Elucidation of genetic changes linked to melanoma progression is hampered by limited access to tissues from
visceral metastases. In this study, we analyzed genomic changes occurring in melanoma patients (n=13) through
progression from primary cutaneous disease to visceral metastases, including via multi-site sampling post-mortem,
using whole exome and genome sequencing. Gain of single nucleotide variants (SNV) and small insertions/deletions
(indel) in visceral metastases was generally limited, although in some sites massive SNV/indel acquisition was
associated with mutations in DNA repair genes. In contrast, changes in chromosomal copy number and large allelic
imbalances (AI) dominated the landscape of visceral metastases, with extensive loss of heterozygosity decreasing
mutational load in end-stage disease in some cases. In one case, multicore sampling of a primary tumor revealed
spatial heterogeneity in copy number. These findings were validated by fluorescence in situ hybridization. Increased
ploidy and AI were identified in treatment-naïve non-visceral metastases and primary tumors in a subset of cases.
Genes associated with chromosomal instability via cell cycle dysregulation, mitotic checkpoint defects and merotely
were mutated in most cases. We hypothesize that extensive acquired AI and ploidy change sculpt mutational profiles
that are strongly selected for during melanoma progression in most patients. Data will be presented describing the
impact of such events on predicted tumor neoantigenicity and on signaling pathway activity. Mechanisms that drive
ploidy change and AI and/or that permit the proliferation of melanoma cells in the face of vast genomic structural
derangement are potentially promising and specific therapy targets.