TY - JOUR
T1 - Next-generation sequencing of disseminated tumor cells
AU - Møller, Elen K.
AU - Kumar, Parveen
AU - Voet, Thierry
AU - Peterson, April
AU - Van Loo, Peter
AU - Mathiesen, Randi R.
AU - Fjelldal, Renathe
AU - Grundstad, Jason
AU - Borgen, Elin
AU - Baumbusch, Lars O.
AU - Naume, Bjørn
AU - Børresen-Dale, Anne Lise
AU - White, Kevin P.
AU - Nord, Silje
AU - Kristensen, Vessela N.
PY - 2013
Y1 - 2013
N2 - Disseminated tumor cells (DTCs) detected in the bone marrow have been shown as an independent prognostic factor for women with breast cancer. However, the mechanisms behind the tumor cell dissemination are still unclear and more detailed knowledge is needed to fully understand why some cells remain dormant and others metastasize. Sequencing of single cells has opened for the possibility to dissect the genetic content of subclones of a primary tumor, as well as DTCs. Previous studies of genetic changes in DTCs have employed single-cell array comparative genomic hybridization which provides information about larger aberrations. To date, next-generation sequencing provides the possibility to discover new, smaller, and copy neutral genetic changes. In this study, we performed whole-genome amplification and subsequently next-generation sequencing to analyze DTCs from two breast cancer patients. We compared copy-number profiles of the DTCs and the corresponding primary tumor generated from sequencing and SNP-comparative genomic hybridization (CGH) data, respectively. While one tumor revealed mostly whole-arm gains and losses, the other had more complex alterations, as well as subclonal amplification and deletions. Whole-arm gains or losses in the primary tumor were in general also observed in the corresponding DTC. Both primary tumors showed amplification of chromosome 1q and deletion of parts of chromosome 16q, which was recaptured in the corresponding DTCs. Interestingly, clear differences were also observed, indicating that the DTC underwent further evolution at the copy-number level. This study provides a proof-of-principle for sequencing of DTCs and correlation with primary copy-number profiles. The analyses allow insight into tumor cell dissemination and show ongoing copy-number evolution in DTCs compared to the primary tumors.
AB - Disseminated tumor cells (DTCs) detected in the bone marrow have been shown as an independent prognostic factor for women with breast cancer. However, the mechanisms behind the tumor cell dissemination are still unclear and more detailed knowledge is needed to fully understand why some cells remain dormant and others metastasize. Sequencing of single cells has opened for the possibility to dissect the genetic content of subclones of a primary tumor, as well as DTCs. Previous studies of genetic changes in DTCs have employed single-cell array comparative genomic hybridization which provides information about larger aberrations. To date, next-generation sequencing provides the possibility to discover new, smaller, and copy neutral genetic changes. In this study, we performed whole-genome amplification and subsequently next-generation sequencing to analyze DTCs from two breast cancer patients. We compared copy-number profiles of the DTCs and the corresponding primary tumor generated from sequencing and SNP-comparative genomic hybridization (CGH) data, respectively. While one tumor revealed mostly whole-arm gains and losses, the other had more complex alterations, as well as subclonal amplification and deletions. Whole-arm gains or losses in the primary tumor were in general also observed in the corresponding DTC. Both primary tumors showed amplification of chromosome 1q and deletion of parts of chromosome 16q, which was recaptured in the corresponding DTCs. Interestingly, clear differences were also observed, indicating that the DTC underwent further evolution at the copy-number level. This study provides a proof-of-principle for sequencing of DTCs and correlation with primary copy-number profiles. The analyses allow insight into tumor cell dissemination and show ongoing copy-number evolution in DTCs compared to the primary tumors.
KW - Circulating tumor cells
KW - Clonal evolution
KW - Disseminating tumor cells
KW - Single tumor cell sequencing
KW - Tumor heterogeneity
UR - http://www.scopus.com/inward/record.url?scp=84892393752&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84892393752&partnerID=8YFLogxK
U2 - 10.3389/fonc.2013.00320
DO - 10.3389/fonc.2013.00320
M3 - Article
C2 - 24427740
AN - SCOPUS:84892393752
SN - 2234-943X
VL - 3 DEC
JO - Frontiers in Oncology
JF - Frontiers in Oncology
M1 - 00320
ER -