Risk Factors for Melanoma by Anatomical Site

An Evaluation of Aetiological Heterogeneity

R. Laskar; A. Ferreiro-Iglesias; D.T. Bishop; M.M. Iles; P.A. Kanetsky; B.K. Armstrong; M.H. Law; A.M. Goldstein; J.F. Aitken; G.G. Giles; H.A. Robbins; A.E. Cust


The British Journal of Dermatology. 2021;184(6):1085-1093. 

In This Article

Abstract and Introduction


Background: Melanoma aetiology has been proposed to have two pathways, which are determined by naevi and type of sun exposure and related to the anatomical site where melanoma develops.

Objectives: We examined associations with melanoma by anatomical site for a comprehensive set of risk factors including pigmentary and naevus phenotypes, ultraviolet radiation exposure and polygenic risk.

Methods: We analysed harmonized data from 2617 people with incident first invasive melanoma and 975 healthy controls recruited through two population-based case–control studies in Australia and the UK. Questionnaire data were collected by interview using a single protocol, and pathway-specific polygenic risk scores were derived from DNA samples. We estimated adjusted odds ratios using unconditional logistic regression that compared melanoma cases at each anatomical site with all controls.

Results: When cases were compared with control participants, there were stronger associations for many naevi vs. no naevi for melanomas on the trunk, and upper and lower limbs than on the head and neck (P-heterogeneity < 0·001). Very fair skin (vs. olive/brown skin) was more weakly related to melanoma on the trunk than to melanomas at other sites (P-heterogeneity = 0·04). There was no significant difference by anatomical site for polygenic risk. Increased weekday sun exposure was positively associated with melanoma on the head and neck but not on other sites.

Conclusions: We found evidence of aetiological heterogeneity for melanoma, supporting the dual pathway hypothesis. These findings enhance understanding of risk factors for melanoma and can guide prevention and skin examination education and practices.


Cutaneous melanoma incidence is increasing in many countries with populations of predominantly European origin, despite improvements in prevention.[1,2] Most of the risk for melanoma is driven by intensity and pattern of sun exposure, host factors such as pigmentary phenotypes, propensity to develop naevi, genetic susceptibility and the complex association among these factors.[3–6] The aetiology of melanoma is also indicated by the anatomical site on which it develops,[7,8] with two main biological pathways proposed.[9–12] The first of these is a naevus pathway that is initiated by early-life sun exposure to epidermal melanocytes, promoted by intermittent sun exposure or host factors, and is predominant on areas less exposed to sun (e.g. trunk) and in younger individuals. The second is a chronic (more continuous) sun-exposure pathway, predominant in sun-sensitive and older people, in which sun damage progressively accumulates on areas of skin that are habitually exposed (e.g. head and neck).[12–14] A third pathway involving increased germline telomere length has been implicated through genetic studies,[15] but its association with pigmentation and naevus count is thus far largely undescribed.

Most epidemiological studies that have examined this hypothesis have focused on the association of sun exposure (or a proxy such as solar elastosis) with melanoma risk stratified by anatomical site.[14,16,17] Few studies have examined associations of other risk factors by anatomical site, such as pigmentary and naevus characteristics, despite their strong associations with melanoma risk and the importance of host characteristics in the dual pathway hypothesis.[3,6,12,18–22] Most of these studies have been case-only designs with small sample sizes and limited statistical power, have captured data for only a few risk factors or have been limited to one sex.[3,14,23] Therefore, we aimed to examine associations with melanoma by anatomical site for a comprehensive set of risk factors including pigmentary and naevus characteristics [measured both phenotypically and genetically using a polygenic risk score (PRS)] and ultraviolet (UV) radiation exposure using two population-based studies from Australia and the UK.