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

Disclosures

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

In This Article

Results

Analysis Dataset

Of the 629 Australian cases and 535 controls, 25 cases and 65 controls were excluded from this analysis because of missing anatomical site (cases), presence of CDKN2A mutation (as genetic factors in this analysis focus on polygenic risk), non-European ancestry or age over 45 years (partner/friend controls). This resulted in 604 Australian cases and 470 controls for analysis. In the Leeds study, 2184 cases and 513 controls were recruited, from which 171 cases and eight controls were excluded owing to either missing or rare anatomical site, presence of CDKN2A mutation, or missing data for some exposures (a shorter questionnaire was used after 2007 when only cases were being recruited), resulting in 2013 cases and 505 controls for analysis. Combined, a total of 2617 cases and 975 controls were included in the analysis.

Participant Characteristics

The characteristics of the pooled study sample are presented in Table 1 and stratified by study in Table S1 (Australia) and Table S2 (Leeds) (see Supporting Information). Melanoma most commonly occurred on the trunk (35%) and lower limbs (34%), followed by the upper limbs (20%) and the head and neck (11%). Compared with male participants, female participants had a higher frequency of melanomas on the upper and lower limbs (male to female ratio 1 : 1·8 and 1 : 3·3, respectively), while the opposite was true for trunk and head and neck melanomas (male to female ratio 1 : 0·68 and 1 : 0·83, respectively). The proportion of melanomas occurring in those aged 70 and older was higher for head and neck (21%) than for any other site (9–10%; χ 2-test, P < 0·001). Family history of melanoma in a first-degree relative was more common for cases with melanoma on the upper limb or trunk (10%) compared with other anatomical sites (5–8%; χ 2-test, P < 0·001).

Pigmentary and Naevus Phenotypic Characteristics

The associations between key pigmentary phenotypic characteristics and melanoma by anatomical site are presented in Figure 1 for the pooled analysis, and separately for Australia and Leeds in Table S3 and Table S4. In the pooled analysis, increased naevus density was associated with higher odds of melanoma for all sites, but the strength of the association differed by anatomical site (P-heterogeneity < 0·001). The association of naevi was stronger for melanoma on the trunk and upper limbs (OR for many naevi compared with no naevi 6·9, 95% CI 4·5–10·6 and 6·1, 95% CI 3·6–10·3, respectively) and lower limbs (OR 4·7, 95% CI 3·0–7·3) than head and neck melanoma (OR 1·9, 95% CI 1·1–3·3).

Figure 1.

Associations between melanoma and naevus and pigmentation phenotypes, stratified by anatomical site, in the pooled Australian Melanoma Family Study and Leeds Melanoma Case–Control Study. P-het, P-heterogeneity; CI, confidence interval. Odds ratios (ORs) were calculated using logistic regression models that compared melanoma cases at each anatomical site with all controls. Models were adjusted for age (continuous), sex and city of recruitment.

The association of skin colour also differed by site (P-heterogeneity = 0·04), with very fair skin being more weakly related to melanoma on the trunk (OR 2·0, 95% CI 1·4–2·9 compared with olive or brown skin) than on other sites (ORs 2·7–3·2). When examined separately by study, the association with skin colour appeared stronger for melanoma on the head and neck in the Leeds study (OR 3·6 for very fair skin), and for melanoma on the lower limbs in the Australian study (OR 4·4).

Red or blonde hair, blue or grey eye colour, increasing number of freckles in childhood, propensity to sunburn, skin phototype and pigmentation score were associated with increased odds of melanoma for all sites, with no significant heterogeneity among the different sites in the pooled analysis (P-heterogeneity > 0·05). When examined separately by study, sun-sensitive skin (skin phototype) was more weakly related to melanoma on the trunk in the Leeds study, and in the Australian study pigmentation score was more strongly related to head and neck melanoma (both P-heterogeneity = 0·02).

The associations did not materially change when the pooled results were adjusted by UV exposures (Table S5).

Given the sex differences in the development of melanoma at different anatomical sites, we examined whether the association of phenotypic characteristics with melanoma risk was modified by sex, separately for each anatomical site (Table S6). The OR for freckles in childhood, comparing many with none, was higher for female participants compared with male participants for melanomas on the head and neck (ratio of ORs 3·4, 95% CI 1·1–10·8) and for melanomas on the trunk (ratio of ORs 2·8, 95% CI 1·3–6·3). Potential interactions with sex were also present for the association of red hair with melanomas on the head and neck (stronger association in female participants), and the association of naevi with melanomas on the lower limb (weaker association in female participants).

Ultraviolet Radiation Exposure

The associations between UV exposures and melanoma by anatomical site are presented in Figure 3 for the pooled multivariable analysis, and separately for Australia and Leeds in Table S7 and Table S8. In the pooled analysis, increased weekday sun exposure was associated with head and neck melanoma (for 1 h per day increase in exposure, OR 1·2, 95% CI 1·1–1·4) but there was no significant heterogeneity by site (P-heterogeneity = 0·43). Summer holiday sun exposure was associated with reduced risk of melanoma on the lower limbs and trunk, and weekend sun exposure was associated with reduced risk of melanoma on the lower limbs, but there was no significant heterogeneity by site.

There was borderline-significant heterogeneity by site (P = 0·07) for sunbed use, which had a stronger association with melanoma on the trunk (Figure 3); this association with the trunk was more apparent in the Australian study (OR 1·8, 95% CI 1·1–2·9; Table S7). There was no association with sunburns at any site in the pooled analysis (Figure 3). Increased risk of melanoma on the trunk was associated with painful sunburns in the Leeds study and blistering sunburns in the Australian study, although there was no significant heterogeneity by site (Tables S7, S8). Painful sunburns were associated with reduced risk of melanoma for all sites except the trunk in the Australian study.

Some risk estimates changed after adjustment for pigmentation and naevus phenotypic characteristics (Tables S7, S8); the inverse associations between sun exposure during weekends and summer holidays and melanoma risk were partly attenuated, associations with sunburns were mostly strengthened, and associations with sunbed use were mostly unchanged.

Genetic Risk Factors

The PRS was used to examine the risk of melanoma across different anatomical sites conferred by common genomic variants in several biological pathways that are important for melanoma development (pigmentation, naevus and telomere/other pathways) (Figure 2 for the pooled analysis and separately for Australia and Leeds in Table S9 and Table S10). Associations with melanoma were strongest for the pigmentation pathway PRS, with more than threefold higher odds per SD increase of melanoma across all anatomical sites without evidence of heterogeneity (P-heterogeneity = 0·14). Similarly, the telomere/other pathway PRS was consistently associated with melanoma at all anatomical sites. The naevus pathway PRS had a statistically significant association only with upper-limb melanoma (OR per SD 1·9, 95% CI 1·2–3·0) and a borderline association with trunk melanoma (OR 1·4, 95% CI 0·97–2·1) but there was no evidence of heterogeneity. For head and neck melanoma, the pooled OR associated with the naevus pathway PRS was 1·3, but it appeared to differ between Australia (OR 0·6) and Leeds (OR 2·0) (Cochran's Q, P = 0·046). A PRS combining all genetic variants indicated an approximate threefold increased odds of melanoma, with no evidence of heterogeneity by anatomical site. The associations did not materially change when the pooled results were adjusted by UV exposures (Table S11).

Figure 2.

Associations between melanoma and genetic pathway scores, stratified by anatomical site, in the pooled Australian Melanoma Family Study and Leeds Melanoma Case–Control Study. P-het, P-heterogeneity; CI, confidence interval. Odds ratios (ORs) were calculated using logistic regression models that compared melanoma cases at each anatomical site with all controls. Models were adjusted for age (continuous), sex and city of recruitment. ORs were calculated per SD increase in polygenic risk score and heterogeneity P-values were computed using variables categorized into tertiles.

Figure 3.

Associations between melanoma and ultraviolet radiation (UVR) exposures, stratified by anatomical site, in the pooled Australian Melanoma Family Study and Leeds Melanoma Case–Control study. P-het, P-heterogeneity; CI, confidence interval. Odds ratios (ORs) were calculated using logistic regression models that compared melanoma cases at each anatomical site with all controls. Models were adjusted for age (continuous), sex, city of recruitment and the following phenotypic characteristics: naevi, hair colour, eye colour, skin colour, freckles in childhood and skin phototype. For continuous measures of sun exposure, the ORs were calculated per 1-h increase in sun exposure per day and heterogeneity P-values were computed using variables categorized into tertiles.

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