Rick Sturm Pigmentation /DNA repair /Signalling Epigenetics MC1R - PowerPoint PPT Presentation

CRE Program 1 How and why do naevi arise? twitter.com/uqdrc Rick Sturm Pigmentation /DNA repair /Signalling Epigenetics MC1R /Diet Genotype Senescence /Microbiome /Autophagy Immuno editing Penetrance Phenotype /Statistical Distribution Dev-Biology /cell-cell Skin Type contact Oxidative Environment Chance Stress DNA damage Melanocytes, naevocytes and melanoma

Brisbane Naevus Morphology Study (BNMS) 2011 to 2016 AIM 600 CMM cases or Family History vs 600 control subjects Actual Total N = 1255 Final analysis of survey at 6 years 592 CMM cases + 161 Family History 502 control subjects (no melanoma history) All have been submitted for Illumina HumanCoreExome genotyping = 500,000 SNPs 62 analysed by Whole Exome Sequencing (100x depth)

BNMS: Naevi classified by size, profile, colour and dermoscopic naevus pattern 37,205 melanocytic naevi >5mm Homogeneous Globular /Nonspecific 3378 (9.1%) 25,456 (68.4%) Complex Reticular 8371 (22.5%)

Ainger et al., Dermatology 2017

GWAS Meta Analysis for Naevi and CMM Numerous GWAS have identified associations between non-coding SNPs at IRF4, MTAP and PLA2G6 loci and naevus count and melanoma susceptibility David Duffy et al “Novel pleotropic risk loci for melanoma and nevus suggest multiple pathways to melanoma” Naevi MTAP MITF? MC1R? (TNC) PLA2G6 IRF4 ASIP Melanoma MC1R Law et al., Nature Genetics 2015

1 “hit” analysis for CMM Bertolotto, Scientifica 2013

Melanoma Predisposition: A “multi-hit” disease CDKN2A High High Intermediate Intermediate MC1R Moderate Moderate Weak Weak Very Rare Rare 1% Common Very Rare Rare 1% Common Minor allele frequency Minor allele frequency MC1R Extreme CDKN2A Box et al, AJHG 2001 Very Rare Rare 1% Common Minor allele frequency

2 “hits” MITF + MC1R High High Intermediate Intermediate MC1R Moderate MITF Moderate Weak Weak Very Rare Rare 1% Common Very Rare Rare 1% Common Minor allele frequency Minor allele frequency Sturm et al, JID 2014 Intermediate MITF MC1R Very Rare Rare 1% Common Minor allele frequency

2 “hits”: MITF + ATM High High Intermediate Intermediate ATM Moderate MITF Moderate Weak Weak Very Rare Rare 1% Common Very Rare Rare 1% Common Minor allele frequency Minor allele frequency MITF ATM High Very Rare Rare 1% Common Minor allele frequency

3 “hits”: MITF + ATM + MC1R MITF ATM High High Intermediate MC1R Moderate Weak Very Rare Rare 1% Common Very Rare Rare 1% Common Minor allele frequency Extreme MITF ATM MC1R Very Rare Rare 1% Common Minor allele frequency

Round 1 Demonstration Project A genomics approach for screening of patients at high risk of melanoma H. ¡Peter ¡Soyer Rick ¡Sturm 380 CMM patients = 280 BNMS + 100 new Mitch ¡Stark Helmut ¡Schaider 1-6 month = 160 exomes Erin ¡McMeniman 7-12 month = 160 exomes Nikolas ¡Haass 13-18 month = 60 exomes Kiaresh ¡Khosrotehrani B. ¡Mark ¡Smithers Victoria ¡Atkinson Develop protocols for targeted Monika ¡Janda melanoma screening in high risk Anna ¡Finnane individuals and families Betsy ¡Peach