We did not observe a reduced risk between prediagnostic vitamin D status, as assessed by 25(OH)D concentrations, and pancreatic cancer risk in this nested case-control study conducted in an American population of men and women. Overall, the highest quintile of vitamin D status was associated with a nonsignificant 45% increased pancreatic cancer risk compared with lower vitamin D status. The positive association seemed somewhat stronger and U shaped with exclusion of cases that occurred during the first 5 years of follow-up. The associations tended to be stronger among participants who had their blood collected during the fall and winter months compared with those collected in the spring and summer months. We observed a significant interaction of the association between 25(OH)D and pancreatic cancer by estimated annual residential exposure to solar UVB light (P interaction <0.015) such that significant positive associations were observed with increasing 25(OH)D concentrations among those living in areas of low annual solar UVB exposure, whereas no gradient of risk was observed among those living in regions with moderate to high annual solar UBV exposure. None of the associations showed significant trends across quantiles.
In the nested case-control study conducted in the ATBC population of male Finnish smokers, higher prediagnostic serum 25(OH)D concentrations were associated with a close to 3-fold risk of pancreatic cancer in men with concentrations >65.5 nmol/L compared with those with concentrations <32.0 nmol/L (OR, 2.92; 95% CI, 1.56–5.48; P
trend = 0.001) and risks were stronger among men who had their blood drawn in the winter season (29
). Although positive associations were observed for pancreatic cancer in the present PLCO study, they were not as strong as that observed in the ATBC study. Notable differences between the ATBC and the PLCO populations include gender, smoking history, and geographic location. We did not observe significant interactions by gender or smoking status in the present study; however, we have limited power to observe interactions by smoking because few subjects are current smokers (35 cases and 25 controls). The associations that we observe are therefore primarily in nonsmokers. Overall, men in the ATBC study had considerably lower vitamin D status compared with those in the PLCO study, which is likely explained by Finland’s northern latitude (60°) with less solar UVB photon exposure compared with the locations of the PLCO screening centers (21° in Hawaii to 44° in Minnesota). The median concentration for 25(OH)D was 46.3 nmol/L and 65.15 nmol/L for ATBC and PLCO controls, respectively, with 40% and 13%, correspondingly in the range of inadequacy (<40 nmol/L; refs. 7
Although higher compared with lower 25(OH)D concentrations have shown fairly consistent protective associations for colorectal adenoma and cancer (36
), most epidemiologic research has not shown clear associations between vitamin D status and other cancers (36
). In addition to the ATBC pancreatic cancer study (29
), several well-conducted studies in varying populations have reported subjects with lower measured 25(OH)D concentrations or in the range of vitamin D deficiency (<25 nmol/L) relative to higher concentrations being associated with a reduced risk for prostate cancer (40
) and esophageal squamous cell cancer (43
) and dysplasia (44
). The subjects in some of these studies had relatively low average vitamin D status (29
). Given the similarity of results in these studies, it is possible that a mechanism related to low vitamin D status, such as its connection with growth factors (22
), might influence the promotion of tumor growth (29
). Mechanisms that may explain these associations are highly speculative because there is a lack of understanding of the molecular mechanism by which 1,25(OH)2
D and the VDR regulate the expression of genes involved in carcinogenesis.
The positive association in the present PLCO study with increasing 25(OH)D concentrations among those having blood collected in the fall and winter months and among subjects living in residential regions at northern latitudes with low estimated annual solar UVB light exposure (i.e., Michigan, Minnesota, and Wisconsin with R-B units ≤105) is similar to the previous ATBC results (29
). Stratifying by season and geographic residence are methods to address misclassification due to seasonal variation and within-person variability from sun exposure in warmer climates. Vitamin D status is predominantly determined by solar UVB exposure and known to display seasonal variability (7
). Other studies have also reported more pronounced cancer associations among subjects who donated blood during the fall/winter months than the spring/summer months (29
). Individuals with high vitamin D concentrations during the sunny months may have either high or low vitamin D concentrations during the winter months, whereas those with high 25(OH) vitamin D during the winter months may have consistently higher vitamin D status throughout the year, regardless of season (46
). The misclassification of exposure during the sunny months could also explain the stronger associations among subjects who provided blood in the darker months. Kimlin and colleagues determined “vitamin D UV” radiation across varying latitude, throughout the year, within the United States using measurements from the U.S. Environmental Protection Agency Brewer Spectrophotometer network (47
). Within the United States, vitamin D UV is relatively high at lower latitudes with warmer climates compared with higher latitudes and does not vary by season (47
). Therefore, the geophysical data support that subjects residing at low latitudes with sunny warm climates have vitamin D UV exposure that could sustain efficient vitamin D synthesis with incidental sun exposure throughout the year. The latter could contribute to greater within-person variability for ambulatory individuals. This could account for the lack of association that we observe among participants residing at lower latitudes with greater estimated annual UVB exposure.
The strength of our study is that it is prospective with vitamin D status being assessed up to 11 years before cancer diagnosis, thereby reducing the influence of reverse causality. The PLCO cohort on average does not have extended follow-up (up to 11 years; median, 5.4 years) and the pancreatic cancer risks we observed may become stronger with extended follow-up as evident in the lagged analysis. Our study has internal validity as both cases and controls are derived from the same cohort. The measurement of serum 25(OH)D concentrations reflects internal dose and status, which encompasses cutaneous production of the vitamin and is considered superior to vitamin D intake alone or predictors of vitamin D status. A single measurement of 25(OH)D in adulthood may not reflect long-term vitamin D status. In a steady-state context, it represents the past several weeks to several months of exposure (49
) and associations between one measure of 25(OH)D and cancer have been reported by others (37
). Tominimize misclassification of vitamin D status due to seasonal variation, we matched the controls to the cases by month of blood collection. High vitamin D dietary sources (i.e., vitamin D intake, milk, and vitamin D supplements) and variables related to endogenous vitamin D synthesis (i.e., season, residency at southern latitude, physical activity, and race/ethnicity) were associated with vitamin D status in the expected manner (10
), which lends external validity to our results. Residual confounding by cigarette smoking is possible, however, not likely because few subjects are current smokers and current smoking tended to be associated with lower rather than higher vitamin D status. In addition, former smoking was not significantly associated with pancreatic cancer in our study (former compared with never smoker OR, 1.08; 95% CI, 0.64–1.78). Men and women, as well as never, former, and current smokers, were included in this study, making our results generalizable to the American population. Finally, we cannot exclude the possibility that a correlate to serum vitamin D status that is unknown and not controlled could explain the association we observe.
In conclusion, we did not confirm the strong positive association between 25(OH)D and pancreatic cancer observed in the earlier study in male Finnish smokers. The increased risks among participants who had their blood drawn during the winter months and living in regions with estimated low UVB exposure are similar to the previous study; however, the result should be interpreted with caution. Neither study results support the hypothesis that higher vitamin D status plays a protective role in pancreatic cancer carcinogenesis. More epidemiologic research is needed, particularly large prospective studies that relate vitamin D status to pancreatic cancer in populations with a wide range of 25(OH)D concentrations and can better evaluate interactions by residential UVB solar exposure and smoking status. There are also many research gaps in the understanding of the role of vitamin D in carcinogenesis, particularly related to benefits and possibly harm with greater vitamin D exposure (36
). Therefore, caution is warranted before public health recommendations related to cancer prevention can be established about increasing vitamin D levels in healthy individuals as well as cancer survivors.