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 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.
Highlights
The spread of cancer cells from primary tumors to regional lymph nodes is often associated with reduced survival
We evaluated our classification by utilizing the Unweighted Pair Group Method with Arithmetic Mean (UPGMA) [33]. (The nature of polyguanine genotyping data suggests the use of distance-based phylogenetic methods; see supplementary methods)
Our data show that lymph node metastases and distant metastases often do have a common origin
Summary
The spread of cancer cells from primary tumors to regional lymph nodes is often associated with reduced survival. We examine the evolutionary relationship between primary tumor, lymph node and distant metastases in human colorectal cancer. The association between lymphatic and distant metastasis has been known for at least 150 years [9] and, together with the observation that lymph node disease often precedes systemic disease, has engendered the view that affected lymph nodes may give rise to distant metastases [10,11,12] The concept of such a sequential progression or metastatic cascade [13], in which the primary tumor (T) seeds lymph node metastases (N), which in turn seed distant metastases (M), provides a mechanistic basis for the TNM staging system. Of the 19 patients, 17 had liver metastases, one had an ovary metastasis, and one had multiple metastases in the omentum
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