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Genome Res. 2017 Aug;27(8):1287-1299. doi: 10.1101/gr.209973.116. Epub 2017 May 25.

Single-cell DNA sequencing reveals a late-dissemination model in metastatic colorectal cancer.

Author information

1
Department of Genetics, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
2
The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, Texas 77030, USA.
3
Department of Pathology.
4
Department of Gastrointestinal Medical Oncology.
5
Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.

Abstract

Metastasis is a complex biological process that has been difficult to delineate in human colorectal cancer (CRC) patients. A major obstacle in understanding metastatic lineages is the extensive intra-tumor heterogeneity at the primary and metastatic tumor sites. To address this problem, we developed a highly multiplexed single-cell DNA sequencing approach to trace the metastatic lineages of two CRC patients with matched liver metastases. Single-cell copy number or mutational profiling was performed, in addition to bulk exome and targeted deep-sequencing. In the first patient, we observed monoclonal seeding, in which a single clone evolved a large number of mutations prior to migrating to the liver to establish the metastatic tumor. In the second patient, we observed polyclonal seeding, in which two independent clones seeded the metastatic liver tumor after having diverged at different time points from the primary tumor lineage. The single-cell data also revealed an unexpected independent tumor lineage that did not metastasize, and early progenitor clones with the "first hit" mutation in APC that subsequently gave rise to both the primary and metastatic tumors. Collectively, these data reveal a late-dissemination model of metastasis in two CRC patients and provide an unprecedented view of metastasis at single-cell genomic resolution.

PMID:
28546418
PMCID:
PMC5538546
DOI:
10.1101/gr.209973.116
[Indexed for MEDLINE]
Free PMC Article

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