title: Plasma 25-hydroxyvitamin D and colorectal cancer risk according to tumour immunity status.
abstract: OBJECTIVE
  Evidence suggests protective effects of vitamin D and antitumour immunity on colorectal cancer risk. Immune cells in tumour microenvironment can convert 25-hydroxyvitamin D [25(OH)D] to bioactive 1α,25-dihydroxyvitamin D3, which influences neoplastic and immune cells as an autocrine and paracrine factor. Thus, we hypothesised that the inverse association between vitamin D and colorectal cancer risk might be stronger for cancers with high-level immune response than those with low-level immune response.
  
  
  METHODS
  We designed a nested case-control study (318 rectal and colon carcinoma cases and 624 matched controls) within the Nurses' Health Study and Health Professionals Follow-up Study using molecular pathological epidemiology database. Multivariable conditional logistic regression was used to assess the association of plasma 25(OH)D with tumour subtypes according to the degree of lymphocytic reaction, tumour-infiltrating T cells (CD3+, CD8+, CD45RO+ (PTPRC) and FOXP3+ cells), microsatellite instability or CpG island methylator phenotype.
  
  
  RESULTS
  The association of plasma 25(OH)D with colorectal carcinoma differed by the degree of intratumoural periglandular reaction (p for heterogeneity=0.001); high 25(OH)D was associated with lower risk of tumour with high-level reaction (comparing the highest versus lowest tertile: OR 0.10; 95% CI 0.03 to 0.35; p for trend<0.001), but not risk of tumour with lower-level reaction (p for trend>0.50). A statistically non-significant difference was observed for the associations of 25(OH)D with tumour subtypes according to CD3+ T cell density (p for heterogeneity=0.03; adjusted statistical significance level of α=0.006).
  
  
  CONCLUSIONS
  High plasma 25(OH)D level is associated with lower risk of colorectal cancer with intense immune reaction, supporting a role of vitamin D in cancer immunoprevention through tumour-host interaction.
authors.affiliation: Department of Nutrition, Harvard School of Public Health, Boston, MA, United States.|Department of Epidemiology, Harvard School of Public Health, Boston, MA, United States.
authors.forename: Mingyang
authors.initials: M
authors.lastname: Song
authors.affiliation: Department of Nutrition, Harvard School of Public Health, Boston, MA, United States.|Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, United States.
authors.forename: Reiko
authors.initials: R
authors.lastname: Nishihara
authors.affiliation: Department of Epidemiology, Harvard School of Public Health, Boston, MA, United States.
authors.forename: Molin
authors.initials: M
authors.lastname: Wang
authors.affiliation: Division of Gastroenterology, Massachusetts General Hospital, Boston, MA, United States.|Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA, United States.
authors.forename: Andrew T
authors.initials: AT
authors.lastname: Chan
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, United States.
authors.forename: Zhi Rong
authors.initials: ZR
authors.lastname: Qian
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, United States.|Laboratory of Human Carcinogenesis, National Cancer Institute, National Institutes of Health, Bethesda, MD, United States.
authors.forename: Kentaro
authors.initials: K
authors.lastname: Inamura
authors.affiliation: Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA, United States.
authors.forename: Xuehong
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, United States.
authors.forename: Kimmie
authors.initials: K
authors.lastname: Ng
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, United States.
authors.forename: Sun A
authors.initials: SA
authors.lastname: Kim
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, United States.
authors.forename: Kosuke
authors.initials: K
authors.lastname: Mima
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, United States.
authors.forename: Yasutaka
authors.initials: Y
authors.lastname: Sukawa
authors.affiliation: Department of Gastroenterology, Rheumatology and Clinical Immunology, Sapporo Medical University School of Medicine, Sapporo, Japan.
authors.forename: Katsuhiko
authors.initials: K
authors.lastname: Nosho
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, United States.|Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA, United States.
authors.forename: Charles S
authors.initials: CS
authors.lastname: Fuchs
authors.affiliation: Department of Nutrition, Harvard School of Public Health, Boston, MA, United States.|Department of Epidemiology, Harvard School of Public Health, Boston, MA, United States.|Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA, United States.
authors.forename: Edward L
authors.initials: EL
authors.lastname: Giovannucci
authors.affiliation: Department of Nutrition, Harvard School of Public Health, Boston, MA, United States.
authors.forename: Kana
authors.initials: K
authors.lastname: Wu
authors.affiliation: Department of Epidemiology, Harvard School of Public Health, Boston, MA, United States.|Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, United States.|Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA, United States.|Department of Pathology, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA, United States.
authors.forename: Shuji
authors.initials: S
authors.lastname: Ogino
mesh_terms: D000328:Adult; D000368:Aged; D002097:C-Reactive Protein / Q000032:analysis; D017252:CD3 Complex / Q000032:analysis; D016022:Case-Control Studies; D002452:Cell Count; D015179:Colorectal Neoplasms / Q000276:immunology* / Q000517:prevention & control; D019992:Databases as Topic; D005260:Female; D006801:Humans; D015850:Interleukin-6 / Q000097:blood; D008297:Male; D008875:Middle Aged; D012044:Regression Analysis; D013601:T-Lymphocytes / Q000166:cytology; D048069:Tumor Necrosis Factors / Q000097:blood; D014807:Vitamin D / Q000031:analogs & derivatives* / Q000097:blood
chemical_list: D017252:CD3 Complex; D015850:Interleukin-6; D048069:Tumor Necrosis Factors; D014807:Vitamin D; D002097:C-Reactive Protein; C104450:25-hydroxyvitamin D
keywords: COLORECTAL CANCER; EPIDEMIOLOGY; IMMUNOLOGY; IMMUNOTHERAPY; NUTRITION