Editors' ChoiceCancer

Fragmenting Malignant Melanoma

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Science Translational Medicine  16 Jan 2013:
Vol. 5, Issue 168, pp. 168ec12
DOI: 10.1126/scitranslmed.3005666

Patients with malignant melanoma display widely disparate survival rates among cases with comparable pathological and clinical characteristics. Now, Hirsch and colleagues show that clues to a patient’s outcome can be found in the DNA of melanoma cells.

Normal skin cells have two copies of the genome, but as cancer cells divide, they accumulate changes in the DNA, often resulting in a change in the DNA copy number. These genetic alterations most commonly occur in a sequential fashion, with individual events accumulating progressively over time. Recently, scientists observed that some cancers, including a fraction of melanomas, have a single catastrophic event, coined “chromothripsis,” in which portions of chromosomes fragment into tens to hundreds of pieces that subsequently get reassembled incorrectly. These events lead to rampant gene copy number changes and rearrangements.

The role that chromothripsis and genomic instability play in the prognosis of individuals with malignant melanoma is poorly understood. In order to identify a link between outcomes and DNA copy number, Hirsch et al. studied a cohort of 20 well-curated malignant melanomas with dichotomous survival rates. Ten patients had a median disease-free survival of 3.7 years, whereas the remaining 10 patients survived for a median of 14.8 years. To 18 of the samples , the authors applied comparative genomic hybridization—a method capable of identifying DNA copy number changes throughout the genome—and discovered that the cases with poor prognoses, including two that demonstrated chromothripsis, had significantly more chromosomal aberrations when compared with the samples associated with good prognoses. When copy number aberrations were seen in cases with favorable prognoses, large segments of chromosomes were lost, in contrast to cases with poor prognoses, in which focal gains or losses predominated.

Although this study provides a potential genetic approach to guide prognostication in malignant melanoma, future large-scale studies will be required to validate these results and determine how such information can inform clinical decision-making.

D. Hirsch et al., Chromothripsis and focal copy number alterations determine poor outcome in malignant melanoma. Cancer Res., published online 27 December 2012 (10.1158/0008-5472). [Abstract]

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