Pigment Cell Melanoma Res. 24; 110–118 HYPOTHESIS Melanoma: is hair the root of the problem? Angela M. Gomez Garcia1,5, Christine E. McLaren1,4 and Frank L. Meyskens, Jr.1–3,5 Departments of: 1 Medicine 2 Biological Chemistry 3 Public Health 4 Epidemiology 5 Chao Family Comprehensive KEYWORDS melanoma ⁄ hair follicle ⁄ stem cell niche ⁄ Cancer Center, University of California, Irvine ultraviolet light CORRESPONDENCE Frank L. Meyskens, e-mail: [email protected] doi: 10.1111/j.1755-148X.2010.00782.x Presented in part and first at the XVth PanAmerican Society for Pigment Cell Research, Memphis Tennessee, September 7, 2009 View the pubcast on this paper at http://www.scivee.tv/node/29174 Why are children more vulnerable to sun 2 sun exposure on men (back, upper arm, chest, and exposure? leg) and women (back and thigh), there is no correlation between body surface area (BSA) and melanoma inci- Epidemiological studies indicate that sunburns in prepu- dence, (Figure 1A, R2 = 0.0237), while a positive corre- bertal children are associated with an increased risk of lation exists between number of vellus hair follicles and melanoma later in life (Autier and Dore, 1998; Oliveria melanoma incidence, (Figure 1B, R2 = 0.2644). How- et al., 2006; Williams and Pennella, 1994; Zanetti et al., ever, in the comparison of body sites subject to level 3 1992). Migrant studies to Australia have shown that sun exposure on men (forearm), and women (forearm, individuals arriving before age 10 have a similar mela- upper arm, and leg), a strong positive correlation is seen noma risk to those born in Australia, while individuals in terms of both BSA and melanoma incidence (Fig- arriving after age 15 exhibit about a quarter of the ure 2A, R2 = 0.8721), and also in terms of number of melanoma incidence (Oliveria et al., 2006). Likewise, vellus hair follicles and melanoma incidence (Figure 2B, studies have shown that in individuals who migrate to R2 = 0.652). (Our postulation for the strong positive cor- an area near the equator, the risk of melanoma relation seen in Figure 2A in terms of BSA and mela- decreases if the individual is older at the age of migra- noma incidence is further discussed in the latter part of tion (Oliveria et al., 2006). These studies suggest that this manuscript.) children are more vulnerable to sun exposure, vis-a-vis Multiple linear regression analyses indicated that the the risk for the development of cutaneous melanoma, most parsimonious model for prediction of melanoma which raises the question, ‘What are the factors that incidence considered the total number of vellus hair folli- may explain an increased vulnerability of children to cles per body site and exposure level (F = 0.01, sun exposure?’ R2 = 0.42). Thus, these two predictors explained 42% of the variation in melanoma incidence. Inclusion of a Epidemiology of melanoma and its variable representing gender did not add information to relationship to vellus hair the model (t = 0.19, P = 0.85). For the model, there was a positive relationship between the total number of Prepubertal children have a much higher proportion of vellus hair follicles per body site and melanoma inci- vellus hair compared to adults, which led us to investi- dence (t = 3.03, P = 0.007), adjusted for exposure level gate whether there may be a relationship between vel- (Figure 3). The mean melanoma incidence was 14% lus hair and melanoma incidence that may explain an higher with high lifetime, but mainly intermittent sun increased vulnerability of children to sun exposure. exposure, when compared to low lifetime exposure. Methods and supplementary information are provided in The results from the these analyses confirm that not Appendix 1. only is sun exposure level an important predictor of Mean melanoma incidence (±standard deviation) was melanoma, but, in addition, areas on the body with 0.11 ± 0.101% in men and 0.12 ± 0.062% in women. higher numbers of vellus hair follicles have an increased This difference was not statistically significant (t = 0.24, vulnerability to developing melanoma. The models also P = 0.81). The relationship between the number of vel- suggest that anatomical areas of the body with higher lus hair follicles and body surface area and melanoma numbers of vellus hair follicles are a far more important incidence for both genders is plotted in Figure 1A,B predictor of melanoma than anatomical areas with larger (sun exposure level 2) and Figure 2A,B (sun exposure surface areas; therefore, indicating that hair follicles are level 3). In the comparison of body sites subject to level potential culprits in melanomagenesis. 110 ª 2010 John Wiley & Sons A/S Melanoma: is hair the root of the problem? A Men and women sun exposure level 2 R2 = 0.0237 0.400 Back, B m 0.350 0.300 Back, S m 0.250 Back, B w 0.200 Thigh, B w 0.150 Back, S w Upper arm, B m Chest, S m Melanoma incidence 0.100 Thigh, S w Upper arm, S m Chest, B m Leg, S m 0.050 Leg, B m 0.000 0 500 1000 1500 2000 2500 3000 3500 4000 BSA (cm2) B Men and women sun exposure level 2 R2 = 0.2644 0.400 Back, B m 0.350 0.300 0.250 Back S m Back, B w 0.200 Thigh, S w 0.150 Back, S w Chest, B m Thigh, S w 0.100 Melanoma incidence Upper arm, S m Chest, S m Upper arm, B m 0.050 Leg, S m Leg, B m 0.000 0 10 000 20 000 30 000 40 000 50 000 60 000 70 000 Number of vellus hair follicles Figure 1. Relationship between the incidence of cutaneous melanoma and body surface area (BSA) (A) or number of vellus hair follicles (B), for sun exposure level 2 (low lifetime, mainly intermittent). Legend data points represent Body site, Country, and Gender. Body site is listed and followed by abbreviations S m, S w, B m, and B w, which represent Switzerland men, Switzerland women, British Columbia men, and British Columbia women, respectively. As hair-type variations exist between children and Hair-type variations between children adults, with children having a much higher proportion of and adults vellus hair, these epidemiological observations suggest that sun exposure and subsequent development of mel- At birth, all hair follicles are present, and no further folli- anoma in children are related to hair variations. In this cles will develop throughout life. However, from birth commentary, we discuss a dual vulnerability of the vel- until adulthood, follicle properties change as does the lus hair follicle to ultraviolet radiation (UVR) resulting type of hair produced because of hormonal changes from increased transmission of the photons in sunlight associated with puberty (Blume-Peytavi, 2008; Randall, in vellus compared to terminal hair and from the rela- 2008). Based on properties such as the depth of the tively superficial location of its stem cell niche. In addi- follicle, the length of the hair cycle, the amount of tion, we discuss ideas regarding skin evolution and a pigment, the relative diameter and the presence or possible co-evolution of hair, as well as hair depilation absence of the medulla in the shaft, hair is categorized and how its increase may relate to the increase in mela- into three main groups: vellus, intermediate, and termi- noma incidence observed over the past few decades. nal hair. The major differences among these three Finally, we conclude that vellus hair follicles likely play a groups are summarized in Table 1 and discussed in substantial role in the early events of melanomagenesis. detail. ª 2010 John Wiley & Sons A/S 111 Gomez Garcia et al. A Men and women sun exposure level 3 R2 = 0.8721 0.250 Leg, S w 0.200 Leg, B w 0.150 Upper arm, Bw 0.100 Upper arm, S w Forearm, B w Melanoma incidence Forearm, S w 0.050 Forearm, B m Forearm, S m 0.000 0 500 1000 1500 2000 2500 3000 BSA (cm2) Men and women sun exposure level 3 B R2 = 0.652 0.250 Leg, S w 0.200 Leg, B w 0.150 Upper arm, B w 0.100 Upper arm, S w Forearm, B w Melanoma incidence Forearm, S w 0.050 Forearm, B m Forearm, S m 0.000 0 5000 10 000 15 000 20 000 25 000 30 000 35 000 40 000 45 000 50 000 Number of vellus hair follicles Figure 2. Relationship between the incidence of cutaneous melanoma and body surface area (BSA) (A) or number of vellus hair follicles (B), for sun exposure level 3 (high lifetime, mainly intermittent). Legend data points represent Body site, Country, and Gender. Body site is listed and followed by abbreviations S m, S w, B m, and B w, which represent Switzerland men, Switzerland women, British Columbia men, and British Columbia women, respectively. In children, vellus hair is the primary hair type. From During puberty, vellus hair follicles in some areas of birth until puberty, vellus hair is present on all skin sur- the body, in response to androgen stimulation, relocate faces of the body, excluding the palms, soles, and lips deeper within the skin and evolve into larger terminal (Blume-Peytavi, 2008; Randall, 2008; Schneider et al., hair follicles. This process occurs in the pubic and axil- 2009). Vellus hair follicles are small and produce fine lary regions in men as well as women and on the face, hair with little pigment and grow no longer than 2 mm chest, limbs, upper pubic diamond, and oftentimes the and no thicker than 30 lm (Blume-Peytavi, 2008; Blume back in men (Blume-Peytavi, 2008; Randall, 2008).