Xenografts as Models of Clonal Selection and Acquired Resistance to Therapy

Featured Article: Ding L, Ellis MJ, Li S, Larson DE, Chen K, Wallis JW, et al. Genome remodeling in a basal-like breast cancer metastasis and xenograft. Nature 2010; 464:999–1005.2In our 2010 Nature article featured here, we described a next-generation sequencing-based whole-genome study to compare 4 related genomes from a single patient: a primary triple negative breast cancer, its counterpart xenograft [or “patient-derived xenograft” (PDX)], and a brain metastasis that occurred upon disease progression, all compared with the blood-derived normal DNA. This comparison identified a high degree of genomic similarity between all 3 tumor samples, and for the first time in a solid tissue malignancy we explored the alterations in genomic heterogeneity that occurred in the transitions from primary to metastatic disease, and from primary to PDX. Effectively, we demonstrated that somatic structural alterations remained constant across all 3 tumor genomes but that there were changes in clonality (inferred from the allele frequencies of point mutations) when comparing the primary to the metastasis and to the …