Skin Cancer and Citrus Consumption 

In the present study, we performed a detailed analysis for the association between citrus consumption and risk of cutaneous BCC and SCC based on data from two large cohorts of men and women. After adjusting for other known skin cancer risk factors and potential confounders, citrus consumption was positively associated with increased risk of BCC and SCC. Among the individual citrus products, grapefruit and orange juice showed consistent positive associations with risk of BCC and SCC. These findings are generally consistent with our previous investigation for citrus consumption and risk of cutaneous malignant melanoma (20), both of which support a potentially increased risk of skin cancer associated with consumption of furocoumarin-containing foods.

The potential photocarcinogenesis of furocoumarins has well-documented biological plausibility. Furocoumarins/psoralens have been identified as a group of carcinogens for decades (5,7). Previous animal experiments have well demonstrated that furocoumarins are able to induce skin tumors in the presence of UV radiation (5–7,11). Mechanistic investigations have revealed a linear relation between epidermal and serum concentrations of psoralens after oral administration, and the appearance of phototoxicity is associated with the serum concentrations of psoralens (27). Furocoumarins plus UV radiation could induce skin erythema, edema, delayed pigmentation and increased activity of epidermal ornithine decarboxylase, which may serve as a biomarker for cutaneous tumor promotion (28,29). Furocoumarins could also induce lethal, mutagenic and clastogenic effects in mammalian cells and other organisms (16,17). Photoexcited furocoumarins can react with biomolecules, especially with pyrimidine bases in DNA, and form mono- and di-adducts (30,31), and photocycloaddition reactions initiated by furocoumarins play an important role in the formation of DNA adducts (18). Although DNA is generally assumed as the primary site of action for furocoumarins (31,32), they may also bind to other specific and high-affinity sites in mammalian cells which may in turn mediate the furocoumarin-induced phototoxicity in part (33).

Citrus products are known to contain furocoumarins (12–15), and orange and grapefruit are the two mostly consumed citrus fruits in the population over the past several decades, accounting for over 90% of citrus market shares (34). Although grapefruit and orange juice were significantly and positively associated with risk of BCC and SCC, grapefruit juice and oranges did not showed appreciable positive associations with these outcome diseases. Several reasons may help explain the different associations. Grapefruit generally contains higher levels of furocoumarins than oranges (12,13). The null association of grapefruit juice with skin cancer risk may be explained by its much lower consumption levels (Supplementary Table 1, available at Carcinogenesis Online) and a much larger number of non-consumers (Table 2) when compared with the other individual citrus products. In contrast, orange juice contributed to more than 50% of the overall citrus consumption, and the significant association of orange juice with skin cancer risk may be explained by its much higher consumption levels when compared with the other individual citrus products (Supplementary Table 1, available at Carcinogenesis Online).

In addition, we found that the positive association between citrus consumption and SCC risk appeared to be more apparent for tumors occurred on the body sites with higher continuous sun exposure (head, neck and extremities) than for tumors occurred on the body sites with lower continuous sun exposure (truncal sites). Interestingly, animal experiments have demonstrated that exposure to furocoumarins or UVA alone is not tumorigenic in mice whereas exposure to furocoumarins plus UVA substantially increases the number of mice with skin tumors (6,11). Therefore, our findings may suggest a potential synergistic effect between citrus consumption and UV radiation.

Our study has several strengths, including the prospective design, the large sample size and large number of skin cancer cases, the long-term follow-up over 24–26 years, the repeated assessment of dietary and lifestyle factors, and the ability to include a number of potential confounders. Nevertheless, our study also has several limitations. Our study populations consisted of well-educated Caucasian health professionals and may not be representative of the general population. Nevertheless, restricting the sample to health professionals also reduces potential residual confounding from socioeconomic status. Our results need to be replicated in future studies with sufficient power to detect similar associations among other populations. In addition, the diagnosis of BCC was assessed based on self-reports without pathological validation. However, the health care background of our study participants suggest that their reports were likely to be highly accurate, as proven in previous validation studies (25,26). The positive association between citrus consumption and BCC risk as reported herein is also consistent between the two study cohorts. These data suggest that the bias due to self-reported BCC is likely to be minimal and unlikely to affect the study results materially. Furthermore, we do not have data on exposure to arsenic, which has been linked to the risk of skin cancer (35). However, our study participants have better health awareness than the general population and are therefore less likely to be exposed to arsenic, either occupationally or non-occupationally.

In conclusion, our study based on two large cohorts of men and women demonstrated that citrus consumption was associated with an increased risk of cutaneous BCC and SCC, the most commonly diagnosed malignancies in the population. These findings together with our previous investigation on citrus consumption and risk of cutaneous malignant melanoma (20) provide evidence for the potential photocarcinogenic effect of commonly consumed foods. However, our study findings need to be confirmed in future studies before a clear causal inference could be obtained. Nevertheless, given the high prevalence of citrus consumption as well as skin cancers in the population, our findings hold general public health significance and may serve as the first effort to initiate future research in this area.

Supplementary material

Supplementary Tables 1-4. can be found at http://carcin.oxfordjournals.org/

Funding

National Institute of Health (UM1 CA186107;, P01 CA87969;, UM1 CA167552; and R01 CA137165). Dr. Shaowei Wu also received an Amgen Medical Dermatology Fellowship support from the National Psoriasis Foundation.