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. Author manuscript; available in PMC: 2009 Jul 1.
Published in final edited form as: J Invest Dermatol. 2009 Feb 5;129(7):1675–1680. doi: 10.1038/jid.2008.451

A Cohort Study of Vitamin D Intake and Melanoma Risk

Maryam M Asgari 1,2, Sonia S Maruti 3,4, Lawrence H Kushi 1, Emily White 3,4
PMCID: PMC2695831  NIHMSID: NIHMS86127  PMID: 19194478

Abstract

Data suggest that vitamin D intake may have chemopreventive efficacy against melanoma, but there have been no published epidemiologic studies examining the association between vitamin D intake and melanoma risk in a large prospective cohort. We examined whether dietary and supplemental vitamin D intake was associated with melanoma risk among 68,611 men and women who were participants of the Vitamins and Lifestyle cohort study. Participants reported dietary vitamin D intake over the past year and 10-year use of multivitamin and individual vitamin D supplements on a baseline questionnaire. After follow-up through 2006, 455 incident melanomas were identified through linkage to the Surveillance, Epidemiology, and End Results cancer registry. Cox proportional hazards regression models were used to estimate relative risks (RRs) and 95% confidence intervals (CIs) for vitamin D intake after adjustment for melanoma risk factors. Compared with the lowest quartile, we did not detect a risk reduction of melanoma in the highest quartiles of dietary vitamin D intake (RR = 1.31, CI = 0.94–1.82), 10-year average supplemental vitamin D intake (RR = 1.13, CI = 0.89–1.43), or combined dietary and supplemental intake (1.05, CI = 0.79–1.40). In this large prospective cohort, we did not find an association between vitamin D intake and melanoma risk.

INTRODUCTION

Melanoma is the sixth most common cancer in the United States (American Cancer Society Fact and Figures, 2007) and its lifetime incidence is rising. It is estimated that one out of every 55 Americans born in 2008 will be diagnosed with melanoma during their lifetime (Ries et al., 2007). The rising incidence of melanoma and its poor prognosis in advanced stages (Gandini et al., 2005a, b) are compelling reasons to identify novel chemopreventative agents. There is accumulating evidence that the vitamin D pathway may play a chemoprotective role in melanoma (Osborne and Hutchinson, 2002). The antiproliferative and prodifferentiation effects of vitamin D and its metabolites have been demonstrated in some melanoma cell lines in vitro (Colston et al., 1981; Evans et al., 1996; Seifert et al., 2004; Reichrath et al., 2007). In vivo, vitamin D suppresses growth in human melanoma-derived xenografts in immunosuppressed mice (Eisman et al., 1987) and inhibits melanoma migration, invasion, and metastasis in mice inoculated with vitamin D-treated melanoma cells (Yudoh et al., 1999). Epidemiologic studies of the association of vitamin D and melanoma risk have shown conflicting results (Veierød et al., 1997; Millen et al., 2004; Nürnberg et al., 2008). We conducted a prospective study of the Vitamins and Lifestyle (VITAL) cohort to investigate whether vitamin D intake is associated with melanoma risk.

RESULTS

The average age of participants was 62 years (range, 50–76 years), and slightly more than half of the participants were female (52%). Most individuals had some college or an advanced degree (80%) and were overweight or obese (63%). Those with higher intakes of total vitamin D were more likely to have some college education, family history of melanoma, personal history of nonmelanoma skin cancer, history of having had a mole removed, history of severe sunburns, and higher total physical activity (Table 1). The majority of cohort participants (64%) regularly took a multivitamin and 14% used individual vitamin D supplements over the 10-year period before baseline. The highest sources of dietary vitamin D in VITAL were dairy and fish products. Specifically, the top five contributors to vitamin D intake were (1) nonfat or skim milk (beverage), (2) dark fish (salmon), (3) white fish (sole, halibut), (4) eggs, and (5) 2% milk.

Table 1.

Association between participant’s characteristics and total vitamin D intake, VITAL cohort (2000–2006)1,2

Quartiles of total vitamin D intake
Q1 Q2 Q3 Q4
Total vitamin D intake (mean in mcg/day, range) 3.3 (0.0–5.1) 7.1 (>5.1–9.5) 12 (>9.5–14) 17 (>14–58)
Sociodemographic factors
 Age at baseline (years) 62 62 62 62
 Male (%) 49 54 47 52
 Some college (%) 75 81 81 83
Melanoma risk factors
 1st degree family history melanoma (%) 5.8 6.0 6.2 6.3
 Personal history of nonmelanoma skin cancer (%) 7.1 7.3 8.0 8.5
 Ever had moles removed (%) 24 26 28 29
 Had freckles between ages 10 and 20 years (%) 20 20 21 21
 Had ≥3 severe sunburns between ages 10 and 20 years (%) 31 32 33 34
 Natural red/blond hair between ages 10 and 20 years (%) 31 32 32 32
 Reaction to 1-h in strong sunlight (%) 82 85 85 85
Lifestyle characteristics
 Height (in) 68 68 68 68
 BMI at baseline (kg m−2) 28 28 27 27
 Total physical activity (MET-h/wk) 9 10 11 13
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1

Total vitamin D intake was calculated as the sum of mcg/day from diet over year before baseline plus 10 year-average mcg/day from all supplements.

2

Age adjusted means or percentages of baseline characteristics were calculated by standardizing to the age distribution of the study population.

3

Less than 1% missing data, except for BMI (3.5% missing).

Through linkage with SEER (Surveillance, Epidemiology, and End Results) between October 2000 and December 2006, we identified 455 incident cases of cutaneous melanoma based on the coding of the International Classification of Diseases for Oncology-O-2. These included melanoma in situ (n = 200), malignant melanoma NOS (n = 120), superficial spreading melanoma (n = 70), lentigo maligna melanoma (n = 33), nodular melanoma (n = 20), and other subtypes including melanoma within a junctional nevus (n = 5), spindle cell melanoma (n = 4), acral lentiginous melanoma (n = 2), and desmoplastic melanoma (n = 1). The majority of tumors (67%) were located on the trunk (n = 127) and extremities (n = 179), whereas 31% (n = 139) of tumors were located on the head and neck and 2% were not otherwise specified.

There was no clear trend of melanoma risk with the duration of use of individual supplements, dose per day of individual supplements or by 10-year average intake of supplemental vitamin D from multivitamins and individual supplements (Table 2). There was a suggestion of a decreased risk of melanoma among the high-dose supplement users [≥15 mcg/day 10-year average, adjusted relative risk (RR) = 0.77, 95% confidence interval (CI) = 0.34–1.72], although the test for trend was not significant (P = 0.67). There was some evidence of an increased risk of melanoma associated with increased dietary vitamin D intake (adjusted RRs across quartiles: 1.0, 1.09, 1.41, 1.31; P for trend = 0.05). There was no association between total intake of vitamin D from diet plus supplements and melanoma risk. The association between total vitamin D and melanoma did not change with further adjustment for physical activity (none, tertiles of MET-hour/week), body mass index (<24, 25–30 and >30 kgm−2), and multivitamin use (never, current, past).

Table 2.

Association between intakes of vitamin D and incident melanoma, VITAL cohort from 2000–2006

Vitamin D Sources Cohort N (%) Cases N (%) Age- and Sex-adjusted RR (95% CI) Multivariate adjusted RR (95% CI)1
10-year use of individual supplements
 Overall use
  None 58,609 (86) 389 (86) 1.00 1.00
  Former/current 9,257 (14) 61 (14) 1.12 (0.85–1.47) 1.08 (0.82–1.43)
 Duration (years)
  None 58,609 (87) 389 (87) 1.00 1.00
  1–3 3,519 (5) 26 (6) 1.31 (0.88–1.96) 1.26 (0.84–1.88)
  4–6 2,028 (3) 18 (4) 1.53 (0.95–2.46) 1.49 (0.93–2.40)
  >7 3,286 (5) 13 (3) 0.64 (0.37–1.11) 0.62 (0.36–1.08)
  P for trend2 0.61
 Mcg/day on days taken
  None 58,609 (89) 389 (90) 1.00 1.00
  10 6,159 (9) 38 (9) 1.03 (0.74–1.45) 1.00 (0.71–1.40)
  ≥15 1,295 (2) 6 (1) 0.79 (0.35–1.77) 0.77 (0.34–1.72)
  P for trend2 0.67
10-year average mcg/day from individual and multivitamin supplements
 None 21,608 (32) 138 (31) 1.00 1.00
 >0.0–3.9 11,675 (17) 73 (16) 1.10 (0.82–1.46) 1.05 (0.79–1.39)
 >3.9–9.9 15,176 (22) 96 (21) 1.09 (0.84–1.41) 1.03 (0.79–1.33)
 >9.9–30 19,398 (29) 143 (32) 1.21 (0.96–1.54) 1.13 (0.89–1.43)
 P for trend2 0.36
Mcg/day from diet3
 0.0–3.0 15,532 (25) 77 (18) 1.00 1.00
 >3.0–4.7 15,775 (25) 93 (22) 1.11 (0.82–1.52) 1.09 (0.80–1.48)
 >4.7–7.1 15,979 (25) 130 (31) 1.48 (1.09–1.99) 1.41 (1.04–1.90)
 >7.1–53 16,060 (25) 120 (29) 1.36 (0.98–1.88) 1.31 (0.94–1.82)
 P for trend2 0.05
Mcg/day of total vitamin D4
 0.0–5.1 15,878 (24) 99 (22) 1.00 1.00
 >5.1–9.5 16,503 (25) 103 (23) 0.95 (0.71–1.27) 0.91 (0.68–1.22)
 >9.5–14 16,487 (25) 113 (26) 1.04 (0.78–1.39) 0.97 (0.73–1.30)
 >14–58 16,705 (25) 126 (29) 1.14 (0.86–1.52) 1.05 (0.79–1.40
 P for trend2 0.56
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1

Adjusted for: age at baseline (years), gender (female, male), education (high school or less, some college, advanced degree), 1st degree family history melanoma (no, yes), personal history of nonmelanoma skin cancer (no, yes), ever had moles removed (no, yes), freckles between ages 10 and 20 years (no, yes), had ≥3 severe sunburns between ages 10 and 20 years (no, yes), natural red/blond hair between ages 10 and 20 years (no, yes), and reaction to 1-h in strong sunlight (tan or no sunburn, mild burning, painful sunburn, severe sunburn with blistering). Dietary and total intakes of vitamin D were adjusted for total energy intake (kcal/day).

2

P for trend calculated by modeling categories of total vitamin D as a single ordinal variable in a Cox regression; a Wald test was used to obtain a P value.

3

Mcg/day from diet over year before baseline.

4

Total (diet plus supplemental) vitamin D intake was calculated as the sum of mcg/day from diet over year before baseline plus 10 year-average mcg/day from all supplements.

We used both tumor subtype and tumor location variables as proxies for patterns of sun exposure and explored their association with vitamin D intake. Lentigo maligna and lentigo maligna melanoma are associated with chronic sun exposure, whereas superficial spreading melanoma is associated with intermittent exposure (Elwood et al., 1987; Weiss et al., 1991). Likewise, tumors of the head and neck are reportedly associated with chronic patterns of sun exposure, whereas trunk melanomas are associated with intermittent patterns of sun exposure (Hoersch et al., 2006; Whiteman et al., 2006). We explored the association between tumor subtype (lentigo maligna versus other and superficial spreading versus other) and total vitamin D intake and found no significant association (P for difference 0.19 and 0.16, respectively, data not shown). Nor was there a significant difference of total vitamin D intake with respect to tumor location (head and neck versus other: adjusted RRs across quartiles: 1.0, 1.17, 1.02, 0.99; P for difference 0.77).

We also examined the effects of vitamin D on progression of melanoma by examining invasion (in situ versus invasive) and Breslow depth of the tumor in relation to total vitamin D intake. There were 200 patients with in situ melanoma and 254 with invasive (including local, regional, and distant) melanoma. The association between total vitamin D intake and the risk of in situ melanoma was not appreciably different than that and the risk of invasive melanoma (P for difference 0.58, data not shown). Breslow depth was available for 230 cases. Among cases, linear regression adjusting for melanoma risk factors was performed with total vitamin D intake, the exposure, divided into quartiles and tumor thickness, the continuous outcome, log transformed to more closely approximate a normal distribution. There was no significant association between vitamin D intake and tumor thickness (P for trend = 0.20).

The association between total vitamin D intake and melanoma risk did not differ by sex. The RRs among men (adjusted RR = 0.97 for quartile 4 versus quartile 1; 95% CI = 0.73–1.29) and women (adjusted RR = 1.10 for quartile 4 versus quartile 1; 95% CI = 0.70–1.73) were similar, and the test for interaction was not significant (P = 0.51).

DISCUSSION

In this prospective study, we found no evidence to support an inverse association between total intake of vitamin D and melanoma risk. There was a suggestion that higher levels of vitamin D intake from foods may be associated with increased risk of melanoma (P trend across 4 quartiles 0.05), but the effect was inconsistent and was no longer statistically significant when intake from foods and supplements were combined. Among cases, we used two variables as proxies for sun exposure patterns: tumor subtype and tumor location, and found no relation in adjusted models between either variables and total vitamin D intake. We also did not detect an association between total vitamin D intake and tumor invasion or Breslow depth. Adjustment for melanoma risk factors did not alter these findings.

Our results differ from those of a large case–control study of 503 melanoma patients and 565 controls (Millen et al., 2004), which found a reduced risk of melanoma with dietary vitamin D intake. However, the association with vitamin D intake in that study was no longer significant when vitamin D from dietary and supplemental sources were combined. As with many case–control studies, exposure data in that study were collected after case diagnosis, making this study potentially vulnerable to recall bias (Austin et al., 1994). Selection bias in case–control studies is also a concern.

Other epidemiologic studies that have examined the association of vitamin D with melanoma risk are consistent with the generally null findings from our study. For example, a smaller case–control study of 165 melanoma patients and 209 controls (Weinstock et al., 1992), found no association between melanoma risk and total vitamin D intake, vitamin D intake from foods or from supplements. Two studies examining serum levels of vitamin D in melanoma patients compared with controls were similarly null, whether the levels were measured prediagnostically (Cornwell et al., 1992) or at the time of diagnosis (Nürnberg et al., 2008). The only other published prospective study of potential relevance to vitamin D intake and melanoma risk reported that cod-liver oil consumption was associated with an increased risk of melanoma among women but not among men (Veierød et al., 1997). Cod-liver oil is known to be a concentrated source of dietary vitamin D (400–1,000 International Unit/tsp). This study followed 50,757 Norwegian men and women over an average of 12.4 years and assessed frequency and types of food, but the published paper did not comment specifically on vitamin D intake. This observation related to cod-liver oil may not be ascribable to a vitamin D specifically, as cod-liver oil has other relatively unique nutritional characteristics, such as its high concentration of n-3 fatty acids. This increased risk is consistent, however, with our observations of a possible increased risk of melanoma due to vitamin D intake from foods.

Compared with the few previous epidemiologic studies on this topic, strengths of this investigation include the availability of baseline information on major potential confounding factors including constitutional, personal, and family skin cancer history, and the prospective collection of information thereby avoiding recall bias. Other advantages include the relatively large number of melanoma cases and the high percentage of supplement users recruited into this study. In addition, we examined a long-term measure (up to 10 years) of supplemental vitamin D use, which may be more etiologically relevant to melanoma development. The high test–retest reliability and validity of the VITAL questionnaire in capturing supplement intake over the past 10 years has been documented previously (Satia-Abouta et al., 2003).

There are several limitations to this study. We did not measure serum vitamin D levels. Studies suggest that vitamin D intake correlates with serum 25-hydroxy vitamin D levels (Lips et al., 1987; Jacques et al., 1997; Sullivan et al., 2005), especially in northern latitudes, where the influence of solar radiation on vitamin D status is diminished (Sullivan et al., 2005). In fact, some experts state that estimates of long-term dietary and supplemental vitamin D intake and long-term sun exposure may be the most logically feasible indicators of lifetime vitamin D status in population-based studies (Millen and Bodnar, 2008).

Also, this study did not ascertain detailed information on some known melanoma risk factors such as number of nevi. Adjusting for other melanoma risk factors did not alter the risks in the multivariable model, thus, it is unlikely that including the residual risk factors for melanoma would appreciably change the results.

Sun exposure could have been a potential confounding variable. The role of sun exposure is melanoma carcinogenesis is complex and differs for intermittent versus chronic exposure (Gruber and Armstrong, 2006). We examined proxies for intermittent versus chronic sun exposure among cases and found no significant association with total vitamin D intake. Western Washington State is also a region of low sun exposure (latitude 47). A previous study of vitamin D levels at a similar northern latitude in the United States (Bangor, ME, latitude 44°N) showed only 28% change in serum 25-hydroxy vitamin D levels between fall and spring, suggesting that sunlight is not as strong a contributor to vitamin D levels in Northern latitudes (Sullivan et al., 2005).

In our cohort, supplemental vitamin D was derived mostly from multivitamins, as most participants (86%) did not use individual vitamin D supplements. Only 2% of the cohort had supplemental vitamin D intake corresponding to a 10-year daily average ≥600 International Unit (15 mcg). Therefore, we had limited ability to examine associations of melanoma risk with high-dose supplemental vitamin D use. Finally, our cohort preferentially recruited supplement users, and the cohort had certain characteristics, such as high level of education, that may limit the generalizability of the findings.

In summary, our data, which are based on a large prospective cohort, suggest no association between total vitamin D intake from diet and supplements and melanoma risk. Future studies that measure serum vitamin D levels and sun exposure should help further elucidate the association between vitamin D and melanoma risk.

MATERIALS AND METHODS

Study population

Participants were 37,382 men and 40,337 women aged 50–76 years residing in western Washington recruited in the VITAL study between 2000 and 2002. The goal of VITAL was to investigate the association between dietary supplement use and cancer risk. Participants answered a 24-page self-administered questionnaire about lifestyle factors, health history, dietary intake, supplement use, personal characteristics, and cancer risk factors. Further details regarding study design, recruitment, and study implementation have been published previously (White et al., 2004). This study was approved by the Fred Hutchinson Cancer Research Center Institutional Review Board. The Declaration of Helsinki protocols were followed and patients gave their written informed consent.

Exclusions

Participants were excluded if they reported a melanoma diagnosis at baseline (n = 1,557). Nonwhites and those who did not report their race were excluded from the analysis (n = 6,491). We also excluded participants with preexisting conditions that could alter the vitamin D synthesis pathway, including a history of cirrhosis of liver (n = 172), chronic liver disease (n = 210), or history of kidney disease (n = 678), leaving 68,611 participants.

Vitamin D

Dietary sources

A food frequency questionnaire was used to ascertain dietary vitamin D intake, as well as other relevant nutrient intakes. On the food frequency questionnaire, participants reported their usual frequency and portion size of 120 foods or food groups and beverages consumed during the year before baseline. This food frequency questionnaire was adapted from those developed for the Women’s Health Initiative and other studies (Kristal et al., 1997; Patterson et al., 1999). Responses were converted into nutrient intake using the Minnesota Nutrient Data System for Research (Schakel et al., 1997).

Supplements

Participants reported intake of multivitamins and vitamin supplements, taken singly or as mixtures over the 10 years before baseline. For all supplement questions, a close-ended format was used to inquire about current/past use, frequency, duration over the previous 10 years, and usual dose per day for individual supplements and brand or exact nutrient formulation for multivitamins. Vitamin D is most commonly found in supplements as cholecalciferol; therefore, International Units of supplemental vitamin D were converted to mcg cholecalciferol by multiplying by 0.025. Ten-year average daily supplemental intake of vitamin D from multivitamins and individual supplements was calculated by summing intakes from multivitamin preparations and individual vitamin sources and was computed as: Σ(dose per day) × (days per week/7) × (years/10).

Total intake (dietary and supplement)

Total intake was calculated by adding mcg/day from dietary sources with the computed average intake in mcg/day over 10 years from multivitamin and individual supplement sources.

Covariates

Other information considered in this analysis included established risk factors for melanoma (listed in the Statistical Analysis section below) and other lifestyle factors that might confound the vitamin D-melanoma association. Body mass index (kgm−2) was computed from self-reported weight at baseline and height when participants were tallest. Total physical activity, in MET-hours/week, was calculated from all reported regular activity in the past 10 years (Littman et al., 2004).

Melanoma ascertainment

Incident melanoma cases were identified though annual linkage of the VITAL cohort database to the SEER cancer registry. For each tumor, we abstracted information about location (head and neck versus other), tumor subtype (lentigo maligna versus superficial spreading versus other), and Breslow depth. We used the tumor location and subtype as proxies for sun exposure history (chronic versus intermittent). We used Breslow depth as a proxy for tumor progression.

Statistical analysis

Cox proportional hazards models were used to estimate age- and multivariate-adjusted RR and 95% CIs for vitamin D intake and melanoma risk. Age was treated as the time variable with participants entering at their baseline age and exiting at their age at diagnosis of melanoma (event) or censor date. Censor date was defined as the earliest date of: withdrawal from the study (0.03%); date of death (4.6% as ascertained from Washington State death files); date moved out from the 13 county catchment area of the SEER registry (5.4% as identified by linkage to the National Change of Address System and other follow-up procedures); or the end of follow-up on December 31, 2006.

For our multivariable models, we adjusted for suspected or established risk factors for melanoma, including age at baseline (years), gender (female, male), education (high school or less, some college, advanced degree), first degree family history melanoma (no, yes), personal history of nonmelanoma skin cancer (no, yes), ever had moles removed (no, yes), freckles between ages 10 and 20 years (no, yes), had ≥3 severe sunburns between ages 10 and 20 years (no, yes), natural red/blond hair between ages 10 and 20 years (no, yes), and reaction to 1-hour in strong sunlight (tan or no sunburn, mild burning, painful sunburn, severe sunburn with blistering). Analyses of dietary vitamin D were adjusted for total energy intake (kcal/day). Participants were excluded from the dietary and total (diet plus supplement) nutrient analyses if they did not complete all pages of the food frequency questionnaire or if their reported total energy intake was <600 or >4,000 kcal for women or <800 or >5,000 kcal for men. Statistical tests were two sided. All statistical analyses were performed using SAS, version 9.1 (SAS Institute Inc., Cary, NC).

Acknowledgments

National Institute of Arthritis Musculoskeletal and Skin Diseases (K23 AR 051037 to MA); National Cancer Institute (CA74846, to EW, R25 CA94880 to SM). The authors had full responsibility for study design, collection, analysis, and interpretation of the data and the decision to submit the manuscript for publication.

Abbreviations

CI

95% confidence interval

RR

relative risk

SEER

Surveillance, Epidemiology, and End Results

VITAL

VITamins and Lifestyle

Footnotes

CONFLICT OF INTEREST

The authors state no conflict of interest.

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