Lymph node metastases develop through a wider evolutionary bottleneck than distant metastases.

Journal Article (Journal Article)

Genetic diversity among metastases is poorly understood but contains important information about disease evolution at secondary sites. Here we investigate inter- and intra-lesion heterogeneity for two types of metastases that associate with different clinical outcomes: lymph node and distant organ metastases in human colorectal cancer. We develop a rigorous mathematical framework for quantifying metastatic phylogenetic diversity. Distant metastases are typically monophyletic and genetically similar to each other. Lymph node metastases, in contrast, display high levels of inter-lesion diversity. We validate these findings by analyzing 317 multi-region biopsies from an independent cohort of 20 patients. We further demonstrate higher levels of intra-lesion heterogeneity in lymph node than in distant metastases. Our results show that fewer primary tumor lineages seed distant metastases than lymph node metastases, indicating that the two sites are subject to different levels of selection. Thus, lymph node and distant metastases develop through fundamentally different evolutionary mechanisms.

Full Text

Duke Authors

Cited Authors

  • Reiter, JG; Hung, W-T; Lee, I-H; Nagpal, S; Giunta, P; Degner, S; Liu, G; Wassenaar, ECE; Jeck, WR; Taylor, MS; Farahani, AA; Marble, HD; Knott, S; Kranenburg, O; Lennerz, JK; Naxerova, K

Published Date

  • July 2020

Published In

Volume / Issue

  • 52 / 7

Start / End Page

  • 692 - 700

PubMed ID

  • 32451459

Pubmed Central ID

  • PMC7343611

Electronic International Standard Serial Number (EISSN)

  • 1546-1718

Digital Object Identifier (DOI)

  • 10.1038/s41588-020-0633-2


  • eng

Conference Location

  • United States