For decades, cancer initiation and progression are thought to occur gradually through small mutational changes in its DNA. After natural selection, winning variants that have accumulated sufficient fitness-conferring traits expand and spread, causing respectively primary tumor growth and metastases. More recent studies have discovered new mechanisms that allow cancer’s DNA or genome to undergo a large number of mutational changes all at once and survive this catastrophic event. This would therefore enable cancer cells to accelerate its evolution by rapidly generating large pools of variants for natural selection. We and others have discovered that such powerful genomic instability mechanisms (specifically referred to as chromothripsis or more generally as complex genomic rearrangements) are operative in advanced metastatic cutaneous melanomas, in particular those causing therapy resistance and death.

Here, we will test the hypothesis that these powerful genomic instability mechanisms are critically important evolutionary events in early (primary) melanoma. To address whether and how complex genomic instability mechanisms drive the growth of primary melanomas, fuel metastases in the same patients, and increase the aggressiveness of the disease course in the affected patients, we will achieve two non-trivial logistical and technical milestones to test this new conceptual paradigm of melanoma evolution. First, we will collect patient-matched primary and metastatic melanomas and normal tissues. Second, we will generate so-called whole-genome sequences from all these tissues. We will deploy a comprehensive suite of computational strategies to analyze a large volume of genomic data to understand how complex genomic rearrangements accelerate melanoma evolution. Moreover, our analysis will generate additional hypotheses pertaining to prognostic and predictive biomarkers as well as preventive and therapeutic targets. Analysis of preliminary data from over 30 patients support the notion that clones of melanoma with these complex alterations drive early and late disease frequently in patients with melanoma, including acral cutaneous, desmoplastic cutaneous, and mucosal melanomas. Within the two-year project period, we can feasibly achieve analysis over one hundred patients, including patients of under-represented minorities. With follow-up expansion, this project will seed an invaluable resource for the melanoma and cancer research community.