Circulating 25-Hydroxyvitamin D3 in Relation to Renal Cell Carcinoma Incidence and Survival in the EPIC Cohort

David C. Muller; Anouar Fanidi; Øivind Midttun; Annika Steffen; Laure Dossus; Marie-Christine Boutron-Ruault; Gianluca Severi; Tilman Kühn; Verena Katzke; Ramón Alonso de la Torre; Carlos A. González; María-José Sánchez; Miren Dorronsoro; Carmen Santiuste; Aurelio Barricarte; Kay-Tee Khaw; Nick Wareham; Ruth C. Travis; Antonia Trichopoulou; Maria Giotaki; Dimitrios Trichopoulos; Domenico Palli; Vittorio Krogh; Rosario Tumino; Paolo Vineis; Salvatore Panico; Anne Tjønneland; Anja Olsen; H. Bas Bueno-de-Mesquita; Petra H. Peeters; Börje Ljungberg; Maria Wennberg; Elisabete Weiderpass; Neil Murphy; Elio Riboli; Per Magne Ueland; Heiner Boeing; Paul Brennan; Mattias Johansson


Am J Epidemiol. 2014;180(8):810-820. 

In This Article

Abstract and Introduction


Normal renal function is essential for vitamin D metabolism, but it is unclear whether circulating vitamin D is associated with risk of renal cell carcinoma (RCC). We assessed whether 25-hydroxyvitamin D3 (25(OH)D3) was associated with risk of RCC and death after RCC diagnosis in the European Prospective Investigation into Cancer and Nutrition (EPIC). EPIC recruited 385,747 participants with blood samples between 1992 and 2000. The current study included 560 RCC cases, 557 individually matched controls, and 553 additional controls. Circulating 25(OH)D3 was assessed by mass spectrometry. Conditional and unconditional logistic regression models were used to calculate odds ratios and 95% confidence intervals. Death after RCC diagnosis was assessed using Cox proportional hazards models and flexible parametric survival models. A doubling of 25(OH)D3 was associated with 28% lower odds of RCC after adjustment for season of and age at blood collection, sex, and country of recruitment (odds ratio = 0.72, 95% confidence interval: 0.60, 0.86; P = 0.0004). This estimate was attenuated somewhat after additional adjustment for smoking status at baseline, circulating cotinine, body mass index (weight (kg)/height (m)2), and alcohol intake (odds ratio = 0.82, 95% confidence interval: 0.68, 0.99; P = 0.038). There was also some indication that both low and high 25(OH)D3 levels were associated with higher risk of death from any cause among RCC cases.


Vitamin D is essential for the efficient absorption of dietary calcium. Beyond its role in bone health, vitamin D has been implicated in the etiology of several cancers, most notably colorectal cancer.[1,2] Vitamin D is produced in the skin after exposure to ultraviolet B (UVB) radiation from sunlight, or it is ingested in the diet or through dietary supplements.[3] After ingestion or endogenous synthesis, vitamin D is hydroxylated in the liver to form 25-hydroxyvitamin D (25(OH)D), the major circulating metabolite of vitamin D, which is subsequently converted into its active form (1,25-dihydroxyvitamin D), primarily in the kidneys. Despite the critical role of the kidneys in vitamin D metabolism, it remains unclear whether vitamin D is relevant to the etiology of kidney cancer.

In 2008, the age-standardized incidence rate of kidney cancer was 3.9 cases per 100,000 people worldwide, but there is notable unexplained variation in incidence from country to country.[4] A link between vitamin D and the most prevalent form of kidney cancer, renal cell carcinoma (RCC), was initially suggested on the basis of ecological evidence. For instance, ecological studies have suggested that RCC incidence is inversely associated with exposure to UVB radiation.[5,6] Similarly, vitamin D deficiency is highly prevalent among blacks,[7] and rates of RCC are higher among blacks than whites in the United States.[8]

To date, 2 prospective studies have assessed prediagnostic circulating 25(OH)D and the risk of RCC, with conflicting results.[9,10] Our aim was to investigate whether circulating 25(OH)D is related to the incidence of RCC and post-RCC survival using a prospective nested case-control sample from a large European cohort.