Rapid phenotypic and genomic change in response to therapeutic pressure in prostate cancer inferred by high content analysis of single circulating tumor cells

Dago, A. E., Stepansky, A., Carlsson, A., Luttgen, M., Kendall, J., Baslan, T., Kolatkar, A., Wigler, M., Bethel, K., Gross, M. E., Hicks, J., Kuhn, P. (August 2014) Rapid phenotypic and genomic change in response to therapeutic pressure in prostate cancer inferred by high content analysis of single circulating tumor cells. PLoS One, 9 (8). e101777. ISSN 1932-6203

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URL: http://www.ncbi.nlm.nih.gov/pubmed/25084170
DOI: 10.1371/journal.pone.0101777

Abstract

Timely characterization of a cancer's evolution is required to predict treatment efficacy and to detect resistance early. High content analysis of single Circulating Tumor Cells (CTCs) enables sequential characterization of genotypic, morphometric and protein expression alterations in real time over the course of cancer treatment. This concept was investigated in a patient with castrate-resistant prostate cancer progressing through both chemotherapy and targeted therapy. In this case study, we integrate across four timepoints 41 genome-wide copy number variation (CNV) profiles plus morphometric parameters and androgen receptor (AR) protein levels. Remarkably, little change was observed in response to standard chemotherapy, evidenced by the fact that a unique clone (A), exhibiting highly rearranged CNV profiles and AR+ phenotype was found circulating before and after treatment. However, clinical response and subsequent progression after targeted therapy was associated with the drastic depletion of clone A, followed by the sequential emergence of two distinct CTC sub-populations that differed in both AR genotype and expression phenotype. While AR- cells with flat or pseudo-diploid CNV profiles (clone B) were identified at the time of response, a new tumor lineage of AR+ cells (clone C) with CNV altered profiles was detected during relapse. We showed that clone C, despite phylogenetically related to clone A, possessed a unique set of somatic CNV alterations, including MYC amplification, an event linked to hormone escape. Interesting, we showed that both clones acquired AR gene amplification by deploying different evolutionary paths. Overall, these data demonstrate the timeframe of tumor evolution in response to therapy and provide a framework for the multi-scale analysis of fluid biopsies to quantify and monitor disease evolution in individual patients.

Item Type: Paper
Subjects: diseases & disorders > cancer
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > genomes
diseases & disorders > cancer > cancer types > prostate cancer
diseases & disorders > cancer > drugs and therapies > tumor microenvironment
CSHL Authors:
Communities: CSHL Cancer Center Program > Cancer Genetics
CSHL Cancer Center Shared Resources > Bioinformatics Service
CSHL Cancer Center Shared Resources > Flow Cytometry Service
CSHL labs > Hicks lab
CSHL labs > Wigler lab
CSHL Cancer Center Shared Resources > DNA Sequencing Service
Depositing User: Matt Covey
Date: 1 August 2014
Date Deposited: 08 Aug 2014 16:54
Last Modified: 04 Nov 2015 16:06
PMCID: PMC4118839
Related URLs:
URI: http://repository.cshl.edu/id/eprint/30670

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