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

Materials and Methods

We analysed data from 3592 participants, including 2617 people with newly diagnosed melanoma (cases) and 975 people without melanoma (controls). Participants were recruited through the Australian Melanoma Family Study, which is a multicentre population-based case–control study, and through the Leeds (UK) population-based case–control study (Leeds Melanoma Case–Control Study). A detailed description of the study designs and data collections for these two studies has been given previously.[6] Identical questionnaires and assessment measures were applied across the study sites. Approval to conduct this study was obtained from the ethics committees of the coordinating centres and cancer registries in Australia, and from the UK Multicentre Research Ethics Committee and the Patient Information Advisory Group. All participants provided written informed consent.

Study Participants

For the Australian Melanoma Family Study, 629 individuals residing within Queensland, New South Wales and Victoria who had histopathologically confirmed first primary invasive cutaneous melanoma diagnosed between 1 July 2000 and 31 December 2002 at ages 18–39 years were included.[24] They were recruited through population-based cancer registries and participation was 54%. Frequency matched population controls for age, sex and city (n = 240) were recruited through electoral rolls (registration to vote is compulsory for adult Australian citizens) and were frequency matched to cases by age (within 5 years) and sex using proportional random sampling; participation was 23% of those eligible. Eligible spouse/partner or friend controls (n = 295) were nominated by case participants as a potential control; 80% of those nominated consented to participate. They were ineligible if they had a previous invasive or in situ melanoma.

For the Leeds case–control study, cases were aged 18–82 years with histopathologically confirmed first primary invasive melanoma, living in a geographically defined area of Yorkshire and the northern region of the UK (67% participation). Between September 2000 and June 2003, all people with invasive melanoma were included, and from July 2003 to September 2011, only cases with Breslow thickness ≥ 0·75mm were included. Age and sex frequency matched population-based controls identified as not having cancer were recruited from general practices (55% participation).

Data Collection

Details of the data collection are described in File S1 (see Supporting Information).

Statistical Analysis

All pigmentary and naevus phenotype variables were analysed as categorical variables. Sun exposure and PRS were analysed as continuous variables. Missing exposure values were excluded from the relevant analysis.

Adjusted odds ratios (ORs), approximating the relative risk,[25] and 95% confidence intervals (CIs) for melanoma were calculated using unconditional logistic regression models fitted separately for each anatomical site (head and neck, trunk, lower limbs, upper limbs) and compared with all controls. Thus, unlike case-only analyses where one anatomical site is used as a reference group for the other sites, in this analysis the cases from each site were compared with the single control group, and the reference category for each exposure corresponded to the lowest exposure level or darkest phenotype. For continuous measures of sun exposure, the ORs were calculated per 1-h increase in sun exposure per day. For continuous measures of PRS, the ORs were calculated per SD increase in PRS. We adjusted regression models for age (continuous), sex and city of recruitment, and for the PRS we additionally adjusted for self-reported ethnicity. We also further adjusted UV-exposure associations for pigmentary and naevus phenotype characteristics, and vice versa. Population controls and spouse/partner/friend controls were combined into one control group for this analysis, as we have previously shown that associations for standard risk factors were similar when either control group or both groups were used.[24]

To examine potential interaction between pigmentary phenotypes and sex, we fitted additional site-specific models including main effects and interaction terms. To test whether the associations for risk factors differed by anatomical subtype, we calculated P-values for aetiological heterogeneity as described by Zabor and Begg[26] using the R package 'riskclustr'.[27,28] Data were analysed using R version 3·5. Statistical significance was assessed using a two-sided threshold P < 0·05. P-values were not adjusted for multiple testing as we had clearly defined hypotheses informed by prior research.[29,30] We reported the study according to STROBE guidelines for observational studies.