Oral Presentation Australasian Society for Dermatological Research Annual Scientific Meeting 2017

Combined genetic and cellular analysis of naevogenesis (#6)

Richard Sturm 1
  1. University of Queensland, Brisbane, QLD, Australia

Total body naevus counts have been shown to be highly influenced by host factors as well as environmental exposure to UVR, however the number of naevi and dermoscopic pattern is a highly heritable trait, with twin studies estimating that approximately 60 to 70% can be explained by genetic factors.  A combination of approaches have been used to identify genes that influence the normal diversity seen in human pigmentation traits and somatic mutations that drive the formation and growth of pigmented lesions. Using genetic data available through large Queensland based population studies of naevi (BLTNS and BNMS), we are modelling the genotypic effects and modifier interactions between pigmentation and naevus gene polymorphisms on human phenotypes.  By performing Illumina CoreExome SNP genotyping of 500,000 coding and tagging SNPs together with selected whole exome sequencing of 1255 participants in the BNMS, we aim to identify genes associated with a range of naevi characteristics including total number, naevus subtype and body site distributions. SNPs and gene haplotypes that are identified genetically are then functionally examined in a large collection (>300) of clonal human neonatal melanocyte strains that have been similarly genotyped, allowing cell strains to be selected as homozygous WT or variant for common gene polymorphisms associated with pigmentation or naevus traits. Specifically, alterations in cell growth, cell cycle dynamics, survival and senescence pathways are examined in these contexts.  The functional role of known naevus associated genes MTAP, PLA2G6, IRF4 and MITF in melanocytic cells are being investigated using these tissue culture based experiments. Notably, higher IRF4 protein levels directed by the rs12203592*C allele were associated with higher basal melanocyte proliferation but decreased cell viability following UVR, an etiological factor in melanoma development.  In addition cultures of adult melanocytes derived from lesional and perilesional naevus tissue from BNMS volunteers are being characterised.