Abstract
Background:
Solar ultraviolet radiation exposure has been inversely related to prostate cancer incidence and mortality, possibly mediated through vitamin D status. Pigmentation-related traits influence endogenous vitamin D synthesis and may alter risk of prostate cancer.
Methods:
We examined prostate cancer in relation to hair and eye colour, and skin phototype in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study cohort. Incident cancer was diagnosed in 1982 out of 20 863 men. Multivariable hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated from Cox proportional hazards models.
Results:
Prostate cancer risk did not differ by eye colour or skin phototype. Men with naturally red hair were significantly less likely to develop prostate cancer (HR=0.46, 95% CI 0.24–0.89) than men with light brown hair (reference).
Conclusion:
The red hair phenotype, which results from polymorphisms in the melanocortin-1-receptor (MC1R) gene, is associated with lower risk of prostate cancer. This pigmentation-related trait may influence prostate cancer development either directly, through genetic effects or regulatory mechanisms related to MC1R, another nearby gene, or other pigmentation genes, or indirectly, through associations with other exposures such as sunlight or vitamin D status.
Keywords: prostate cancer, MC1R, vitamin D, hair colour, red hair, pigmentation traits
Exposure to solar ultraviolet (UV) radiation is an established causal factor for skin cancer (Rouzaud et al, 2005), but may be associated inversely with prostate cancer (Freedman et al, 2002; Moon et al, 2005). This latter association is hypothesised to be mediated through improved vitamin D status resulting from sunlight-induced epidermal vitamin D synthesis (Bodiwala et al, 2003; Moon et al, 2005). However, meta-analyses have not demonstrated a vitamin D–prostate cancer association (Yin et al, 2009; Gandini et al, 2011). We sought to test the hypothesis through an alternative approach by examining the pigmentation-related traits of hair colour, eye colour, and skin phototype, which influence vitamin D synthesis (Moon et al, 2005), in relation to prostate cancer incidence.
Materials and methods
Study population
The Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) study included 29 133 male smokers, aged 50–69 years, recruited between 1985 and 1988 from southwestern Finland (latitude of study area 60—64°N) (The ATBC Cancer Prevention Study Group, 1994).
The original randomised trial tested the effects of daily supplementation with α-tocopherol (50 mg per day), β-carotene (20 mg per day), both, or placebo on cancer incidence. Study supplementation continued for 5–8 years until death or trial closure (30 April 1993), after which participants were followed as a longitudinal cohort. At study entry, participants completed detailed questionnaires including data on education, physical activity, medical history, and smoking and dietary habits. A follow-up questionnaire that queried hair colour at age 20, eye colour, and skin phototype (patterned after the Fitzpatrick (1988) classification) was administered between 1989 and 1993 to the 20 863 active study participants (among these men, 1105 had fasting serum 25-hydroxyvitamin D (25(OH)D) subsequently measured as controls in other substudies (Weinstein et al, 2011)). The ATBC study was approved by the institutional review boards of the US National Cancer Institute and the National Public Health Institute of Finland, with written informed consent obtained from each participant.
Prostate cancer ascertainment
A total of 1982 incident prostate cancers were identified through the Finnish Cancer Registry from among all 20 863 subjects who completed the follow-up questionnaire (including all trial arms). The Registry has been shown to identify and correctly classify nearly all cancers occurring in the ATBC cohort (Korhonen et al, 2002).
Statistical analysis
Follow-up time for each participant was calculated from the date of randomisation through the date of prostate cancer diagnosis, death or end of follow-up (31 December 2009), with up to 25 years of individual follow-up. Calculating follow-up time from the date of the follow-up questionnaire did not alter the findings. Baseline descriptive statistics, contrasting participants with and without self-reported red hair, were compared using Wilcoxon rank sum tests (continuous variables) or χ2-tests (categorical variables). Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated using Cox proportional hazards regression, with the most common hair colour, eye colour, and skin phototype categories as reference. Multivariate-adjustment (see Table 2 for adjustment factors) did not alter the risk estimates substantially. The hazard proportionality assumption was met. Statistical analyses were performed using SAS software version 9.1.3 (SAS Institute, Inc., Cary, NC, USA).
Results
Only 188 men (0.9%), including 9 who developed prostate cancer, reported their natural hair colour as red, whereas 12%, 40%, 35%, and 12% reported it being blonde, light brown, dark brown, or black/almost black, respectively. Men with red hair were more educated, more likely to use vitamin D or calcium supplements, and more likely to report that their skin burns easily and does not tan upon prolonged exposure to direct sunlight, compared with men of other hair colour (Table 1). Serum vitamin D did not differ by hair colour.
Table 1. Selected baseline characteristics – median (interquartile range) or number (%) for the ATBC cohort by hair colour at age 20.
Characteristic | Men with hair colour other than red, N=20 675 | Men with red hair, N=188 | P-valuea |
---|---|---|---|
Age (y) |
56 (53–60) |
57 (53–61) |
0.71 |
Height (cm) |
174 (170–178) |
174 (170–178) |
0.68 |
Body mass index (kg m−2) |
26.0 (23.8–28.5) |
26.7 (24.1–29.2) |
0.02 |
Cigarettes smoked per day |
20 (15–25) |
20 (15–25) |
0.95 |
Years smoked |
36 (30–41) |
37 (32–42) |
0.27 |
Education (>elementary) |
4583 (22.2%) |
58 (30.9%) |
0.004 |
Leisure physical activity (moderate and heavy) |
12 526 (60.6%) |
110 (58.5%) |
0.52 |
Eye colour |
|
|
0.09 |
Blue | 13 603 (65.9%) | 121 (64.7%) | |
Brown | 2246 (10.9%) | 12 (6.4%) | |
Green | 1390 (6.7%) | 18 (9.6%) | |
Grey |
3409 (16.5%) |
36 (19.3%) |
|
Skin typeb |
|
|
0.0001 |
Will not burn and gets tanned | 7357 (35.7%) | 11 (5.9%) | |
Burns slightly and gets tanned slowly and evenly | 5727 (27.8%) | 18 (9.6%) | |
Burns easily, but gets tanned | 6031 (29.2%) | 64 (34.0%) | |
Burns easily and will not get tanned |
1512 (7.3%) |
95 (50.5%) |
|
Family history of prostate cancer |
612 (3.0%) |
8 (4.3%) |
0.25 |
History of benign prostatic hyperplasia |
796 (3.8%) |
8 (4.3%) |
0.75 |
Vitamin D supplement use (yes%)c |
1435 (6.9%) |
20 (10.6%) |
0.05 |
Calcium supplement use (yes%)c |
2299 (11.1%) |
34 (18.1%) |
0.003 |
Serum 25(OH)D (nmol l−1)d | 33.5 (21.4–48.5) | 33.6 (17.7–41.3) | 0.65 |
Abbreviations: ATBC= Alpha-Tocopherol, Beta-Carotene Cancer Prevention; 25(OH)D=25-hydroxyvitamin D; y=year.
P-value based on χ2-tests (for categorical variables) and Wilcoxon rank sum tests (for continuous variables).
The skin type questions were patterned after the Fitzpatrick classification, and the responses are generally equivalent to skin types IV, III, II, and I, respectively.
Only 21.2% of subjects reported any supplement use.
On the basis of 1105 men (9 with red hair) who were included as controls in other substudies that measured 25(OH)D.
Men with red hair had a significantly lower prostate cancer risk compared with men with light brown hair, the most common hair colour in the cohort (HR=0.46, 95% CI 0.24–0.89, Table 2). The risk for red hair compared with all other hair colours combined was similar (multivariate HR=0.48, 95% CI 0.25–0.92). There was no evidence of confounding. We were unable to examine the association in subgroups defined by disease stage, the trial vitamin supplementation, vitamin D status, or other potential effect modifiers because of the small number of prostate cancer cases with red hair. Risk did not differ by eye colour or skin phototype, although lower risk was suggested for men with brown eyes.
Table 2. HRs and 95% CIs for the association between pigmentation-related phenotypes (hair colour, eye colour, and skin phototype) and risk of prostate cancer.
Pigmentation-related phenotypes | Cases/non-casesa, N | Age-adjusted | Multivariate adjustedb |
---|---|---|---|
Hair colour | |||
Light brown (reference) | 818/7416 | 1.00 | 1.00 |
Dark brown | 702/6609 | 0.96 (0.87–1.06) | 0.97 (0.88–1.08) |
Black | 225/2354 | 0.89 (0.77–1.04) | 0.93 (0.80–1.08) |
Blonde | 228/2323 | 0.90 (0.77–1.04) | 0.89 (0.77–1.03) |
Red |
9/179 |
0.47 (0.25–0.91) |
0.46 (0.24–0.89) |
Eye colour | |||
Blue (reference) | 1307/12422 | 1.00 | 1.00 |
Grey | 344/3101 | 1.03 (0.91–1.16) | 1.02 (0.90–1.15) |
Brown | 190/2068 | 0.88 (0.75–1.02) | 0.87 (0.74–1.02) |
Green |
137/1271 |
1.02 (0.85–1.22) |
1.00 (0.84–1.20) |
Skin phototypec | |||
Will not burn and gets tanned (reference) | 690/6680 | 1.00 | 1.00 |
Burns slightly and gets tanned slowly and evenly | 573/5172 | 1.03 (0.92–1.15) | 1.01 (0.90–1.13) |
Burns easily, but gets tanned | 576/5520 | 1.01 (0.90–1.13) | 1.01 (0.90–1.13) |
Burns easily and will not get tanned | 141/1468 | 0.98 (0.82–1.17) | 1.01 (0.84–1.22) |
Abbreviations: CI=confidence interval; HR=hazard ratio.
Non-cases are cohort members without prostate cancer.
Adjusted for age, body mass index, education, number of cigarettes smoked per day, family history of prostate cancer, use of vitamin D and calcium supplements, trial supplementation group, and mutually adjusted for hair colour, eye colour, and skin phototype.
The skin type questions were patterned after the Fitzpatrick classification, and the responses are generally equivalent to skin types IV, III, II, and I, respectively.
Discussion
In this large cohort, men with naturally red hair experienced approximately half the risk of prostate cancer compared with men with light brown hair. Eye colour and skin phototype were not associated with risk.
The melanocortin-1-receptor (MC1R) gene is among several loci regulating pigmentation in humans, and the first to be identified (Chhajlani and Wikberg, 1992; Mountjoy et al, 1992). Over 80 allelic variants in the gene have been reported (Gerstenblith et al, 2007; Raimondi et al, 2008), which are associated with red hair, fair skin, increased susceptibility to epidermal injury from exposure to UV radiation, and higher risks of melanoma and non-melanoma skin cancer (Schaffer and Bolognia, 2001; Raimondi et al, 2008; Randerson-Moor et al, 2009; Kanetsky et al, 2010; Rees, 2010; Williams et al, 2011). The MC1R protein determines the relative synthesis and secretion by melanocytes of black/brown eumelanin and red/yellow pheomelanin, with many allelic variants expressing a red hair trait. Recent genome-wide association studies have identified other genetic variants associated with hair colour, eye colour, and skin pigmentation in European populations (Sulem et al, 2007; Han et al, 2008) and have associated MC1R with risk of cutaneous melanoma, but not with prostate cancer or other cancers (Ioannidis et al, 2010).
Melanocortin-1-receptor may also influence cell cycle control, apoptosis, and DNA damage and repair in melanocytes and keratinocytes (Rees, 2010); however, whether such functions are expressed by MC1R in other cells is unknown. In addition, MC1R, along with α-MSH, which has anti-inflammatory properties and both immunostimulatory and immunosuppressive effects, may have a role in inflammation (Schaffer and Bolognia, 2001; Rouzaud et al, 2005; Raimondi et al, 2008) and may consequently influence cancer development (Vendramini-Costa and Carvalho, 2012).
The wild-type allele of the MC1R variant Arg160Trp has been associated with increased prostate cancer risk in a case–control study, and the authors speculated that this variant may mediate the UV/sunlight–prostate cancer association (Luscombe et al, 2001). Others have also hypothesised that the association between geographic latitude, sun exposure, and prostate cancer risk is through a vitamin D mechanism (Bodiwala et al, 2003; Moon et al, 2005); however, prospective studies of circulating 25(OH)D and prostate cancer have generally been null (Gandini et al, 2011), with some studies (Yin et al, 2009), including our own (Albanes et al, 2011), suggesting an adverse association for higher vitamin D status. Although 25(OH)D concentrations in our study did not differ by hair colour, they were lower among individuals with red hair in another study and postulated to reflect avoidance of sun exposure (Randerson-Moor et al, 2009). Whether the lower prostate cancer risk in men with red hair relates to vitamin D, some aspect of melanogenesis, or another mechanism is unclear and will require investigation. A genetic association between hair colour or pigmentation-related traits and family history of prostate cancer can also be studied. Although skin phototype appeared associated with hair colour, mutual adjustment for these factors and eye colour did not influence the hazard estimates. Why only hair colour, but not eye colour or skin phototype, was associated with prostate cancer risk is unclear.
Strengths of our study include the prospective design and complete endpoint ascertainment. Men who dropped out of the ATBC study before the clinic visit during which hair and eye colour and skin phototype information would have been collected could not be included in the present analysis, and, as a result, we do not have data to examine the red hair–prostate cancer association in that initial post-baseline period. In addition, as the trial excluded men who were not 50–69 years of age at baseline, our study does not include prostate cancers occurring at younger ages. Natural hair colour at age 20 was self-reported, but misclassification due to recall bias seems unlikely for such a physical characteristic. The ATBC study cohort included only smokers and may not be generalisable to non-smokers; however, smoking intensity and duration were not related to hair colour or prostate cancer. Because the red hair trait was uncommon, our finding is based on a relatively small number of men (and cases) with red hair.
In conclusion, in the present study we found that men with naturally red hair experienced significantly lower prostate cancer incidence than men with other hair colours. Although the novelty of our findings warrant reexamination in other study populations, they support the idea that some pigmentation-related traits may influence the development of prostate cancer, either directly through genetic effects or regulatory mechanisms related to MC1R, another nearby gene, or other pigmentation genes or indirectly through associations with other exposures that may have an impact on risk (e.g., effects of UV-B or vitamin D status).
Acknowledgments
This work was supported in part by the Intramural Research Program of the National Institutes of Health and the National Cancer Institute. In addition, this research was supported by the US Public Health Service contracts N01-CN-45165, N01-RC-45035, N01-RC-37004, and HHSN261201000006C from the Department of Health and Human Services, National Cancer Institute.
Footnotes
This work is published under the standard license to publish agreement. After 12 months the work will become freely available and the license terms will switch to a Creative Commons Attribution-NonCommercial-Share Alike 3.0 Unported License
References
- Albanes D, Mondul AM, Yu K, Parisi D, Horst RL, Virtamo J, Weinstein SJ. Serum 25-hydroxy vitamin D and prostate cancer risk in a large nested case-control study. Cancer Epidemiol Biomarkers Prev. 2011;20:1850–1860. doi: 10.1158/1055-9965.EPI-11-0403. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Bodiwala D, Luscombe CJ, French ME, Liu S, Saxby MF, Jones PW, Ramachandran S, Fryer AA, Strange RC. Susceptibility to prostate cancer: studies on interactions between UVR exposure and skin type. Carcinogenesis. 2003;24:711–717. doi: 10.1093/carcin/bgg021. [DOI] [PubMed] [Google Scholar]
- Chhajlani V, Wikberg JES. Molecular cloning and expression of the human melanocyte stimulating hormone receptor cDNA. FEBS Lett. 1992;309:417–420. doi: 10.1016/0014-5793(92)80820-7. [DOI] [PubMed] [Google Scholar]
- Fitzpatrick TB. The validity and practicality of sun-reactive skin types I through VI. Arch Dermatol. 1988;124:869–871. doi: 10.1001/archderm.124.6.869. [DOI] [PubMed] [Google Scholar]
- Freedman DM, Dosemeci M, McGlynn K. Sunlight and mortality from breast, ovarian, colon, prostate, and non-melanoma skin cancer: a composite death certificate based case-control study. Occup Environ Med. 2002;59:257–262. doi: 10.1136/oem.59.4.257. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Gandini S, Boniol M, Haukka J, Byrnes G, Cox B, Sneyd MJ, Mullie P, Autier P. Meta-analysis of observational studies of serum 25-hydroxyvitamin D levels and colorectal, breast and prostate cancer and colorectal adenoma. Int J Cancer. 2011;128:1414–1424. doi: 10.1002/ijc.25439. [DOI] [PubMed] [Google Scholar]
- Gerstenblith MR, Goldstein AM, Fargnoli MC, Peris K, Landi MT. Comprehensive evaluation of allele frequency differences of MC1R variants across populations. Hum Mutat. 2007;28:495–505. doi: 10.1002/humu.20476. [DOI] [PubMed] [Google Scholar]
- Han J, Kraft P, Nan H, Guo Q, Chen C, Qureshi A, Hankinson SE, Hu FB, Duffy DL, Zhao ZZ, Martin NG, Montgomery GW, Hayward NK, Thomas G, Hoover RN, Chanock S, Hunter DJ. A genome-wide association study identifies novel alleles associated with hair color and skin pigmentation. PLoS Genet. 2008;4:e1000074. doi: 10.1371/journal.pgen.1000074. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Ioannidis JP, Castaldi P, Evangelou E. A compendium of genome-wide associations for cancer: critical synopsis and reappraisal. J Natl Cancer Inst. 2010;102:846–858. doi: 10.1093/jnci/djq173. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Kanetsky PA, Panossian S, Elder DE, Guerry D, Ming ME, Schuchter L, Rebbeck TR. Does MC1R genotype convey information about melanoma risk beyond risk phenotypes. Cancer. 2010;116:2416–2428. doi: 10.1002/cncr.24994. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Korhonen P, Malila N, Pukkala E, Teppo L, Albanes D, Virtamo J. The Finnish Cancer Registry as follow-up source of a large trial cohort—accuracy and delay. Acta Oncol. 2002;41:381–388. doi: 10.1080/028418602760169442. [DOI] [PubMed] [Google Scholar]
- Luscombe CJ, French ME, Liu S, Saxby MF, Jones PW, Fryer AA, Strange RC. Prostate cancer risk: associations with ultraviolet radiation, tyrosinase and melanocortin-1 receptor genotypes. Br J Cancer. 2001;85:1504–1509. doi: 10.1054/bjoc.2001.2097. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Moon SJ, Fryer AA, Strange RC. Ultraviolet radiation: effects on risks of prostate cancer and other internal cancers. Mutat Res. 2005;571:207–219. doi: 10.1016/j.mrfmmm.2004.09.015. [DOI] [PubMed] [Google Scholar]
- Mountjoy KG, Robbins LS, Mortrud MT, Cone RD. The cloning of a family of genes that encode the melanocortin receptors. Science. 1992;257:1248–1251. doi: 10.1126/science.1325670. [DOI] [PubMed] [Google Scholar]
- Raimondi S, Sera F, Gandini S, Iodice S, Caini S, Maisonneuve P, Fargnoli MC. MC1R variants, melanoma and red hair color phenotype: a meta-analysis. Int J Cancer. 2008;122:2753–2760. doi: 10.1002/ijc.23396. [DOI] [PubMed] [Google Scholar]
- Randerson-Moor JA, Taylor JC, Elliott F, Chang YM, Beswick S, Kukalizch K, Affleck P, Leake S, Haynes S, Karpavicius B, Marsden J, Gerry E, Bale L, Bertram C, Field H, Barth JH, Silva IS, Swerdlow A, Kanetsky PA, Barrett JH, Bishop DT, Bishop JA. Vitamin D receptor gene polymorphisms, serum 25-hydroxyvitamin D levels, and melanoma: UK case–control comparisons and a meta-analysis of published VDR data. Eur J Cancer. 2009;45:3271–3281. doi: 10.1016/j.ejca.2009.06.011. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Rees JL. Vexed by red-headed conundrums. J Invest Dermatol. 2010;130:1771–1773. doi: 10.1038/jid.2010.132. [DOI] [PubMed] [Google Scholar]
- Rouzaud F, Kadekaro AL, Abdel-Malek ZA, Hearing VJ. MC1R and the response of melanocytes to ultraviolet radiation. Mutat Res. 2005;571:133–152. doi: 10.1016/j.mrfmmm.2004.09.014. [DOI] [PubMed] [Google Scholar]
- Schaffer JV, Bolognia JL. The melanocortin-1 receptor: red hair and beyond. Arch Dermatol. 2001;137:1477–1485. doi: 10.1001/archderm.137.11.1477. [DOI] [PubMed] [Google Scholar]
- Sulem P, Gudbjartsson DF, Stacey SN, Helgason A, Rafnar T, Magnusson KP, Manolescu A, Karason A, Palsson A, Thorleifsson G, Jakobsdottir M, Steinberg S, Palsson S, Jonasson F, Sigurgeirsson B, Thorisdottir K, Ragnarsson R, Benediktsdottir KR, Aben KK, Kiemeney LA, Olafsson JH, Gulcher J, Kong A, Thorsteinsdottir U, Stefansson K. Genetic determinants of hair, eye and skin pigmentation in Europeans. Nat Genet. 2007;39:1443–1452. doi: 10.1038/ng.2007.13. [DOI] [PubMed] [Google Scholar]
- The ATBC Cancer Prevention Study Group The alpha-tocopherol, beta-carotene lung cancer prevention study: design, methods, participant characteristics, and compliance. Ann Epidemiol. 1994;4:1–10. doi: 10.1016/1047-2797(94)90036-1. [DOI] [PubMed] [Google Scholar]
- Vendramini-Costa DB, Carvalho JE. Molecular link mechanisms between inflammation and cancer. Curr Pharm Des. 2012;18:3831–3852. doi: 10.2174/138161212802083707. [DOI] [PubMed] [Google Scholar]
- Weinstein SJ, Yu K, Horst RL, Ashby J, Virtamo J, Albanes D. Serum 25-hydroxyvitamin D and risks of colon and rectal cancer in Finnish men. Am J Epidemiol. 2011;173:499–508. doi: 10.1093/aje/kwq398. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Williams PF, Olsen CM, Hayward NK, Whiteman DC. Melanocortin 1 receptor and risk of cutaneous melanoma: a meta-analysis and estimates of population burden. Int J Cancer. 2011;129:1730–1740. doi: 10.1002/ijc.25804. [DOI] [PubMed] [Google Scholar]
- Yin L, Raum E, Haug U, Arndt V, Brenner H. Meta-analysis of longitudinal studies: Serum vitamin D and prostate cancer risk. Cancer Epidemiol. 2009;33:435–445. doi: 10.1016/j.canep.2009.10.014. [DOI] [PubMed] [Google Scholar]