R Laskar1, A Ferreiro-Iglesias1, D T Bishop2, M M Iles3,4, P A Kanetsky5, B K Armstrong6, M H Law7,8, A M Goldstein9, J F Aitken10, G G Giles11,12,13, H A Robbins1, A E Cust1,6,14. 1. International Agency for Research on Cancer, Lyon, France. 2. Leeds Institute of Haematology and Immunology, University of Leeds, Leeds, UK. 3. Division of Haematology and Immunology, Leeds Institute of Medical Research at St James's, University of Leeds, Leeds, UK. 4. Leeds Institute of Data Analytics, University of Leeds, Leeds, UK. 5. Cancer Epidemiology Program, Moffitt Cancer Center, Tampa, FL, USA. 6. Cancer Epidemiology and Prevention Research Group, Sydney School of Public Health, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia. 7. Statistical Genetics, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia. 8. Queensland University of Technology (QUT), Brisbane, QLD, Australia. 9. Human Genetics Program, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA. 10. Viertel Centre for Research in Cancer Control, the Cancer Council Queensland, Brisbane, QLD, Australia. 11. Cancer Epidemiology Division, Cancer Council Victoria, 615 St Kilda Road, Melbourne, VIC, Australia. 12. Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, VIC, Australia. 13. Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, VIC, Australia. 14. The Melanoma Institute Australia, The University of Sydney, Sydney, NSW, Australia.
Abstract
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.
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.