Serum Retinol and Risk of Overall and Site-Specific Cancer in the ATBC Study

Manila Hada; Alison M. Mondul; Stephanie J. Weinstein; Demetrius Albanes


Am J Epidemiol. 2020;189(6):532-542. 

In This Article

Abstract and Introduction


Retinol, the most biologically active form of vitamin A, might influence cancer-related biological pathways. However, results from observational studies of serum retinol and cancer risk have been mixed. We prospectively examined serum retinol and risk of overall and site-specific cancer in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study (n = 29,104 men), conducted in 1985–1993, with follow-up through 2012. Serum retinol concentration was measured using reverse-phase high-performance liquid chromatography. Cox proportional hazards models estimated the association between baseline serum retinol quintile and overall and site-specific cancer risk in 10,789 cases. After multivariable adjustment, higher serum retinol was not associated with overall cancer risk (highest vs. lowest quintile: hazard ratio (HR) = 0.97, 95% confidence interval (CI): 0.91, 1.03; P for trend = 0.43). Higher retinol concentrations were, however, associated with increased risk of prostate cancer (highest vs. lowest quintile: HR = 1.28, 95% CI: 1.13, 1.45; P for trend < 0.0001) and lower risk of both liver and lung cancers (highest vs. lowest quintile: for liver, HR = 0.62, 95% CI: 0.42, 0.91; P for trend = 0.004; and for lung, HR = 0.80, 95% CI: 0.72, 0.88; P for trend < 0.0001). No associations with other cancers were observed. Understanding the mechanisms that underlie these associations might provide insight into the role of vitamin A in cancer etiology.


Retinoids are a class of synthetic and biological molecules that have chemical structures similar to vitamin A, of which retinol is the most biologically active in humans.[1] Retinol is found in some foods, but much of the body's retinol is derived from ingestion of provitamin A carotenoids which are subsequently converted to retinol. These compounds have been shown to have potentially anticarcinogenic properties such as induction of apoptosis and cellular differentiation, inhibition of proliferation, antioxidant/free radical quenching activities, and enhancement of immune surveillance.[2] However, there is also evidence that retinoids might enhance tumor growth at some sites.[3,4] Thus, the multifaceted role of retinol in cancer remains unclear.

Previous studies, examining the association between vitamin A and cancer at various sites by measuring dietary and supplemental intake of vitamin A and provitamin A carotenoids using food frequency questionnaires, have had inconsistent results. The recent World Cancer Research Fund Second Expert Report on diet and cancer judged that there was probable evidence that foods containing carotenoids protect against cancers of the head and neck and of the lung, and that foods containing β-carotene protect against cancer of the esophagus.[5] However, studies have demonstrated poor correlation between dietary or supplemental intake and circulating retinol levels,[6] likely due to dietary measurement error and because retinol concentrations are contributed to not only by dietary and supplemental intake but also by factors related to absorption, cleavage of provitamin A compounds, and transport to and from retinol stores in the liver.[7] Thus, circulating retinol concentration is a better measurement of retinol status than self-reported intake.

Several epidemiologic studies have examined circulating retinol concentrations and risk of cancer, with inconsistent results. For example, an inverse association between retinol and cancer has been reported at several sites such as oral,[8] liver,[9–11] prostate,[12,13] lung,[14–17] and stomach,[18] while other studies have reported no association between retinol and cancers of the cervix,[19] colon,[20] prostate,[21] breast,[22] and liver.[23] Meanwhile, a positive association between retinol and prostate cancer has been reported by several groups.[24–27] In some of these studies, the inconsistency in the findings might be due to small sample sizes (i.e., n < 100), which limit the statistical power to detect true associations.[12,23] Furthermore, differences in study design, screening prevalence, dietary and lifestyle factors, and laboratory methods for measuring retinol could also contribute to the differences in the findings.[8,18] Therefore, to comprehensively evaluate the role of retinol across cancer sites within the same cohort, we investigated the association between serum retinol and risk of cancer at multiple sites within the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study.