RT Journal
A1 Leung, Marco L.
A1 Davis, Alexander
A1 Gao, Ruli
A1 Casasent, Anna
A1 Wang, Yong
A1 Sei, Emi
A1 Sanchez, Eduardo
A1 Maru, Dipen
A1 Kopetz, Scott
A1 Navin, Nicholas E
T1 Single cell DNA sequencing reveals a late-dissemination model in metastatic colorectal cancer
JF Genome Research 
JO Genome Research 
YR 2017 
FD May 25 
DO 10.1101/gr.209973.116 
SP gr.209973.116 
UL http://genome.cshlp.org/content/early/2017/05/24/gr.209973.116.abstract 
AB Metastasis is a complex biological process that has been difficult to delineate in human colorectal (CRC) cancer patients.  A major obstacle in understanding metastatic lineages is the extensive intratumor 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.