Complex tumor genomes inferred from single circulating tumor cells by array-CGH and next-generation sequencing
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Complex tumor genomes inferred from single circulating tumor cells by array-CGH and next-generation sequencing. / Heitzer, Ellen; Auer, Martina; Gasch, Christin; Pichler, Martin; Ulz, Peter; Hoffmann, Eva Maria; Lax, Sigurd; Waldispuehl-Geigl, Julie; Mauermann, Oliver; Lackner, Carolin; Höfler, Gerald; Eisner, Florian; Sill, Heinz; Samonigg, Hellmut; Pantel, Klaus; Riethdorf, Sabine; Bauernhofer, Thomas; Geigl, Jochen B; Speicher, Michael R.
In: CANCER RES, Vol. 73, No. 10, 15.05.2013, p. 2965-75.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - Complex tumor genomes inferred from single circulating tumor cells by array-CGH and next-generation sequencing
AU - Heitzer, Ellen
AU - Auer, Martina
AU - Gasch, Christin
AU - Pichler, Martin
AU - Ulz, Peter
AU - Hoffmann, Eva Maria
AU - Lax, Sigurd
AU - Waldispuehl-Geigl, Julie
AU - Mauermann, Oliver
AU - Lackner, Carolin
AU - Höfler, Gerald
AU - Eisner, Florian
AU - Sill, Heinz
AU - Samonigg, Hellmut
AU - Pantel, Klaus
AU - Riethdorf, Sabine
AU - Bauernhofer, Thomas
AU - Geigl, Jochen B
AU - Speicher, Michael R
N1 - ©2013 AACR.
PY - 2013/5/15
Y1 - 2013/5/15
N2 - 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.
AB - 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.
KW - Colorectal Neoplasms
KW - Comparative Genomic Hybridization
KW - Gene Dosage
KW - Genome
KW - Humans
KW - Mutation
KW - Neoplastic Cells, Circulating
KW - Sequence Analysis, DNA
KW - Single-Cell Analysis
U2 - 10.1158/0008-5472.CAN-12-4140
DO - 10.1158/0008-5472.CAN-12-4140
M3 - SCORING: Journal article
C2 - 23471846
VL - 73
SP - 2965
EP - 2975
JO - CANCER RES
JF - CANCER RES
SN - 0008-5472
IS - 10
ER -