Genetic changes during tumorigenesis are usually acquired sequentially. However, a recent study showed that in 2 to 3% of all cancers a single catastrophic event, termed chromothripsis, can lead to massive genomic rearrangements confined to one or a few chromosomes. In order to explore whether the degree of genomic instability and chromothripsis influences prognosis in cancer, we retrospectively applied array comparative genomic hybridization (aCGH) to 20 malignant melanomas (MM) that showed, despite comparable conventional clinical and pathological parameters, a profoundly different clinical course. We compared 10 patients who died of MM 3.7 years (median, range 0.9 to 7.6 years) after diagnosis with 10 patients who survived MM and had a median disease-free survival of 14.8 years (range 12.5 to 16.7 years; P = 0.00001). We observed a striking association between the degree of chromosomal instability, both numerical and structural, and outcome. MM associated with good prognosis showed only few chromosomal imbalances (mean 1.6 alterations per case), predominantly whole chromosome or chromosome arm gains and losses while MM with poor prognosis harbored significantly more chromosomal aberrations (13.9 per case; P = 0.008). Array-based CGH demonstrated that these aberrations were mostly focal events, culminating in two cases in a pattern consistent with the phenomenon of chromothripsis, which was confirmed by paired-end sequencing. This is the first description of chromothripsis in primary MM. Our study therefore links focal copy number alterations and chromothripsis with poor outcome in MM patients (P = 0.0002) and provides a genetic approach to predict outcome in MM.

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