Complex Tumor Genomes Inferred from Single Circulating Tumor Cells by Array-CGH and Next-Generation Sequencing
Ellen Heitzer,Martina Auer,Christin Gasch,Martin Pichler,Peter Ulz,Eva M. Hoffmann,Sigurd Lax,Julie Waldispuehl-Geigl,Oliver Mauermann,Carolin Lackner,Gerald Höfler,Florian Eisner,Heinz Sill,Hellmut Samonigg,Klaus Pantel,Sabine Riethdorf,Thomas Bauernhofer,Jochen B. Geigl,Michael R. Speicher +18 more
TLDR
This study paves the way to use CTCs as a liquid biopsy in patients with cancer, providing more effective options to monitor tumor genomes that are prone to change during progression, treatment, and relapse.Abstract:
Circulating tumor cells (CTC) released into blood from primary cancers and metastases reflect the current status of tumor genotypes, which are prone to changes. Here, we conducted the first comprehensive genomic profiling of CTCs using array-comparative genomic hybridization (CGH) and next-generation sequencing. We used the U.S. Food and Drug Administration-cleared CellSearch system, which detected CTCs in 21 of 37 patients (range, 1-202/7.5 mL sample) with stage IV colorectal carcinoma. In total, we were able to isolate 37 intact CTCs from six patients and identified in those multiple colorectal cancer-associated copy number changes, many of which were also present in the respective primary tumor. We then used massive parallel sequencing of a panel of 68 colorectal cancer-associated genes to compare the mutation spectrum in the primary tumors, metastases, and the corresponding CTCs from two of these patients. Mutations in known driver genes [e.g., adenomatous polyposis coli (APC), KRAS, or PIK3CA] found in the primary tumor and metastasis were also detected in corresponding CTCs. However, we also observed mutations exclusively in CTCs. To address whether these mutations were derived from a small subclone in the primary tumor or represented new variants of metastatic cells, we conducted additional deep sequencing of the primary tumor and metastasis and applied a customized statistical algorithm for analysis. We found that most mutations initially found only in CTCs were also present at subclonal level in the primary tumors and metastases from the same patient. This study paves the way to use CTCs as a liquid biopsy in patients with cancer, providing more effective options to monitor tumor genomes that are prone to change during progression, treatment, and relapse.read more
Citations
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Journal ArticleDOI
Challenges in circulating tumour cell research.
TL;DR: A conceptual framework of CTC assays is proposed and current challenges of C TC research are pointed out, which might structure this dynamic field of translational cancer research.
Journal ArticleDOI
Clinical Applications of Circulating Tumor Cells and Circulating Tumor DNA as Liquid Biopsy.
TL;DR: This review focuses on key areas of clinical applications of CTCs and ctDNA, including detection of cancer, prediction of prognosis in patients with curable disease, monitoring systemic therapies, and stratification of patients based on the detection of therapeutic targets or resistance mechanisms.
Journal ArticleDOI
Current and future perspectives of liquid biopsies in genomics-driven oncology.
TL;DR: The potential of liquid biopsies is highlighted by studies that show they can track the evolutionary dynamics and heterogeneity of tumours and can detect very early emergence of therapy resistance, residual disease and recurrence, but their analytical validity and clinical utility must be rigorously demonstrated before this potential can be realized.
Journal ArticleDOI
Targeting TGF-β Signaling in Cancer.
TL;DR: The rationale for targeting TGF-β signaling in cancer is reviewed, the clinical status of pharmacological inhibitors are summarized, and the direct effects of TGF -β signaling blockade on tumor and stromal cells are discussed.
Journal ArticleDOI
Tumor metastasis: moving new biological insights into the clinic
TL;DR: The explosive growth of metastasis research in the past decade has yielded an unprecedented wealth of information, but integration of such new knowledge into an improved, metastasis-oriented oncological drug development strategy is needed to thwart the development of metastatic disease at every stage of progression.
References
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Detection of Mutations in EGFR in Circulating Lung-Cancer Cells
Shyamala Maheswaran,Lecia V. Sequist,Sunitha Nagrath,Lindsey Ulkus,Brian W. Brannigan,Chey V. Collura,Elizabeth J. Inserra,Sven Diederichs,A. John Iafrate,Daphne W. Bell,Subba R. Digumarthy,Alona Muzikansky,Alona Muzikansky,Daniel Irimia,Jeffrey Settleman,Ronald G. Tompkins,Ronald G. Tompkins,Thomas J. Lynch,Mehmet Toner,Mehmet Toner,Daniel A. Haber,Daniel A. Haber +21 more
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