Copy number analysis indicates monoclonal origin of lethal metastatic prostate cancer

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Abstract
Primary prostate cancer is genomically highly heterogeneous and is thought to derive from multiple independent clones of cancer cells. Using high-resolution genomic analyses, Bova et al. now show that, in contrast to primary tumors, metastases are monoclonal, originating from a single cancer cell. These findings call into question current views of the origins of primary prostate cancer and suggest that the genomic profile of prostate cancer metastases should inform therapeutic decisions. Many studies have shown that primary prostate cancers are multifocal1,2,3 and are composed of multiple genetically distinct cancer cell clones4,5,6. Whether or not multiclonal primary prostate cancers typically give rise to multiclonal or monoclonal prostate cancer metastases is largely unknown, although studies at single chromosomal loci are consistent with the latter case. Here we show through a high-resolution genome-wide single nucleotide polymorphism and copy number survey that most, if not all, metastatic prostate cancers have monoclonal origins and maintain a unique signature copy number pattern of the parent cancer cell while also accumulating a variable number of separate subclonally sustained changes. We find no relationship between anatomic site of metastasis and genomic copy number change pattern. Taken together with past animal and cytogenetic studies of metastasis7 and recent single-locus genetic data in prostate and other metastatic cancers8,9,10, these data indicate that despite common genomic heterogeneity in primary cancers, most metastatic cancers arise from a single precursor cancer cell. This study establishes that genomic archeology of multiple anatomically separate metastatic cancers in individuals can be used to define the salient genomic features of a parent cancer clone of proven lethal metastatic phenotype.