The interplay of sun-damage and genetic risk in Australian multiple and single primary melanoma cases and controls

E K McMeniman, D L Duffy, K Jagirdar, K J Lee, E Peach, A M McInerney-Leo, B De'Ambrosis, J E Rayner, B M Smithers, H P Soyer, R A Sturm
British Journal of Dermatology 2019 December 3

BACKGROUND: Skin phenotype, host genotype and UV damage play a role in development of melanoma.

OBJECTIVE: To ascertain whether the level of UV damage at the site of melanomas was associated with genetic polymorphisms.

METHODS: Deep phenotyping was performed on 1244 individuals: 281 with multiple primary melanomas (MPM), 304 with single primary melanoma (SPM) and 659 convenience controls. Genotype data was generated using the Illumina CoreExome microarray platform assaying over 500,000 SNPs. A subset of variants were combined to assess a polygenic risk score (PRS) for melanoma.

RESULTS: Most MPM cases were diagnosed >40 years, in sites with visible chronic UV damage. Females and those diagnosed at ≤40 years were less likely to have perilesional UV damage. Multiple melanoma patients had higher frequencies of MITF E318K, MC1R R-alleles, and the ASIP risk haplotype. Individuals having melanoma in a visibly UV-damaged site were more likely to carry MC1R rs75570604 (odds ratio [OR] 2.5), 9q31.2 rs10816595 (OR 2.5), and MTAP rs869329 (OR 1.4); these same alleles were more common in MPM patients diagnosed ≤40 years. Mean PRS was significantly higher in MPM than SPM and controls. Naevus count was comparable in early onset MPM cases and those diagnosed >40 years.

CONCLUSION: Our cohort demonstrated higher frequencies of previously reported alleles associated with melanoma. MPM melanomas more commonly occur in UV-damaged areas, and these individual are more likely to carry MC1R RHC alleles. Awareness of the interplay of genetic vulnerability with UV damage can stratify risk and guide recommendations for melanoma screening.

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