Kuhn, P., Dago, A. E., Stepansky, A., Carlsson, A., Felch, N., Luttgen, M., Kolatkar, A., Hicks, J., Gross, M. E. (April 2013) Sequential monitoring of single-cell copy number variation in metastatic prostate cancer. Cancer Research, 73 (8 (Sup). p. 4599. ISSN 0008-5472
Abstract
The high-definition circulating tumor cell (HD-CTC) assay provides for an enrichment-free approach to CTC identification. Here, we utilized the HD-CTC approach to study androgen receptor (AR) expression combined with single-nucleus sequencing for genome-wide analysis of copy number variation (CNV) in sequential CTCs samples obtained from a patient with metastatic prostate cancer treated with abiraterone acetate (an androgen synthesis inhibitor). At baseline, before initiation of abiraterone treatment, we observed a balanced proportion of AR-negative and AR-positive CTCs. During a brief period of clinical response (marked with a decreased serum PSA and decreased pain) the proportion of AR-positive CTCs declined followed by a rapid increase associated with clinical progression (increased PSA and pain). CNV analysis of single CTCs revealed multiple genomic rearrangements, such as AR amplification along with the chromosomal gains and losses typical of prostate cancer, in multiple cells at baseline. During treatment response, the frequency of CNV alterations significantly declined, followed by a reemergence to a pattern of multiple, complex alterations associated with clinical progression. Detailed analysis of the CNV profiles revealed that many abnormalities were commonly shared between the CTC populations, but a number were unique to the AR+ resistant/hormone refractory CTC population including increased MYC amplification alteration and the AR amplicon that include additional adjacent genes. Remarkably, the reconstruction of tumor lineage history based on the CTC genomic profiles enables us to trace and identify the precise treatment time point where the putative therapy-resistant CTC clone emerges, under therapeutic pressure, until it eventually expanded to become the AR+ resistant CTC population at the point of therapeutic relapse. Overall, our results demonstrated that the integration of the HD-CTC enumeration technology with protein expression and single cell genomic analyses could successfully be applied to real time monitoring of ADT therapy emergent change in a prostate cancer patient, and may provide a direct roadmap for personalized cancer medicine in the near future.
| Item Type: | Paper |
|---|---|
| Additional Information: | Meeting Abstract |
| Subjects: | diseases & disorders > cancer bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > copy number variants Publication Type > Meeting Abstract diseases & disorders > cancer > metastasis diseases & disorders > cancer > cancer types > prostate cancer |
| CSHL Authors: | |
| Communities: | CSHL labs > Hicks lab |
| Depositing User: | Matt Covey |
| Date: | April 2013 |
| Date Deposited: | 11 Apr 2014 15:59 |
| Last Modified: | 21 Feb 2018 17:11 |
| URI: | https://repository.cshl.edu/id/eprint/29757 |
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