Malignant tumors are frequently incurable because of their evolutionary nature. However, revealing the extent of heritable molecular variation in cancer has been difficult, as it has not been possible to study genetic and epigenetic change in individual cells from the same tumor. In overcoming this, we have found that genetic and epigenetic changes are remarkably dynamic in human melanoma.
Using melanomas from four separate patients, we performed serial in vivo
xenotransplantation of single cells isolated from each tumor, creating
multi-generational clonal tumor families. SNP genotyping and DNA methylation
arrays were performed on each clonal tumor. Inter-clonal comparisons of CNVs
and DNA methylomes revealed widespread and rapidly emergent changes in a high
proportion of tumorigenic clones; a majority of clones in each family were
genetically and epigenetically distinct from one other. Importantly, some of
the changes were found to affect genes known to be functionally relevant in
melanoma, such as N-RAS and BRAF. This indicates that potentially targetable
molecular changes may evolve in melanoma after tumors are already established.
These data reveal pervasive and profound instability of the human melanoma
genome and epigenome that helps to explain the rapid emergence of resistance commonly
seen against anti-melanoma therapies.