Associations of pigmentary and naevus phenotype with melanoma risk in two populations with comparable ancestry but contrasting levels of ambient sun exposure

Abstract

Background: People at high risk of developing melanoma are usually identified by pigmentary and naevus phenotypes. Objective: We examined whether associations of these phenotypes with melanoma risk differed by ambient sun exposure or participant characteristics in two population-based, case-control studies with comparable ancestry but different ambient sun exposure. Methods: Data were analysed from 616 cases and 496 controls from the Australian Melanoma Family Study and 2,012 cases and 504 controls from the Leeds (UK) case-control study. Questionnaire, interview and dermatological skin examination data were collected using the same measurement protocols. Relative risks were estimated as odds ratios using unconditional logistic regression, adjusted for potential confounders. Results: Hair and skin colour were the strongest pigmentary phenotype risk factors. All associations of pigmentary phenotype with melanoma risk were similar across countries. The median number of clinically assessed naevi was approximately three times higher in Australia than Leeds, but the relative risks for melanoma associated with each additional common or dysplastic naevus was higher for Leeds than Australia, especially for naevi on the upper and lower limbs. Higher naevus counts on the head and neck were associated with a stronger relative risk for melanoma for women than men. The two countries had similar relative risks for melanoma based on self-reported naevus density categories, but personal perceptions of naevus number differed by country. There was no consistent evidence of interactions between phenotypes on risk. Conclusions: Classifying people at high risk of melanoma based on their number of naevi should ideally take into account their country of residence, type of counts (clinical or self-reported), body site on which the naevus counts are measured, and sex. The presence of naevi may be a stronger indicator of a genetic predisposition in the UK than in Australia based on less opportunity for sun exposure to influence naevus development.

Risk factors for melanoma by anatomical site: an evaluation of aetiological heterogeneity*

“…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 .…”

“…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 .…”

Self‐reported naevus density may lead to misclassification of melanoma risk

“…Our study was limited by the relatively small sample size, such that we lacked power to detect significant associations. However, the differences in accuracy of self‐reported naevus density observed by age, and previous keratinocyte cancer, in addition to the previously reported sex and melanoma history, approached significance and warrant further investigation. If these differences prove significant in larger studies, the effect on risk modelling and prediction requires exploration and correction sought, for example, using Bayesian methodology.…”

A different finding on whether naevus numbers change during adulthood

“…Melanocytic naevi are one of the strongest risk factors for melanoma, 1,2 and the number of naevi on a person’s body is commonly used as a marker for level of risk 3 . For example, a meta‐analysis suggested that people with ≥ 25 common naevi and/or at least one atypical naevus form a high‐risk group, 1 and international clinical practice guidelines commonly consider people with > 100 common naevi or more than five atypical naevi to be a group at very high risk 3 .…”

“…3 It is well known that naevi predominantly originate in childhood, and their development is influenced by sun exposure and genetic factors. 2,4,5 However, cross-sectional studies have indicated that naevus counts decrease during adulthood, particularly after age 40 years, which would make naevi a less reliable indicator of risk at older ages.…”