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PLoS One. 2014 Aug 1;9(8):e101777. doi: 10.1371/journal.pone.0101777. eCollection 2014.

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

Author information

1
Department of Cell and Molecular Biology, The Scripps Research Institute, La Jolla, California, United States of America.
2
Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, United States of America; Skyline Genomics, Roslyn Heights, New York, United States of America.
3
Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, United States of America; Department of Molecular and Cellular Biology, Stony Brook University, Stony Brook, New York, United States of America.
4
Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, United States of America.
5
Department of Cell and Molecular Biology, The Scripps Research Institute, La Jolla, California, United States of America; Department of Pathology, Scripps Clinic, La Jolla, California, United States of America.
6
Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America.
7
Dornsife College of Letters, Arts and Sciences, University of Southern California, Los Angeles, California, United States of America.

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.

PMID:
25084170
PMCID:
PMC4118839
DOI:
10.1371/journal.pone.0101777
[Indexed for MEDLINE]
Free PMC Article
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