (cyclooxygenase-2) expression and KRAS, BRAF and PIK3CA mutations. Results: The association of postdiagnosis 25(OH)D score with colorectal cancer-specific mortality differed by levels of peritumoural lymphocytic reaction (pinteraction = 0.001). Multivariable-adjusted mortality hazard ratios for a quintile-unit increase of 25(OH)D score were 0.69 [95% confidence interval (CI), 0.54–0.89] in cases with negative/low peritumoural lymphocytic reaction, 1.08 (95% CI, 0.93–1.26) in cases with intermediate peritumoural reaction and 1.25 (95% CI, 0.75–2.09) in cases with high peritumoural reaction. The survival association of the 25(OH)D score did not significantly differ by Crohn's-like lymphoid reaction, intratumoural periglandular reaction or tumour-infiltrating lymphocytes. Conclusions: The association between the 25(OH)D score and colorectal cancer survival is stronger for carcinomas with lower peritumoural lymphocytic reaction. Our results suggesting interactive effects of vitamin D and immune response may contribute to personalised dietary and lifestyle intervention strategies.

Original languageEnglish
Pages (from-to)98-107
Number of pages10
JournalEuropean Journal of Cancer
StatePublished - Nov 2018
Externally publishedYes


FundersFunder number
Bennett Family Fund
National Colorectal Cancer Research Alliance
National Institutes of HealthK07 CA188126, R35 CA197735, U01 CA167552, K24 DK098311, R01 CA137178, 2016-02, P01 CA87969, P01 CA55075, R01 CA118553, R01 CA205406, R01 CA151993, P50 CA127003, R01 CA169141, UM1 CA186107
National Institutes of Health
American Association for Cancer Research
National Cancer InstituteK07CA190673
National Cancer Institute
Entertainment Industry Foundation
Dana-Farber Cancer Institute
Dana-Farber/Harvard Cancer Center
Uehara Memorial Foundation
Stand Up To CancerSU2C-AACR-DT22-17
Stand Up To Cancer
Japan Society for the Promotion of ScienceJP2017-775
Japan Society for the Promotion of Science
National Natural Science Foundation of China31601077
National Natural Science Foundation of China
Huazhong University of Science and Technology
National Research Foundation of KoreaNRF-2018R1A4A1022589, NRF-2018R1C1B6008822
National Research Foundation of Korea
China Scholarship Council
Mochida Memorial Foundation for Medical and Pharmaceutical Research


    • Clinical outcome
    • Immunology
    • Molecular pathological epidemiology
    • Precision medicine
    • Tumour microenvironment


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