Poster Presentation Australasian Society for Dermatology Research 2022 Annual Scientific Meeting

Genomic comparison of primary dermal melanoma (PDM) and subcutaneous metastatic melanoma (SCM) (#6)

Peinan Zhao 1 , Christopher Chew 1 2 , Pacman Szeto 1 , Nicholas Wong 3 , Tony Papenfuss 4 , William Berry 2 , Louise Photiou 2 , Catriona McLean 5 , Vikki Marshall 6 , Jen G. Cheung 1 6 , Victoria Mar 2 , Mark Shackleton 1 6
  1. Department of Medicine, Central Clinical School, Monash University, Alfred Hospital, Melbourne, Victoria, Australia
  2. Victorian Melanoma Service, Alfred Health, Melbourne, Victoria, Australia
  3. Australian Centre for Blood Diseases, Central Clinical School, Monash University, Alfred Hospital, Melbourne, Victoria, Australia
  4. Bioinfomatics Division, WEHI, Melbourne, Victoria, Australia
  5. Department of Anatomical Pathology, Alfred Health, Melbourne, Victoria, Australia
  6. Department of Oncology, Alfred Health, Melbourne, Victoria, Australia

Background: Primary dermal melanoma (PDM) and subcutaneous metastatic melanoma (SCM) are typically histologically similar but prognostically distinct. PDMs arise in the dermal layer of the skin without epidermal involvement and have a five-year survival rate of 73-100%. In contrast, SCMs represent metastatic disease originating from a separate primary site, and are associated with a five-year survival of only 10-23%. Despite the impacts on patient prognosis and treatment, distinguishing PDM and SCM by clinical criteria alone is challenging, and there are currently no known unique molecular markers. The study's primary objective was to identify molecular markers that distinguish PDMs and SCMs, and infer underlying disease mechanisms based on genetic features.

Method: A cohort of 20 PDMs and 23 SCMs were studied. Formalin-fixed paraffin-embedded (FFPE) blocks of PDM and SCM samples were sequenced using the Illumina TSO500 panel, which included 523 known cancer genes. Sequencing data were analysed to identify mutational and copy number profiles of each sub-type. A predictive model of patient prognosis was established using Cox-regression modelling.

Results: Clinically, SCM patients had a worse prognosis (shorter recurrence free survival (RFS)) compared to PDM patients. Genetically, SCMs had significantly higher copy numbers of seven known oncogenes (EGFR, CDK6, FGF2, PDGFRA, BRAF, MET, MYC). Poorer RFS was most closely associated (c-index=0.785,p<<0.001) with the combined features of elevated BRAF copy number and a clinical diagnosis of SCM. Extrachromosomal DNA (ecDNA) was identified in 3/23 SCMs patients but not in PDMs. A trend of higher copy number variation load and lower tumour mutational burden was found in SCM patients.

Conclusion: Incorporating molecular markers as part of clinical diagnosis can improve PDM and SCM prognosis prediction. Compared to PDM, there were significant oncogenes gains and cases with ecDNA in the SCM cohort, suggesting structural genomic derangement as a potential disease driver linked to metastasis.