The Association Between Citrus Consumption and Melanoma Risk in the UK Biobank

A.R. Marley; M. Li; V.L. Champion; Y. Song; J. Han; X. Li

Disclosures

The British Journal of Dermatology. 2021;185(2):353-362. 

In This Article

Discussion

In the current study, we found a significant association between total citrus consumption and melanoma risk after adjusting for potential confounders. This result is consistent with findings from the NHS and HPFS,[25] but not with those from EPIC,[26] WHI[27] or NIH-AARP.[28] In the NHS and HPFS study, participants with the highest total citrus consumption had a 36% increased risk of melanoma. The greater effect size in the current analysis (63% increased risk) may reflect the fact that the NHS and HPFS are comprised of healthcare professionals, who may be more likely to work indoors and/or have greater knowledge of UV protection compared with our UKBB sample drawn from the general population. In the WHI, there was no significant association between total citrus and melanoma risk. The null finding from the WHI could potentially be explained by the fact that the WHI cohort is comprised of postmenopausal women. As men have a greater melanoma risk,[41,42] and older women are less likely than younger women to engage in certain melanoma risk behaviours, such as indoor tanning, solarium use and sunbathing,[43–46] it is plausible to see lower risk estimates in this sample.

In EPIC, there was also no significant association between melanoma risk and total citrus intake [hazard ratio (HR) 0·98, 95% CI 0·83–1·15], but there was a significant association between citrus fruit intake and melanoma risk (HR 1·23, 95% CI 1·02–1·48).[26] These results respectively oppose and support our current hypothesis and findings. The inconsistency for total citrus consumption between the current analysis and the EPIC study could possibly be due to study population differences. While the current study utilizes an all-British sample, EPIC combined data from several different European countries with differing levels of citrus intake, as well as other possible physical or behavioural characteristics. Additionally, different countries may have different food processing or agricultural regulations that could possibly influence furocoumarin concentrations in citrus products from country to country.

There was also no significant association between citrus consumption and melanoma risk in the NIH-AARP. Although some subgroup analyses showed significant trends towards an increased melanoma risk associated with citrus consumption, none of the risk estimates were statistically significant, and neither was the overall association between total citrus and melanoma risk (HR 1·09, 95% CI 0·86–1·39).[28] However, these findings were limited by a rough estimate of participants' UV exposure based on geographical residence rather than actual characteristics or behaviours, and were further limited by the inability to control for key sun exposure variables such as childhood sunburn history, skin pigmentation and tanning ability. If such data were available, the NIH-AARP study could have provided a more accurate estimation for the association of interest.

The results of all five of these studies (the current analysis, NHS/HPFS, WHI, EPIC and NIH-AARP) are in contrast with the findings of Fortes et al., who reported a protective effect of citrus for melanoma risk for high citrus fruit consumption (> 5 times per week) relative to low citrus fruit consumption (up to twice per week) (OR 0·51, 95% CI 0·32–0·80).[13] However, this small, Italian case–control study was based on a total of 304 cases of melanoma and utilized hospital patients for cases and controls. Furthermore, that study did not control for several key dietary or sun exposure variables. Because of these limitations, we believe that the results of the current study, and of the NHS/HPFS, WHI, EPIC and NIH-AARP analyses, provide a more accurate estimation of the association between citrus consumption and melanoma risk.

We also found that orange and orange juice consumption were independently associated with melanoma risk. These findings are consistent with results from the NHS and HPFS, which found a significant increased risk associated with orange consumption (age-adjusted model only) and a 25% increased risk associated with orange juice consumption. Unlike in the NHS and HPFS findings, the current study found no significant results associated with grapefruit consumption. Grapefruits are rich sources of psoralens,[24] and, according to Melough et al., have an exponentially higher total furocoumarin concentration (21 858 ng g−1) than oranges (0·5 ng g−1), orange juice (3·2 ng g−1) or satsumas (0·2 ng g−1),[47] so a significant association between grapefruit consumption and melanoma risk would have been plausible. However, our UKBB sample had low grapefruit consumption (5·7% of our UKBB cases reported grapefruit consumption vs. 83% of cases in the NHS and HPFS), limiting power for statistical evaluation. If consumption of grapefruit in our sample more closely resembled consumption of oranges or orange juice (20·7% and 39·2% of our UKBB cases reported orange and orange juice consumption, respectively), then our results for grapefruit consumption may have been more consistent with the NHS/HPFS results.[25]

In subgroup analyses, skin colour was found to play a significant role in the relationship between total citrus consumption and melanoma risk, but only before adjustment for multiple comparisons. Participants with fair to very fair skin complexion had a citrus-associated melanoma risk that was greater than in participants with olive complexions. This result is biologically plausible as fairer skin is a known melanoma risk factor[12,15] due to the lack of melanin, which helps protect the skin against UV radiation.[48] As psoralens and furocoumarins have known photosensitizing properties,[49] it is plausible that psoralen-rich foods could magnify melanoma risk in people particularly susceptible to sun and UV damage.

As with all studies, the current analysis has limitations. Dietary data were self-reported, likely resulting in nondifferential misclassification. However, we calculated a cumulative average intake over several timepoints to minimize random error, and 82% of participants reported the same or adjacent intake category across timepoints.[33] Another potential limitation of this study could be the difficulty of generalizing results from UK-based data to other populations. Different countries may have differing dietary patterns that influence the amount of citrus consumed, or may have different methods of agricultural processing that could impact the furocoumarin concentration found in citrus products. Differences in climate could be another challenge to generalizability. However, as the UK generally gets fewer hours of sunshine than many other areas with white populations, such as the USA, Australia and elsewhere in Europe,[50–53] the results of our current analysis may be biased towards the null, and implications could be even greater for other populations with more sun exposure. Finally, we are limited by the inability to control for family history of melanoma. Melanoma can be heritable,[54,55] so residual confounding from the inability to adjust for this factor is a limitation.

In conclusion, our current analysis, based on a large, prospective, population-based cohort, found that high citrus consumption was associated with a significantly increased risk of melanoma. Consumption of oranges and orange juice was independently associated with melanoma risk. These findings support previous evidence of the photosensitivity and photocarcinogenicity of psoralens and support the hypothesis that high consumption of psoralen-rich foods may increase melanoma risk. Although this is biologically plausible, further investigation is needed to confirm our findings, particularly those that support potential effect modification by skin colour. Further investigation and confirmation of these findings could lead to updated sun exposure guidance and improved melanoma risk-reduction strategies.

processing....