Abstract
Background
Caffeine has been shown to prevent ultraviolet radiation-induced carcinogenesis and to inhibit growth of melanoma cells in experimental studies.
Objectives
We evaluated the association between caffeine intake, coffee consumption, and melanoma risk among three large cohort studies.
Methods
The analysis used data from 163,886 women in the Nurses’ Health Study II (NHS II, 1991–2009) and Nurses’ Health Study (NHS, 1980–2008) and 39,424 men in the Health Professionals Follow-up Study (HPFS, 1986–2008). We used Cox proportional hazards models to estimate the hazard ratios (HR) with 95% confidence intervals (CI) of melanoma associated with dietary intakes.
Results
We documented 2,254 melanoma cases over 4 million person-years of follow-up. After adjustment for other risk factors, higher total caffeine intake was associated with a lower risk of melanoma (≥393 mg/d vs. <60 mg/d: HR=0.78, 95% CI=0.64–0.96, Ptrend=0.048). The association was more apparent in women (≥393 mg/d vs. <60 mg/d: HR=0.70, 95% CI=0.58–0.85, Ptrend=0.001) than in men (HR=0.94, 95% CI=0.75–1.18, Ptrend=0.81), and more apparent for melanomas occurred on the body sites with higher continuous sun exposure (head, neck and extremities) (≥393 mg/d vs. <60 mg/d: HR=0.71, 95% CI=0.59–0.86, Ptrend=0.001) than for melanomas occurred on the body sites with lower continuous sun exposure (trunk including shoulder, back, hip, abdomen and chest) (HR=0.90, 95% CI=0.70–1.16, Ptrend=0.60). This pattern of association was similar to that for caffeinated coffee consumption, whereas no association was found for decaffeinated coffee consumption and melanoma risk.
Conclusions
Increasing caffeine intake and caffeinated coffee consumption may be protective against cutaneous malignant melanomas.
Keywords: caffeine, cancer epidemiology, coffee, melanoma, sun exposure
INTRODUCTION
Cutaneous malignant melanoma is a potentially lethal form of skin cancer, and its incidence has been increasing in the United States and worldwide1–3. Numerous studies have identified solar ultraviolet (UV) radiation as the predominant environment risk factor for the development of cutaneous melanoma4, and the number of UV-induced sunburns is a strong predictor of melanoma incidence5. Interestingly, caffeine, a stimulant that is rich in coffee, has been shown to inhibit UV-induced sunburn lesions in the epidermis of mice and thus may mimic the effect of a sunscreen6–8. Oral administration of caffeine also has been demonstrated to enhance UV-induced cell apoptosis thereby enhancing the elimination of damaged precancerous cells9–11. In addition, both in vitro and in vivo studies have demonstrated an inhibitory effect of caffeine on the growth of melanoma cells12–15. Therefore, there is a good biological rationale for a potential preventive role of caffeine in the development of cutaneous melanoma.
To date, epidemiologic evidence for the association of coffee consumption and risk of cutaneous melanoma has been ambiguous. Limited prior studies have yielded conflicting results. Some studies suggested an inverse association between coffee consumption and risk of melanoma16–19, while others showed no association20–23. The heterogeneous results may be due to differences in study design and range of coffee consumption and inconsistent control for potential confounders. Furthermore, the numbers of melanoma cases have been limited in most previous studies. These studies also did not distinguish caffeinated vs. decaffeinated coffee16–19,21–23.
It has been documented that the role of sunlight in causing melanoma differs according to anatomic site, which is supportive of the hypothesis that melanomas may arise through divergent etiological pathways24,25. However, potential variation in the relation between coffee consumption and risk of melanoma by anatomic site has been unknown. According to the existing biological evidence that caffeine may prevent UV-induced skin cancer11, it is plausible that caffeine may have a stronger protective effect against cutaneous carcinogenesis on the body sites receiving higher continuous UV radiation versus that on the body sites receiving lower continuous UV radiation.
To address the hypothesis that caffeine intake and coffee consumption may be associated with a reduced risk of cutaneous malignant melanoma, we investigated these questions of interest by using data from three large cohorts of women and men, including the Nurses’ Health Study II (NHS II, 1991–2009), Nurses’ Health Study (NHS, 1980–2008), and Health Professionals Follow-up Study (HPFS, 1986–2008).
METHODS
Study Populations
The NHS II was established in 1989 when 116,430 registered female nurses aged 25–42 years were enrolled using a mailed baseline questionnaire which inquired about medical history and lifestyle practices. The NHS was established in 1976 when 121,700 married, registered, female nurses between the ages of 30 and 55 and residing in the United States at the time of enrollment responded to a baseline questionnaire that included questions about their medical history and lifestyle risk factors. The HPFS was established in 1986 when 51,529 US male health professionals aged 40 to 75 years completed a baseline questionnaire on lifestyle, diet, and newly diagnosed diseases. Biennial questionnaires were used to collect data on disease outcomes and health related factors in all three cohorts. We had investigated the association of caffeine intake, coffee consumption and melanoma risk using data from the NHS and HPFS20, which lacked a detailed investigation for body site information on melanoma and used different cutoffs on caffeine intake levels. Thus, we revisited these studies and performed a meta-analysis of all three studies. The institutional review boards of Partners Health Care System and Harvard School of Public Health approved this study. We consider the participants’ completion and return of the self-administered questionnaires as informed consent.
Assessment of Melanoma Cases
Participants reported new diagnoses of skin cancer biennially. Permission is obtained from participants to acquire their medical and pathological reports if melanoma is reported. The medical and pathological records were reviewed by physicians who were unaware of exposure status to retrieve information on tumor histology if available. Melanomas were initially classified as the following three subgroups according to tumor location: head/neck melanomas, extremity melanomas (upper extremities between shoulder and hand fingers and lower extremities between hip and feet) and trunk melanomas (shoulder, back, hip, abdomen, and chest), according to the existing literature that head/neck melanomas may arise through a different causal pathway when compared to trunk melanomas25, and extremity melanomas may have a risk factor profile intermediate between the profiles for head/neck melanomas and trunk melanomas24,26. Because the associations with caffeine intake for melanomas of head/neck and extremities were similar, we then collapsed these two subgroups as a single group. In-situ melanomas were defined as early-stage tumors restricted to the epidermis, and invasive melanomas were defined as those had grown into the dermis or surrounding tissues based on the pathological reports. A detailed body site and histological description for incident melanomas in each study is shown in eTable 1.
Assessment of Dietary Exposure
The dietary assessment was repeated using a food-frequency questionnaire (FFQ) at least 4 years during the follow-up. Specifically, dietary information was collected in 1991, 1995, 1999, 2003 and 2007 in the NHS II, in 1980, 1984, 1986, 1990, 1994, 1998, 2002 and 2006 in the NHS, and in 1986, 1990, 1994, 1998, 2002 and 2006 in the HPFS. On all FFQs, participants were asked how often on average (i.e., never to 6+ servings/d) during the previous year they had consumed caffeinated and decaffeinated coffee (“one cup”), tea (“one cup or glass”), carbonated beverages (“one glass, bottle, or can”), and other food items. Carbonated beverages included caffeinated and caffeine-free colas and carbonated soft drinks. We calculated the total caffeine intake by summing the caffeine content for a specific amount of each food during the previous year multiplied by a weight proportional to the frequency of its consumption. By using the food-composition database of the US Department of Agriculture, we estimated that the caffeine content was 137 mg per cup of caffeinated coffee, 47 mg per cup of caffeinated tea, 46 mg per bottle or can of caffeinated carbonated beverage, and 7 mg per serving of caffeine-containing chocolate. The validity and reproducibility of the FFQ has been detailed elsewhere27,28. Specifically, high correlations were found between FFQ and diet records for coffee and other caffeine-rich beverage intake (coffee: r=0.78; tea: r=0.93; and caffeinated carbonated beverages: r=0.84)27,28. In addition, information on other dietary intakes including total energy and alcohol was also collected using the FFQs.
Assessment of Covariates
In the biennial follow-up questionnaires, we inquired and updated information on anthropometric and lifestyle factors for chronic diseases, including body height and weight, cigarette smoking, and physical activity. Data on menopausal status, post-menopausal hormone use, and rotating night shifts were collected in women29. Data on the following phenotypic and sun exposure related factors were collected through the follow-up questionnaires: family history of melanoma in first-degree relatives (parents and siblings); natural hair color; number of moles on legs (NHS II) or arms (NHS and HPFS); skin reaction to sun exposure for 2 hours or more as a child/adolescent; number of severe or blistering sunburns; average time spent in direct sunlight since high school; and cumulative UV flux since baseline30,31.
Statistical Analysis
A total of 95,248 women in the NHS II, 74,666 women in the NHS, and 39,424 men in the HPFS who had completed a dietary questionnaire and had no history of any cancer at baseline were included in the present analysis. We used cumulatively updated intakes in analyses to create the best estimates of long-term intake. That is, at the beginning of every 2-year follow-up cycle, each intake was calculated as the mean of all reported intakes up to that time32. Participants contributed to follow-up time from the return month of baseline questionnaire to the month of the first diagnosis of a skin cancer (melanoma, squamous cell carcinoma, or basal cell carcinoma), month of death, loss to follow-up, or the end of follow-up (June 2009 for NHS II, June 2008 for NHS, and January 2008 for HPFS), whichever came first. We used Cox proportional hazards models to estimate the age-adjusted and multivariate hazard ratios (HRs) with 95% confidence intervals (CIs) of incident melanoma associated with dietary intakes. Multivariate analyses for caffeine intake were conducted with adjustment for known melanoma risk factors and potential lifestyle confounders which have been associated with skin cancer risk in previous studies29,30,33–35. Missing data during any follow-up period were coded as a missing indicator category for categorical variables (e.g., smoking status) and with carried-forward values for continuous variables (e.g., body mass index). Trend tests across categories of dietary intake were performed by assigning median values for these categories and treating the variables as continuous terms in the models. Results from different study cohorts were pooled using a random-effect model. P values for heterogeneity between studies were calculated with the use of the Q statistic. We used SAS software version 9.2 (SAS Institute Inc., Cary, North Carolina) for all statistical analyses. All statistical tests were 2-tailed, and the significance level was set at P<0.05.
RESULTS
We documented a total of 1,483 incident melanomas among women over 3,302,700 person-years of follow-up (NHS II: 642 cases/1,543,932 person-years; NHS: 841 cases/1,758,768 person-years) and 771 incident melanomas among men over 663,991 person-years of follow-up. Among women, 199 (13.4%) melanomas occurred on head and neck, 793 (53.5%) on extremities, and 457 (30.8%) on trunk. Among men, 233 (30.2%) melanomas occurred on head and neck, 169 (21.9%) on extremities, and 307 (39.8%) on trunk (eTable 1). To control for the heterogeneity in caffeine intake ranges across the study cohorts, we used the caffeine intake quintiles in the NHS II to regroup NHS and HPFS participants. Table 1 shows the characteristics of study participants by quintiles of caffeine intake in the NHS II. Participants with higher caffeine intake had higher consumption levels of caffeinated coffee, caffeinated tea, and caffeinated carbonated beverages; and were more likely to smoke, drink alcohol, and work in night shifts.
Table 1.
Baseline Characteristics of Study Participants According to Caffeine Intake in the NHS II (1991–2009), NHS (1980–2008), and HPFS (1986–2008).a
| NHS II |
NHS |
HPFS |
|||||||
|---|---|---|---|---|---|---|---|---|---|
| Q1 | Q3 | Q5 | Q1 | Q3 | Q5 | Q1 | Q3 | Q5 | |
| Intake range, mg/db | <60 | 141–246 | ≥393 | <60 | 141–246 | ≥393 | <60 | 141–246 | ≥393 |
| Participants, n | 17 750 | 17 855 | 17 802 | 8074 | 11 557 | 32 926 | 11 605 | 5896 | 9191 |
| Age, year | 35.5(4.8)c | 35.9(4.7) | 37.1(4.4) | 46.4(7.5) | 45.7(7.5) | 46.1(7.0) | 53.8(9.9) | 53.8(9.8) | 52.3(8.9) |
| Dietary variables | |||||||||
| Alcohol intake, g/d | 1.8(4.5) | 3.1(5.7) | 4.2(7.0) | 4.7(9.9) | 5.7(10.2) | 7.1(11.1) | 8.9(14.1) | 11.8(15.4) | 13.2(16.6) |
| Caffeinated coffee, servings/d | 0.0(0.0) | 0.6(0.4) | 3.5(1.3) | 0.0(0.0) | 0.6(0.5) | 3.8(1.5) | 0.0(0.1) | 0.8(0.6) | 3.5(1.4) |
| Decaffeinated coffee, servings/d | 0.4(0.9) | 0.4(0.8) | 0.2(0.7) | 0.7(1.2) | 0.4(0.9) | 0.6(1.2) | 0.8(1.3) | 0.7(1.1) | 0.3(0.9) |
| Caffeinated tea, servings/d | 0.1(0.2) | 1.0(1.2) | 0.8(1.3) | 0.1(0.2) | 1.2(1.0) | 1.0(1.4) | 0.1(0.2) | 0.7(0.9) | 0.6(1.1) |
| Decaffeinated tea, servings/d | 0.3(0.7) | 0.3(0.8) | 0.2(0.6) | 0.2(0.6) | 0.3(0.7) | 0.2(0.6) | 0.2(0.6) | 0.2(0.6) | 0.2(0.5) |
| Caffeinated carbonated beverages, servings/d | 0.1(0.2) | 0.7(1.0) | 0.8(1.0) | 0.0(0.1) | 0.1(0.2) | 0.1(0.2) | 0.1(0.1) | 0.3(0.4) | 0.2(0.4) |
| Decaffeinated carbonated beverages, servings/d | 0.4(0.8) | 0.3(0.6) | 0.2(0.6) | 0.0(0.2) | 0.1(0.2) | 0.1(0.2) | 0.1(0.3) | 0.1(0.3) | 0.1(0.2) |
| Caffeine-containing chocolate, servings/d | 0.1(0.2) | 0.2(0.2) | 0.1(0.2) | 0.2(0.3) | 0.2(0.3) | 0.2(0.3) | 0.1(0.2) | 0.1(0.3) | 0.1(0.3) |
| Total energy intake, kcal | 1768(528) | 1770(542) | 1644(543) | 1559(498) | 1549(485) | 1526(496) | 1982(614) | 1972(621) | 1826(561) |
| Non-dietary variables | |||||||||
| Family history of melanoma, % | 13.4 | 12.9 | 11.8 | 6.8 | 6.4 | 6.6 | 4.5 | 3.7 | 3.7 |
| Red/blonde hair, % | 20.6 | 20.0 | 20.3 | 15.3 | 15.8 | 15.9 | 13.4 | 12.4 | 13.8 |
| Number of moles on legs or arms ≥10, % | 16.7 | 14.6 | 13.5 | 2.0 | 2.1 | 2.1 | 2.3 | 2.8 | 2.4 |
| Painful/blistering sunburn reaction as a child/adolescent, % | 24.5 | 24.1 | 24.5 | 13.9 | 15.1 | 15.2 | 24.7 | 23.0 | 23.3 |
| Number of blistering sunburns ≥5, % | 9.1 | 9.7 | 11.0 | 58.1 | 59.4 | 60.8 | 18.9 | 19.3 | 18.0 |
| Average time spent in direct sunlight since high school ≥5 hrs/wk, % | 39.6 | 42.2 | 45.5 | 50.3 | 52.0 | 52.8 | 38.4 | 35.7 | 39.9 |
| Annual ultraviolet flux, × 10−4 Robertson-Berger unit | 124.9(24.0) | 125.5(24.4 | ) 124.1(24.5) | 121.1(22.9) | 119.3(22.0) | 119.8(23.2) | 128.7(26.6) | 129.7(26.9) | 129.2(26.9) |
| Body mass index, kg/m2 | 24.5(5.4) | 24.8(5.5) | 24.6(4.9) | 24.4(4.7) | 24.6(4.8) | 24.3(4.3) | 24.7(4.9) | 24.9(5.3) | 25.2(5.1) |
| Current smoking, % | 4.6 | 9.6 | 27.1 | 19.1 | 19.0 | 38.0 | 5.7 | 8.6 | 16.8 |
| Physical activity, met-hrs/wk | 20.9(25.8) | 21.0(27.7) | 20.7(28.2) | 14.4(18.9) | 14.0(19.2) | 13.5(19.5) | 22.6(32.5) | 20.3(26.5) | 18.7(29.6) |
| Rotating night shifts, % | 57.3 | 61.6 | 64.1 | 9.7 | 9.6 | 12.4 | - | - | - |
| Postmenopausal status, % | 2.9 | 3.3 | 3.5 | 31.8 | 31.0 | 31.7 | - | - | - |
| Postmenopausal hormone use, %d | 84.5 | 81.9 | 84.5 | 22.4 | 22.3 | 18.9 | - | - | - |
All variables other than age have been standardized to the age distribution of the study population.
Quintile cutoffs based on the NHS II.
Mean (standard deviation) for all such values.
Percentages among postmenopausal women.
We found significant inverse association between increased caffeine intake and risk of overall melanoma in both NHS II and NHS cohorts (Table 2). After adjustment for other risk factors, the pooled multivariate HRs for overall melanoma from the lowest to highest category of caffeine intake in women were 1.00 (reference), 0.84 (95% CI, 0.70 to 1.01), 0.90 (95% CI, 0.75 to 1.07), 0.80 (95% CI, 0.67 to 0.96), and 0.70 (95% CI, 0.58 to 0.85) (Ptrend=0.001). However, the association was not apparent in men (Ptrend=0.81). Pooled analysis for all three cohorts also suggested a significant inverse association between caffeine intake and risk of overall melanoma (multivariate HR=0.78 comparing the extreme categories of ≥393 mg/d vs. <60 mg/d, 95% CI, 0.64 to 0.96, Ptrend=0.048).
Table 2.
Hazard Ratios of Incident Melanoma According to Caffeine Intake in the NHS II (1991–2009), NHS (1980–2008), and HPFS (1986–2008).
| Categories of caffeine intake (mg/d)a |
P for Trend |
P for heterogeneity |
|||||
|---|---|---|---|---|---|---|---|
| 1 (<60) | 2 (60–140) | 3 (141–246) | 4 (247–392) | 5 (≥393) | |||
| NHS II | |||||||
| No. of cases | 141 | 126 | 142 | 135 | 98 | ||
| No. of person-years | 309 301 | 308 196 | 308 808 | 308 220 | 309 407 | ||
| Age-adjusted HR(95% CI) | 1.00 | 0.87 (0.69–1.11) | 0.97 (0.77–1.23) | 0.89 (0.71–1.13) | 0.66 (0.51–0.85) | 0.003 | |
| Multivariate HR (95% CI)b | 1.00 | 0.85 (0.67–1.08) | 0.93 (0.73–1.18) | 0.81 (0.64–1.04) | 0.66 (0.51–0.87) | 0.004 | |
| NHS | |||||||
| No. of cases | 84 | 118 | 187 | 226 | 226 | ||
| No. of person-years | 151 421 | 226 168 | 343 546 | 451 642 | 585 991 | ||
| Age-adjusted HR(95% CI) | 1.00 | 0.87 (0.65–1.14) | 0.92 (0.71–1.19) | 0.86 (0.67–1.11) | 0.75 (0.58–0.97) | 0.02 | |
| Multivariate HR (95% CI)b | 1.00 | 0.82 (0.62–1.09) | 0.85 (0.66–1.11) | 0.79 (0.61–1.01) | 0.74 (0.57–0.96) | 0.04 | |
| HPFS | |||||||
| No. of cases | 191 | 146 | 145 | 152 | 137 | ||
| No. of person-years | 163 904 | 123 280 | 116 404 | 119 733 | 140 670 | ||
| Age-adjusted HR(95% CI) | 1.00 | 0.94 (0.76–1.17) | 0.97 (0.78–1.20) | 1.00 (0.81–1.24) | 0.89 (0.71–1.10) | 0.41 | |
| Multivariate HR (95% CI)b | 1.00 | 0.93 (0.74–1.15) | 0.96 (0.77–1.20) | 0.99 (0.80–1.24) | 0.94 (0.75–1.18) | 0.81 | |
| Pooled for women (NHS II and NHS) | |||||||
| Multivariate HR (95% CI)b | 1.00 | 0.84 (0.70–1.01) | 0.90 (0.75–1.07) | 0.80 (0.67–0.96) | 0.70 (0.58–0.85) | 0.001 | 0.31 |
| Pooled for women and men (NHS II, NHS and HPFS) | |||||||
| Multivariate HR (95% CI)b | 1.00 | 0.87 (0.76–1.00) | 0.92 (0.80–1.06) | 0.87 (0.75–1.01) | 0.78 (0.64–0.96) | 0.048 | 0.11 |
Abbreviations: CI, confidence interval; HR, hazard ratio.
Quintile cutoffs based on the NHS II.
Multivariate hazard ratios were further adjusted for family history of melanoma (yes or no), personal history of non-skin cancer (yes or no), natural hair color (red, blonde, light brown, dark brown, black), number of moles on legs or arms (none, 1–2, 3–9, ≥10), sunburn reaction as a child/adolescent (none/some redness, burn, painful burn/blisters), number of blistering sunburns (none, 1–2, 3–4, ≥5), time spent in direct sunlight since high school (<1, 1–4, ≥5 hrs/wk), cumulative ultraviolet flux since baseline (quintiles), body mass index (<25.0, 25.0–29.9, 30.0–34.9, ≥35.0 kg/m2), smoking status (never, past, current with 1–14, 15–24, or ≥25 cigarettes/d), physical activity (quintiles), total energy intake (quintiles), and alcohol intake (none, 0.1–4.9, 5.0–9.9, ≥10.0 g/d). Analyses for women were also adjusted for rotating night shifts (never, 1–2, 3–9, ≥10 years) and menopausal status and postmenopausal hormone use (premenopausal, postmenopausal never, past, or current use).
Interestingly, the inverse association appeared to be more apparent for melanomas occurred on head/neck and extremities than for melanomas occurred on trunk in all three cohorts. The inverse association for head/neck melanoma was similar with that for extremity melanoma (eTable 2), and the pooled multivariate HRs for melanoma on head, neck and extremities comparing the extreme categories were 0.66 (95% CI, 0.53 to 0.83, Ptrend=0.001) in women and 0.71 (95% CI, 0.59 to 0.86, Ptrend=0.001) in both women and men (Table 3). In contrast, the association trend was not evident for trunk melanoma over the intake categories in the pooled analyses (all pooled Ptrend>0.20).
Table 3.
Multivariate Hazard Ratios of Site-Specific Incident Melanoma According to Caffeine Intake in the NHS II (1991–2009), NHS (1980–2008), and HPFS (1986–2008).
| Categories of caffeine intake (mg/d)a |
P for trend |
P for heterogeneity |
|||||
|---|---|---|---|---|---|---|---|
| 1 (<60) | 2 (60–140) | 3 (141–246) | 4 (247–392) | 5 (≥393) | |||
| Risk of overall melanoma on head, neck, and extremities | |||||||
| NHS II | |||||||
| No. of cases/person-years | 96/309 301 | 77/308 196 | 92/308 808 | 87/308 220 | 65/309 407 | ||
| Multivariate HR (95% CI)b | 1.00 | 0.76 (0.56–1.03) | 0.88 (0.66–1.18) | 0.75 (0.55–1.02) | 0.66 (0.47–0.91) | 0.02 | |
| NHS | |||||||
| No. of cases/person-years | 62/151 421 | 88/226 168 | 123/343 546 | 153/451 642 | 149/585 991 | ||
| Multivariate HR (95% CI)b | 1.00 | 0.83 (0.60–1.15) | 0.75 (0.55–1.02) | 0.72 (0.53–0.97) | 0.67 (0.50–0.91) | 0.02 | |
| HPFS | |||||||
| No. of cases/person-years | 110/163 | 84/123 280 | 65/116 404 | 78/119 733 | 65/140 670 | ||
| Multivariate HR (95% CI)b | 1.00 | 0.91 (0.68–1.21) | 0.74 (0.54–1.02) | 0.89 (0.66–1.20) | 0.82 (0.59–1.13) | 0.29 | |
| Pooled for women (NHS II and NHS) | |||||||
| Multivariate HR (95% CI)b | 1.00 | 0.79 (0.63–0.99) | 0.82 (0.66–1.01) | 0.73 (0.59–0.91) | 0.66 (0.53–0.83) | 0.001 | 0.70 |
| Pooled for women and men (NHS II, NHS and HPFS) | |||||||
| Multivariate HR (95% CI)b | 1.00 | 0.83 (0.70–0.99) | 0.79 (0.67–0.95) | 0.78 (0.66–0.93) | 0.71 (0.59–0.86) | 0.001 | 0.63 |
| Risk of overall melanoma on trunk | |||||||
| NHS II | |||||||
| No. of cases/person-years | 44/309 301 | 47/308 196 | 45/308 808 | 48/308 220 | 33/309 407 | ||
| Multivariate HR (95% CI)b | 1.00 | 1.02 (0.67–1.54) | 0.95 (0.62–1.45) | 0.97 (0.63–1.48) | 0.70 (0.43–1.12) | 0.13 | |
| NHS | |||||||
| No. of cases/person-years | 19/151 421 | 26/226 168 | 61/343 546 | 68/451 642 | 66/585 991 | ||
| Multivariate HR (95% CI)b | 1.00 | 0.77 (0.43–1.40) | 1.22 (0.73–2.05) | 1.03 (0.61–1.72) | 0.94 (0.55–1.58) | 0.82 | |
| HPFS | |||||||
| No. of cases/person-years | 72/163 904 | 48/123 280 | 65/116 404 | 61/119 733 | 61/140 670 | ||
| Multivariate HR (95% CI)b | 1.00 | 0.84 (0.58–1.21) | 1.17 (0.83–1.65) | 1.06 (0.74–1.51) | 1.03 (0.72–1.47) | 0.61 | |
| Pooled for women (NHS II and NHS) | |||||||
| Multivariate HR (95% CI)b | 1.00 | 0.93 (0.66–1.31) | 1.05 (0.76–1.46) | 0.99 (0.71–1.38) | 0.80 (0.56–1.13) | 0.25 | 0.33 |
| Pooled for women and men (NHS II, NHS and HPFS) | |||||||
| Multivariate HR (95% CI)b | 1.00 | 0.88 (0.69–1.14) | 1.11 (0.87–1.40) | 1.02 (0.80–1.30) | 0.90 (0.70–1.16) | 0.60 | 0.32 |
Abbreviations: CI, confidence interval; HR, hazard ratio.
Quintile cutoffs based on the NHS II.
Multivariate HRs were adjusted for the covariates listed in Table 2 footnote.
Caffeinated coffee consumption was also inversely associated with risk of overall melanoma in women, whereas decaffeinated coffee consumption showed no association with risk of overall melanoma in women (Table 4). Compared to women who abstained from caffeinated coffee, the pooled multivariate HRs for overall melanoma were 0.86 (95% CI, 0.72 to 1.02) for women who consumed less than 1 cup/d, 0.83 (95% CI, 0.70 to 0.98) for 1 to 2 cup/d, and 0.76 (95% CI, 0.64 to 0.89) for more than 2 cup/d (Ptrend=0.001). There was no apparent association for caffeinated coffee consumption and risk of overall melanoma in men (Ptrend=0.55). However, caffeinated coffee consumption appeared to be more strongly associated with melanoma on head, neck and extremities in all three cohorts (Table 5), and the pooled multivariate HRs comparing the extreme consumption levels (>2 cup/d vs. never) were 0.70 (95% CI, 0.58 to 0.85, Ptrend<0.001) in women and 0.74 (95% CI, 0.63 to 0.88, Ptrend<0.001) in both women and men. The inverse association for head/neck melanoma was also similar with that for extremity melanoma (eTable 3). In contrast, there was no evident association trend for caffeinated coffee consumption and risk of trunk melanoma over the consumption categories (all pooled Ptrend>0.60, Table 5). There was no apparent association between decaffeinated coffee consumption and melanoma on either head/neck/extremities or trunk (data not shown).
Table 4.
Hazard Ratios of Incident Melanoma According to Caffeinated and Decaffeinated Coffee Consumption in the NHS II (1991–2009), NHS (1980–2008), and HPFS (1986–2008).
| Serving category |
P for trend |
P for heterogeneity |
||||
|---|---|---|---|---|---|---|
| Never | <1 cup/d | 1–2/d | >2/d | |||
| Caffeinated coffee | ||||||
| NHS II | ||||||
| No. of cases/person-years | 215/480 408 | 122/298 989 | 141/317 098 | 164/446 995 | ||
| Age-adjusted HR(95% CI) | 1.00 | 0.87 (0.69–1.08) | 0.91 (0.73–1.13) | 0.78 (0.63–0.95) | 0.04 | |
| Multivariate HR (95% CI)a | 1.00 | 0.81 (0.65–1.02) | 0.81 (0.65–1.01) | 0.72 (0.58–0.89) | 0.007 | |
| Multivariate HR (95% CI)b | 1.00 | 0.80 (0.63–1.03) | 0.79 (0.62–1.01) | 0.70 (0.55–0.89) | 0.008 | |
| NHS | ||||||
| No. of cases/person-years | 132/285 692 | 163/284 570 | 218/402 071 | 328/786 435 | ||
| Age-adjusted HR(95% CI) | 1.00 | 1.05 (0.83–1.33) | 1.00 (0.80–1.24) | 0.87 (0.71–1.07) | 0.07 | |
| Multivariate HR (95% CI)a | 1.00 | 0.99 (0.79–1.25) | 0.92 (0.73–1.14) | 0.84 (0.68–1.03) | 0.04 | |
| Multivariate HR (95% CI)b | 1.00 | 0.92 (0.72–1.17) | 0.86 (0.68–1.08) | 0.81 (0.65–1.00) | 0.04 | |
| HPFS | ||||||
| No. of cases/person-years | 158/160 151 | 213/167 908 | 186/137 937 | 214/197 995 | ||
| Age-adjusted HR(95% CI) | 1.00 | 1.12 (0.91–1.38) | 1.13 (0.91–1.40) | 1.06 (0.87–1.31) | 0.70 | |
| Multivariate HR (95% CI)a | 1.00 | 1.10 (0.89–1.35) | 1.11 (0.89–1.39) | 1.10 (0.89–1.37) | 0.47 | |
| Multivariate HR (95% CI)b | 1.00 | 1.04 (0.83–1.30) | 1.06 (0.84–1.33) | 1.07 (0.86–1.34) | 0.55 | |
| Pooled for women (NHS II and NHS) | ||||||
| Multivariate HR (95% CI)b | 1.00 | 0.86 (0.72–1.02) | 0.83 (0.70–0.98) | 0.76 (0.64–0.89) | 0.001 | 0.49 |
| Pooled for women and men (NHS II, NHS and HPFS) | ||||||
| Multivariate HR (95% CI)b | 1.00 | 0.92 (0.80–1.07) | 0.90 (0.76–1.07) | 0.85 (0.66–1.08) | 0.18 | 0.04 |
| Decaffeinated coffee | ||||||
| NHS II | ||||||
| No. of cases/person-years | 345/856 121 | 209/491 087 | 65/135 975 | 23/60 308 | ||
| Age-adjusted HR(95% CI) | 1.00 | 0.98 (0.83–1.17) | 1.08 (0.83–1.41) | 0.93 (0.61–1.43) | 0.86 | |
| Multivariate HR (95% CI)a | 1.00 | 0.88 (0.74–1.05) | 0.99 (0.75–1.29) | 0.88 (0.58–1.35) | 0.59 | |
| Multivariate HR (95% CI)b | 1.00 | 0.96 (0.79–1.17) | 1.07 (0.80–1.42) | 0.93 (0.60–1.44) | 0.91 | |
| NHS | ||||||
| No. of cases/person-years | 212/477 068 | 308/482 160 | 148/240 643 | 71/141 564 | ||
| Age-adjusted HR(95% CI) | 1.00 | 1.25 (1.04–1.51) | 1.19 (0.96–1.49) | 1.06 (0.80–1.42) | 0.55 | |
| Multivariate HR (95% CI)a | 1.00 | 1.17 (0.97–1.41) | 1.12 (0.89–1.39) | 1.01 (0.75–1.34) | 0.91 | |
| Multivariate HR (95% CI)b | 1.00 | 1.15 (0.94–1.39) | 1.07 (0.84–1.36) | 0.98 (0.72–1.32) | 0.76 | |
| HPFS | ||||||
| No. of cases/person-years | 256/263 401 | 321/239 648 | 137/94 152 | 57/66 791 | ||
| Age-adjusted HR(95% CI) | 1.00 | 1.19 (1.01–1.41) | 1.24 (1.00–1.53) | 0.89 (0.67–1.19) | 0.79 | |
| Multivariate HR (95% CI)a | 1.00 | 1.13 (0.95–1.33) | 1.16 (0.94–1.44) | 0.92 (0.69–1.23) | 0.86 | |
| Multivariate HR (95% CI)b | 1.00 | 1.10 (0.92–1.32) | 1.14 (0.91–1.42) | 0.92 (0.68–1.24) | 0.98 | |
| Pooled for women (NHS II and NHS) | ||||||
| Multivariate HR (95% CI)b | 1.00 | 1.05 (0.88–1.25) | 1.07 (0.89–1.29) | 0.96 (0.75–1.23) | 0.86 | 0.77 |
| Pooled for women and men (NHS II, NHS and HPFS) | ||||||
| Multivariate HR (95% CI)b | 1.00 | 1.07 (0.96–1.20) | 1.10 (0.95–1.26) | 0.94 (0.78–1.14) | 0.91 | 0.96 |
Abbreviations: CI, confidence interval; HR, hazard ratio.
Multivariate hazard ratios were adjusted for the covariates listed in Table 2 footnote.
Multivariate hazard ratios were additionally adjusted for consumption of caffeinated tea, decaffeinated tea, caffeinated carbonated beverages, decaffeinated carbonated beverages, caffeine-containing chocolate, and the other coffee (depending on the model) listed in the table.
Table 5.
Multivariate Hazard Ratios of Site-Specific Incident Melanoma According to Caffeinated Coffee Consumption in the NHS II (1991–2009), NHS (1980–2008), and HPFS (1986–2008).
| Caffeinated coffee serving category |
P for trend |
P for Heterogeneity |
||||
|---|---|---|---|---|---|---|
| Never | <1 cup/d | 1–2 cup/d | >2 cup/d | |||
| Risk of overall melanoma on head, neck, and extremities | ||||||
| NHS II | ||||||
| No. of cases/person-years | 143/480 408 | 77/298 989 | 91/317 098 | 106/446 995 | ||
| Multivariate HR (95% CI)a | 1.00 | 0.76 (0.56–1.03) | 0.75 (0.55–1.01) | 0.68 (0.51–0.91) | 0.02 | |
| NHS | ||||||
| No. of cases/person-years | 93/285 692 | 115/284 570 | 151/402 071 | 216/786 435 | ||
| Multivariate HR (95% CI)a | 1.00 | 0.89 (0.67–1.19) | 0.80 (0.61–1.06) | 0.72 (0.56–0.93) | 0.009 | |
| HPFS | ||||||
| No. of cases/person-years | 93/160 151 | 109/167 908 | 95/137 937 | 105/197 995 | ||
| Multivariate HR (95% CI)a | 1.00 | 0.86 (0.64–1.17) | 0.88 (0.64–1.20) | 0.86 (0.63–1.16) | 0.48 | |
| Pooled for women (NHS II and NHS) | ||||||
| Multivariate HR (95% CI)a | 1.00 | 0.83 (0.67–1.02) | 0.78 (0.63–0.95) | 0.70 (0.58–0.85) | <0.001 | 0.96 |
| Pooled for women and men (NHS II, NHS and HPFS) | ||||||
| Multivariate HR (95% CI)a | 1.00 | 0.84 (0.71–1.00) | 0.81 (0.68–0.96) | 0.74 (0.63–0.88) | <0.001 | 0.43 |
| Risk of overall melanoma on trunk | ||||||
| NHS II | ||||||
| No. of cases/person-years | 69/480 408 | 43/298 989 | 47/317 098 | 58/446 995 | ||
| Multivariate HR (95% CI)a | 1.00 | 0.89 (0.59–1.36) | 0.87 (0.57–1.33) | 0.77 (0.51–1.15) | 0.23 | |
| NHS | ||||||
| No. of cases/person-years | 32/285 692 | 44/284 570 | 67/402 071 | 97/786 435 | ||
| Multivariate HR (95% CI)a | 1.00 | 1.05 (0.65–1.69) | 1.15 (0.73–1.81) | 1.07 (0.70–1.65) | 0.71 | |
| HPFS | ||||||
| No. of cases/person-years | 57/160 151 | 82/167 908 | 78/137 937 | 90/197 995 | ||
| Multivariate HR (95% CI)a | 1.00 | 1.14 (0.79–1.64) | 1.26 (0.87–1.82) | 1.26 (0.88–1.80) | 0.19 | |
| Pooled for women (NHS II and NHS) | ||||||
| Multivariate HR (95% CI)a | 1.00 | 0.96 (0.70–1.31) | 0.99 (0.73–1.35) | 0.90 (0.65–1.25) | 0.62 | 0.27 |
| Pooled for women and men (NHS II, NHS and HPFS) | ||||||
| Multivariate HR (95% CI)a | 1.00 | 1.03 (0.81–1.31) | 1.10 (0.87–1.39) | 1.02 (0.76–1.37) | 0.80 | 0.21 |
Abbreviations: CI, confidence interval; HR, hazard ratio.
Multivariate hazard ratios were adjusted for the covariates listed in Table 2 footnote and consumption of decaffeinated coffee, caffeinated tea, decaffeinated tea, caffeinated carbonated beverages, decaffeinated carbonated beverages, and caffeine-containing chocolate.
Associations of caffeine intake and caffeinated coffee consumption with in-situ and invasive melanomas were generally similar (eTable 4 and eTable 5). We conducted stratified analyses to evaluate whether the association between caffeine intake and risk of melanoma varied according to potential confounders, such as smoking status, alcohol use, and rotating night shifts in women. Results of subgroup analyses suggested associations generally similar to those from the main analyses, and there was no significant interaction between caffeine intake and these potential confounders (all Pinteraction>0.10, data not shown).
DISCUSSION
Based on data from three large prospective cohorts, we found that higher caffeine intake and caffeinated coffee consumption was associated with a lower risk of cutaneous malignant melanoma. In contrast, no association was found between consumption of decaffeinated coffee and risk of melanoma. Participants in the highest caffeine intake category (≥393 mg/d) had a 22% lower risk of melanoma compared to those in the lowest intake category (<60 mg/d). The inverse association with caffeine intake and caffeinated coffee consumption was more apparent in women than in men, and more apparent for melanomas occurred on head, neck and extremities than for melanomas occurred on trunk . In contrast, no inverse association was found for melanoma on trunk with caffeinated coffee consumption. These findings are consistent with the existing literature from animal studies that caffeine may eliminate sunburn cells by enhancing UV-induced apoptosis and thereby prevent UV-induced carcinogenesis6–10,36,37.
Caffeine may inhibit UV-induced carcinogenesis through several biological mechanisms. Animal studies indicate that caffeine has a sunscreen effect that inhibits UV-induced formation of thymine dimers and sunburn lesions in the epidermis of mice7,11. Caffeine administration enhances UV-induced apoptosis by p53-dependent and p53-independent mechanisms. Pretreatment with oral caffeine enhanced UV-induced increases in p53 positive cells, p21 positive cells, and apoptotic sunburn cells9. Oral administration of coffee had a similar stimulatory effect on UV-induced apoptosis10. However, oral administration of caffeine had no effect on p53, p21, or apoptosis in the absence of UV irradiation, indicating that caffeine enhanced apoptosis only in DNA damaged epidermis but not in normal epidermis11. Previous experimental studies in tumor cells have found that caffeine can arrest cell cycle at the G2 checkpoint and preferentially radiosensitize tumor cells38,39, and that the radiosensitizing effects of caffeine are related to inhibition of the protein kinase activities of ataxia telangiectasia mutated and Rad3-related (ATR)40. A more recent study further demonstrated that administration of caffeine could enhance the removal of DNA-damaged cells by inhibiting the ATR-mediated phosphorylation of checkpoint kinase 1 and prematurely increasing the number of cyclin B1-containing cells that undergo lethal mitosis, and thereby inhibit UV-induced carcinogenesis37. In addition, UV-mediated NF-κB activation has been shown to result in acquired resistance to apoptosis and promotes the development of skin cancer41,42, whereas caffeine can inhibit UV-mediated NF-κB activation in melanoma cells43. Notably, caffeine also has been demonstrated to inhibit the growth of melanoma cells in vitro and in vivo12–15. An early study found that caffeine caused murine melanoma cells treated with cisplatin to differentiate, and this inhibited growth12. Further studies found that treatment with caffeine not only can inhibit tumor growth, prevent neovascularization, increase apoptosis of melanoma cells13, but also can inhibit metastatic behavior of melanoma cells14,15. Therefore, there exists a convincing biological plausibility that caffeine intake may play an important role in the prevention of cutaneous melanoma.
The findings of the present study are different from that in our previous analysis20. Several reasons may help explain the previous null results. First, the ranges of caffeine intake differed between the study cohorts, causing the heterogeneity in the HRs of higher intake groups vs. reference groups over study populations. Specifically, the ranges of the first quintiles were 0–59 mg/d in the NHS II, 0–132 mg/d in the NHS, and 0–42 mg/d in the HPFS. Table 2 shows the results using NHS II intake quintiles for all 3 cohorts, and the HR of the second category 60–140 mg/d vs. the first category 0–59 (<60) mg/d was 0.83 (0.60–1.15) in the NHS. Therefore, when we use the 0–132 mg/d range (equals to <60 mg/d plus 60–140 mg/d approximately) as the reference group for NHS, it will diminish the relative risk difference over intake categories and results in null HR estimates. To control for the heterogeneity in intake ranges over studies, we therefore used the same intake cutoffs for different study cohorts. Second, we treated melanoma as a single outcome in the previous analysis but did not account for the body site categories (head/neck/extremities vs. trunk) of the tumors. In the present study, we performed a more detailed, hypothesis-driven subtype analysis for melanoma, and found that the inverse association between caffeine intake, caffeinated coffee consumption and risk of melanoma was mainly attributable to melanomas occurred on head, neck and extremities with higher continuous sun exposure but not melanomas occurred on trunk with lower continuous sun exposure. Third, we also expanded the follow-up period to start from 1980 (instead of 1984 in the previous analysis) in the NHS when the first FFQ was used to collect diet information in the NHS participants32, and thus increased the statistical power. Melanoma was first asked in 1982 in the NHS, and we sought to validate self-reported melanoma diagnoses during 1980–1982 by medical and pathological records.
The association between caffeine intake, caffeinated coffee consumption and melanoma risk was not apparent among men in the HPFS, though the inverse association was also more apparent for melanoma on head, neck and extremities than for melanoma on trunk. This may be due to a modest statistical power for men, and a lower proportion of melanoma on head, neck and extremities and a higher proportion of melanoma on trunk in men than in women (eTable 1). It is evident that sun exposure patterns differ between women and men. Men generally receive less continuous solar UV radiation on extremities as compared to women because of different dressing styles, thereby resulting in different proportions of extremity melanoma over genders (21.9% in men vs. 53.5% in women). Therefore, it is possible that caffeine’s protective effect against melanoma among men may not be as apparent as among women when overall melanoma is treated as a single outcome. Similarly, a previous study from Norway also documented a significant inverse association between coffee consumption and melanoma risk in women but not in men18. The Norwegian study included 25,049 women and 25,708 men, among whom a total of 108 malignant melanomas were documented18. However, this study did not differentiate between caffeinated coffee and decaffeinated coffee and also did not account for the variation in the association by tumor site.
The strengths of this study include its prospective design, large sample size, long-term follow-up, detailed melanoma case ascertainment with clear separation for different subtypes, repeated assessments of dietary and lifestyle factors, and the ability to differentiate between caffeinated coffee and decaffeinated coffee. Our study also has several limitations. The cohorts studied mostly comprised white, well-educated health professionals, which potentially limits the generalizability of the findings. However, restricting the sample to health professionals also reduces potential residual confounding from socioeconomic status. In the present study, caffeine intake was also positively associated with several lifestyle factors including alcohol intake, smoking status and rotating night shifts. However, we did not detect appreciable interaction between caffeine intake, coffee consumption and these potential confounders, suggesting that residual confounding by these variables should not be a substantial concern.
In sum, we found that caffeine intake and caffeinated coffee consumption were inversely associated with risk of cutaneous malignant melanoma based on data from three large cohorts. The association was more apparent in women than in men, and was also more apparent for melanomas occurred on head, neck and extremities than for melanomas occurred on trunk. We did not find any association between decaffeinated coffee consumption and melanoma risk. These findings are consistent with previous biological evidence that caffeine may prevent UV-induced carcinogenesis, and support the hypothesis that melanoma on different body sites may arise through divergent causal pathways24–26. Given the highly prevalent coffee consumption and sun exposure behaviors in the general population and the rising melanoma incidence over the decades worldwide1–3, our findings may help convey important public health implication, and may be potentially useful for the prevention of sun-induced malignant melanomas.
Supplementary Material
Acknowledgements
We would like to thank the participants and staff of the cohort studies for their valuable contributions as well as the following state cancer registries for their help: AL, AZ, AR, CA, CO, CT, DE, FL, GA, ID, IL, IN, IA, KY, LA, ME, MD, MA, MI, NE, NH, NJ, NY, NC, ND, OH, OK, OR, PA, RI, SC, TN, TX, VA, WA, WY. In addition, this study was approved by the Connecticut Department of Public Health (DPH) Human Investigations Committee. Certain data used in this publication were obtained from the DPH. The authors assume full responsibility for analyses and interpretation of these data. Dr. Wu and Dr. Qureshi had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.
Source of Funding
This study was supported in part by National Institute of Health (Grants UM1 CA186107, P01 CA87969, UM1 CA176726, UM1 CA167552, and R01 CA137365).
Footnotes
Conflict of Interest
The author(s) indicated no potential conflicts of interest.
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