Origins of lymphatic and distant metastases in human colorectal cancer
Naxerova, Kamila; Reiter, Johannes G.; Brachtel, Elena; Lennerz, Jochen K.; Van De Wetering, Marc; Rowan, Andrew; Cai, Tianxi; Clevers, Hans; Swanton, Charles; Nowak, Martin A.; Elledge, Stephen J.; Jain, Rakesh K.
(2017) Science, volume 357, issue 6346, pp. 55 - 60
(Article)
Abstract
The spread of cancer cells from primary tumors to regional lymph nodes is often associated with reduced survival. One prevailing model to explain this association posits that fatal, distant metastases are seeded by lymph node metastases. This view provides a mechanistic basis for the TNM staging system and is the
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rationale for surgical resection of tumor-draining lymph nodes. Here we examine the evolutionary relationship between primary tumor, lymph node, and distant metastases in human colorectal cancer. Studying 213 archival biopsy samples from 17 patients, we used somatic variants in hypermutable DNA regions to reconstruct high-confidence phylogenetic trees. We found that in 65% of cases, lymphatic and distant metastases arose from independent subclones in the primary tumor, whereas in 35% of cases they shared common subclonal origin. Therefore, two different lineage relationships between lymphatic and distant metastases exist in colorectal cancer.
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Keywords: General Medicine, General
ISSN: 0036-8075
Publisher: American Association for the Advancement of Science
Note: Funding Information: We thank M. Nahrendorf, F. Swirski, J. Gerold, and T. Padera for helpful comments and careful review of the manuscript, and N. Sasaki and V. Sasselli for their help with organoid culture. This work was supported by the Department of Defense W81XWH-10-0016 (R.K.J.), W81XWH-12-1-0362 (S.J.E.), and W81XWH-15-1-0579 (K.N.); National Human Genome Research Institute U54 HG007963 (T.C.); National Cancer Institute P01-CA080124 (R.K.J.) and R35-CA197743 (R.K.J.); Francis Crick Institute FC001169 (CS.); Austrian Science Fund J-3996 (J.G.R.); National Foundation for Cancer Research (R.K.J.); and Ludwig Center at Harvard (S.J.E. and R.K.J.). The Program for Evolutionary Dynamics is supported in part by a gift from B. Wu and E. Larson. K.N. conceived and designed the study and performed experiments. K.N. and J.G.R. analyzed data. E.B. and J.K.L. reviewed tissue specimens and clinical records. M.v.d.W., A.R., H.C., and CS. provided DNA samples. K.N., J.G.R., E.B., J.K.L., T.C., CS., M.A.N., S.J.E., and R.K.J. discussed results and strategy. R.K.J. supervised the study. K.N. wrote the manuscript, which was revised and approved by all authors. Raw polyguanine-profiling data, distance matrices, and phylogenetic trees can be downloaded from https://steelelabs.mgh.harvard.edu/lymphmet and from datadryad.org (http://dx.doi.org/10.5061/dryad.vv53d).
(Peer reviewed)