Genomic alterations indicate tumor origin and varied metastatic potential of disseminated cells from prostate cancer

Disseminated epithelial cells can be isolated from the bone marrow of a far greater frac-tion of prostate-cancer patients than the fraction of patients who progress to metastatic disease. To provide a better understanding of these cells, we have characterized their genomic altera-tions. We first present an array comparative genomic hybridization method capable of detecting genomic changes in the small number of disseminated cells (10-20) that can typically be ob-tained from bone-marrow aspirates of prostate-cancer patients. We show multiple regions of copy-number change, including alterations common in prostate cancer, such as 8p loss, 8q gain, and gain encompassing the androgen-receptor gene on Xq, in the disseminated cell pools from 11 metastatic patients. We found fewer and less striking genomic alterations in the 48 pools of disseminated cells from patients with organ-confined disease. However, we identify changes shared by these samples with their corresponding primary tumors and prostate-cancer altera-tions reported in the literature, evidence that these cells, like those in advanced disease, are disseminated tumor cells (DTCs). We also demonstrate that DTCs from patients with advanced and localized disease share several abnormalities, including losses containing cell-adhesion genes and alterations reported to associate with progressive disease. These shared alterations might confer the capability to disseminate or establish secondary disease. Overall, the spectrum of genomic deviations is evidence for metastatic capacity in advanced-disease DTCs and varia-tion in that capacity in DTCs from localized disease. Our analysis lays the foundation for eluci-dation of the relationship between DTC genomic alterations and progressive prostate cancer. Keywords: array comparative genomic hybridization, prostate cancer, disseminated cells The aim of this study was to characterize the genomic changes identified in disseminated cells isolated from the bone marrow of prostate cancer patients. As these samples were composed of pools of 10-20 cells, we verified that amplification of this material by ligation mediated PCR was compatible with array CGH. Tests of the method were conducted using nine samples of a small number of normal cells and five LNCaP samples (one bulk sample and four samples of 10-20 cells). Genomic profiles of disseminated cells were produced from 48 samples collected from the bone marrow of 48 patients (i.e. one sample per patient) with localized prostate cancer and from 13 samples collected from the bone marrow of 11 patients with advanced disease (3 biological replicates were collected from one individual with advanced disease).