Caffeine May Lower Risk of Common Skin Cancer
Download the PDF here |
By Charles Bankhead, Staff Writer, MedPage Today
Published: July 02, 2012
"We thus conducted a prospective analysis to evaluate the association between the intake of caffeine, caffeinated coffee, decaffeinated coffee, and other foods known to be high in caffeine and the risk of melanoma and nonmelanoma skin cancer in the Nurses' Health Study (NHS) and the Health Professionals Follow-up Study (HPFS)......In this study, we found an inverse association between coffee consumption and the risk of BCC, which is likely due to the effect of caffeine. No association was found for SCC or melanoma"
Relatively modest caffeine consumption was associated with a significantly lower relative risk of basal cell carcinoma (BCC), data from two large cohort studies showed.
People who consumed more than three cups of coffee a month had a 17% reduction in the relative risk of BCC versus individuals who drank less than one cup per month.
The association pertained to men and women and to sources of caffeine other than coffee.
Investigators found no association between caffeine consumption and squamous-cell carcinoma (SCC) or melanoma, as reported in the July 1 issue of Cancer Research.
"Given that nearly one million new cases [of BCC] are diagnosed each year in the U.S., modification in daily dietary factors with even small protective effects may have great public health impact," Jilali Han, PhD, of Harvard and Brigham and Women's Hospital in Boston, and co-authors wrote in conclusion.
Skin cancers are the most common malignancy among white people in the U.S. White Americans have an estimated 1 in 5 lifetime risk of developing skin cancer.
Laboratory studies have consistently shown that oral and topical caffeine prevents SCC in mice exposed to ultraviolet (UV) light, the authors wrote in their introduction. Other preclinical studies have suggested a potential mechanistic explanation, as topical caffeine has been shown to induce apoptosis in UV-damaged keratinocytes in mice.
Observational data have been less convincing, as studies have shown inconsistent associations between caffeine and skin cancer, including melanoma and nonmelanoma. None of these studies distinguished between caffeinated and decaffeinated coffee or tea, a key piece of evidence that might show whether other components of coffee or tea have anticancer activity.
To address limitations of current information, Han and co-authors reviewed data from the Nurses' Health Study (NHS) and the Health Professionals Follow-up Study (HPFS). The NHS included 121,700 women ages 30 to 55 at enrollment in 1976. HPFS enrolled 51,529 men ages 40 to 75 when the study began in 1976.
NHS participants provided information on caffeine intake on several occasions from 1984 to 2006, as did the HPFS participants from 1986 to 2006.
Han and co-authors analyzed data for 112,897 participants from the two studies (72,921 women and 39,976 men). During 24 and 22 years of follow-up in the NHS and HPFS, respectively, 22,786 participants developed BCC, 1,953 developed SCC, and 741 developed melanoma.
Using U.S. Department of Agriculture data, Han and co-authors estimated caffeine content 137 mg per cup of caffeinated coffee, 47 mg per cup of tea, 46 mg per 12-oz container of caffeinated soda, and 7 mg per 1-oz serving of chocolate.
Investigators stratified the study participants into quintiles of daily caffeine consumption, which range from 31 to 604 mg in NHS and 8 to 584 mg in the HPFS. The analysis showed an inverse association between caffeine consumption from all sources combined and the risk of BCC.
Comparison of the highest and lowest quintile of caffeine consumption resulted in a relative risk of 0.82 for BCC in women and 0.87 in men (P<0.0001 for trend in both groups). The relative risk was 0.84 for men and women combined.
Coffee accounted for 78.5% of all caffeine consumption. A separate comparison of skin cancer risk by coffee consumption produced a relative risk of 0.83 for the highest versus lowest quintile (95% CI 0.77 to 0.87). Investigators found a dose-response relationship between caffeine and BCC risk in women (P<0.0001 for trend) and men (P=0.003 for trend).
Caffeine from sources other than coffee tended to have an inverse association with BCC (0.88 in women, 0.93 in men), although the effect did not achieve statistical significance.
The authors noted a number of limitations including the reliance on self-report of BCC without confirmation from histology. Also, they noted that statistical power to calculate any relationship between caffeine and melanoma or SCC was lacking because the number of those cancers in the population was much lower than BCC.
Finally, they said they were "not able to rule out other differences between caffeinated and decaffeinated coffee that could also be etiologically relevant."
Increased Caffeine Intake Is Associated with Reduced Risk of Basal Cell Carcinoma of the Skin
Studies in animals suggest that caffeine administration helps prevent squamous cell skin cancer development, but there have been limited epidemiologic studies on the association between caffeine consumption and skin cancer risk. Using data from the Nurses' Health Study and the Health Professionals Follow-up Study, we prospectively examined risks of basal cell carcinoma (BCC, 22,786 cases), squamous cell carcinoma (SCC, 1,953 cases), and melanoma (741 cases) in relation to caffeine intake. Cox proportional hazard models were used to calculate relative risks (RR) and 95% confidence intervals (CI). The amount of caffeine intake from all dietary sources was inversely associated with BCC risk. Compared with the lowest quintile, the highest quintile had the lowest risk (RR, 0.82 in women; 95% CI:,0.77-0.86 and RR, 0.87 in men; 95% CI, 0.81-0.94; Ptrend < 0.0001 in both). A significant inverse association was also found between caffeinated coffee consumption and BCC risk. Compared with individuals who consumed caffeinated coffee less than 1 cup per month, women who consumed more than 3 cups/d had the lowest risk (RR, 0.79; 95% CI, 0.74-0.85; Ptrend < 0.0001) and the RR for men was 0.90 (95% CI, 0.80-1.01; Ptrend = 0.003). Caffeine from other dietary sources (tea, cola, and chocolate) was also inversely associated with BCC risk. Decaffeinated coffee consumption was not associated with a similar decrease in BCC risk. In contrast, caffeine intake was not found to be inversely associated with risks of SCC or melanoma. Our findings argue that caffeine intake in men and women is inversely associated with risk of BCC. Cancer Res; 72(13); 3282-9. ©2012 AACR.
Skin cancers, broadly divided into basal cell carcinoma (BCC), squamous cell carcinoma (SCC), and melanoma, are the most frequently diagnosed malignant tumors among white people in the United States. One in 5 Americans develops skin cancer in his or her lifetime (1). An individual's risk of developing skin cancer depends on both constitutional and environmental factors. Constitutional risk factors include skin phototype, eye and hair color, and tanning ability (2), which represents certain component of genetic susceptibility. UV radiation is an established environmental risk factor for both melanoma and nonmelanoma skin cancer (3).
Animal studies have consistently shown that oral or topical administration of caffeine inhibits SCC development in mice treated with UV light (4-8). Oral administration of tea inhibited UV-induced carcinogenesis in mice, whereas decaffeinated tea elicited substantially less inhibitory activity, which was restored by caffeine (6). One potential mechanism for the inhibitory effect of caffeine is the induction of apoptosis in UV-damaged keratinocytes (9, 10). Apoptosis is an important pathway for keratinocytes to prevent tumor transformation (11). It was shown that topical caffeine administration to mice after UV-B exposure increased the number of apoptotic keratinocytes as evaluated by sunburn cell formation and other markers of programmed cell death (12, 13). These findings suggest that caffeine intake might protect against the development of skin cancer in humans.
However, the results of epidemiologic studies about the association between coffee and skin cancer have been far from convincing. A prospective study from Norway first reported an inverse association between coffee and nonmelanoma skin cancer risk in 1986 (14). Further studies of this cohort with 108 cases of melanoma reported a significant inverse association between coffee consumption and melanoma risk in women [relative risk (RR) = 0.4; 95% confidence interval (CI), 0.2-0.8] but not in men (RR, 1.8; 95% CI, 0.4-3.2; refs. 15, 16). However, a case-control study from Italy did not confirm the inverse association for melanoma (17). An inverse association for nonmelanoma skin cancer was also found in a cross-sectional analysis of 93,676 Caucasian women, which reported a 30% lower prevalence of nonmelanoma skin cancer for those drinking 6 cups or more than nondrinkers (18). There were also studies suggesting a protective effect of tea consumption against the risk of skin cancer (19, 20). However, these prior studies did not distinguish between caffeinated and decaffeinated coffee or tea. Therefore, it was unknown whether the inverse association was due to caffeine or other components of coffee. We thus conducted a prospective analysis to evaluate the association between the intake of caffeine, caffeinated coffee, decaffeinated coffee, and other foods known to be high in caffeine and the risk of melanoma and nonmelanoma skin cancer in the Nurses' Health Study (NHS) and the Health Professionals Follow-up Study (HPFS).
A total of 112,897 eligible participants were included in the analyses (72,921 female nurses and 39,976 male health professionals). Characteristics of participants in 1986 were similar among the 5 groups of caffeine intake in both cohorts except for smoking, which was correlated with caffeine intake (Table 1).
During 24 years of follow-up in the NHS and 22 years of follow-up in the HPFS, a total of 22,786 participants developed BCC, 1,953 participants developed SCC, and 741 participants developed melanoma. The associations between caffeine intake and the risks of BCC, SCC, and melanoma are shown in Table 2. The amount of caffeine intake per day was inversely associated with BCC risk. Compared with the lowest quintile, the highest quintile of intake had the lowest risk. The RR was 0.82 in women (95% CI, 0.77-0.86) and was 0.87 in men (95% CI, 0.81-0.94; Ptrend < 0.0001 in both). The RR was 0.84 (95% CI, 0.80-0.87) for men and women combined by meta-analysis. The restricted cubic spline curve (Fig. 1) confirms the inverse association between caffeine intake and the risk of BCC. The consumption of caffeine was not significantly associated with SCC risk or melanoma risk (Table 2).
A significant inverse association was also observed between caffeinated coffee consumption and BCC risk. The dose-response relationship was significant (Ptrend < 0.0001 in women, and Ptrend = 0.003 in men). Compared with individuals who consumed caffeinated coffee less than 1 cup per month, women who consumed more than 3 cups per day had the lowest risk (RR, 0.79; 95% CI, 0.74-0.85), and the RR for men was 0.90 (95% CI, 0.80-1.01). The RR was 0.83 (95% CI, 0.77-0.87) for men and women combined by meta-analysis. However, decaffeinated coffee consumption was not associated with a decreased risk of BCC (Table 3).
The association between caffeine intake per day (mg, continuous variable) from different sources and the risk of BCC is shown in Table 4. Caffeine from coffee, which accounted for 78.5% of total caffeine intake in our study population, was inversely associated with the risk of BCC in both women (RR for 100 mg/d = 0.97; 95% CI, 0.97-0.98) and men (RR for 100 mg/d = 0.99; 95% CI, 0.98-0.998). Caffeine from other dietary sources (tea, 18%; cola, 3%; and chocolate, 0.5%), which accounts for 21.5% of total caffeine intake, was also inversely associated with BCC risk with nonsignificant RR comparable with that of caffeine from coffee. The RR for 100 mg/d was 0.88 (95% CI, 0.75-1.04) in women and 0.93 (95% CI, 0.18-4.84) in men.
The consumption of caffeinated coffee or decaffeinated coffee was not significantly associated with risk of SCC (Supplementary Table S1) or melanoma (Supplementary Table S2).
No significant interactions were found between the susceptibility score (or individual risk factor) and caffeine intake on the risk of BCC, SCC, or melanoma. The association between caffeine intake and the risk of SCC or melanoma did not vary across different body sites (data not shown).
Previous studies were inconsistent about the association between coffee or tea consumption and the risk of skin cancer, whereas an overall decreased risk was suggested for nonmelanoma skin cancer (14-20, 28). In this study, we found an inverse association between coffee consumption and the risk of BCC, which is likely due to the effect of caffeine. No association was found for SCC or melanoma. Our study has extended previous findings by adding a clearer attribution of the risk reduction for BCC to caffeine intake as distinct from coffee consumption and highlighting differences between BCC and SCC.
UV radiation induces DNA damage in epidermal cells. If the DNA damage is not repaired or the damaged cells are not eliminated by apoptosis, the consequences can be cell transformation, uncontrolled proliferation, and eventually skin tumor formation (29). Mouse studies have shown that oral or topical caffeine administration promotes elimination of UV-damaged keratinocytes (the cells from which nonmelanoma skin cancer arises) via apoptosis and markedly reduces the risk of subsequent skin cancer development (8, 30-32).
The mechanisms and molecular targets for the proapoptotic effect of caffeine after DNA damage have been investigated in cultured cell lines (human osteosarcoma cells). Studies indicate that the ATR (ataxia telangiectasia mutated- and Rad3-related) protein is an important proapoptotic target for caffeine (33). ATR has higher affinity for DNA in UV-damaged cells than in undamaged cells, and damaged DNA stimulates the kinase activity of ATR significantly more than undamaged DNA (34). Caffeine either directly disrupts the ATR/Chk1 checkpoint pathway (35) or inhibits UV-induced phosphorylation of Chk1 and prematurely increases the number of mitotic cells with cyclin B1 that are likely to go on to apoptosis (5). In human keratinocytes, inhibition of the ATR-Chk1 pathway with caffeine augmented UV-induced apoptosis in a p53-independent manner, whereas other known and plausible targets of caffeine were not found to be involved in the UV response (9). These effects of caffeine via the ATR/Chk1 pathway may increase UV-induced apoptosis and decrease the risk of UV-induced skin cancer.
Nonmelanoma skin cancers arise via the transformation of keratinocytes from different layers of the skin (SCC from the top layer and BCC from the basal layer; ref. 36). We found an inverse association between caffeine intake and BCC risk, but not for SCC risk. This is somewhat different from findings in mouse studies, which have suggested a protective effect of caffeine for SCC (4, 6, 8). BCC was not specifically examined in these studies. Clear differences exist between BCC and SCC in their pathogenesis. Intermittent UV exposure and exposure during childhood was causative for the development of BCC, whereas chronic UV exposure is more closely associated with SCC development (37). The UV exposure pattern for BCC is similar to that reported in animal models. Squamous cells have a lower tolerance for DNA damage and a lower apoptotic threshold, which makes apoptosis a predominant protective mechanism against SCC. The less-differentiated basal cells have less tendency than squamous cells to undergo apoptosis (38). Hence, the triggering effect of caffeine on apoptosis may be apparent only in basal cells but not in squamous cells.
We did not find an association between caffeine intake and melanoma risk. Melanoma originates from pigment-producing melanocytes in the basal layer of the epidermis (36). Damaged melanocytes limit their proliferation and mutation accumulation by entering the senescence state instead of undergoing apoptosis (39, 40). There is no evidence that caffeine promotes elimination of UV-damaged melanocytes via apoptosis; it is possible that this effect is restricted to keratinocytes.
The strengths of our study include the prospective and updated assessment of coffee, long follow-up, and a large number of incident skin cancer cases. Coffee intake was accurately reported on food frequency questionnaires (22), and because any misclassification in coffee intake due to differences in cup size or brewing strength would be expected to bias observed associations toward the null, such bias would not explain the inverse associations that we found. Our use of repeated measures of diet over time captured changes in diet and reduced measurement error; however, we were not able to assess coffee intake in young adulthood or total lifetime coffee intake. We had detailed data on relevant covariates to comprehensively adjust for potential confounders. Nevertheless, we cannot completely rule out the potential for residual confounding.
This study also has some limitations. First, the identification of BCC cases was based on self-report without pathologic confirmation. However, the participants in the 2 cohorts were nurses and health professionals, so the validity of their reports was expected to be high and has been proven in validation studies (23, 24, 41). This validation was conducted on a very small subset of BCC cases and did not include assessment of the underreported BCC. Nevertheless, misclassification of BCC cases would be expected to be nondifferential and to bias any associations toward the null, and thus would not explain the inverse associations. In addition, previous studies of BCC in the NHS using self-reported cases identified both constitutional and sun exposure risk factors as expected, such as lighter pigmentation, less childhood and adolescent tanning tendency, higher tendency to sunburn, and tanning salon attendance (24, 42). We recently confirmed the MC1R gene as the top BCC risk locus using the NHS and HPFS samples (43). These data together suggest that the bias due to self-report of BCC is likely to be minimal in our study. Second, the statistical power for melanoma and SCC in our study was much lower, due to the substantially smaller number of cases. Third, we are not able to rule out other differences between caffeinated and decaffeinated coffee that could also be etiologically relevant. Decaffeinated coffee has been artificially treated so as to remove caffeine, and other possibly cancer protective compounds might also be removed in that process. Fourth, we are not able to address a number of possibly relevant issues about tea consumption, such as green or black tea, or brewing strength because of the lack of detailed information about tea consumption on the food frequency questionnaires.
The incidence of BCC, which accounts for approximately 80% of newly diagnosed skin cancers and 30% of all newly diagnosed cancers in the United States, is still increasing by 4% to 8% per year, suggesting that the prevalence of BCC will soon equal that of all other cancers combined (44). Furthermore, an estimated 40% to 50% of patients with a primary carcinoma will develop one or more additional basal cell carcinomas within 5 years (45), causing considerable morbidity and placing a huge burden on healthcare systems. Given the nearly one million new cases diagnosed each year in the United States (46, 47), modification in daily dietary factors with even small protective effects may have great public health impact. Further studies specifically confirming this association are warranted.