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

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 m...

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Published inNature genetics Vol. 52; no. 7; pp. 692 - 700
Main Authors Reiter, Johannes G., Hung, Wei-Ting, Lee, I-Hsiu, Nagpal, Shriya, Giunta, Peter, Degner, Sebastian, Liu, Gang, Wassenaar, Emma C. E., Jeck, William R., Taylor, Martin S., Farahani, Alexander A., Marble, Hetal D., Knott, Simon, Kranenburg, Onno, Lennerz, Jochen K., Naxerova, Kamila
Format Journal Article
LanguageEnglish
Published New York Nature Publishing Group US 01.07.2020
Nature Publishing Group
Subjects
45/77
631/208
631/67/322
Agriculture
Animal Genetics and Genomics
Biological diversity
Biomedical and Life Sciences
Biomedicine
Biopsy
Cancer Research
Cohort Studies
Colorectal cancer
Colorectal carcinoma
Colorectal Neoplasms - genetics
Colorectal Neoplasms - pathology
Disease Progression
Evolution
Gene Function
Genetic diversity
Genetic Heterogeneity
Genetic Variation
Heterogeneity
Human Genetics
Humans
Lesions
Liver
Lymph nodes
Lymphatic Metastasis - genetics
Lymphatic system
Mastectomy
Metastases
Metastasis
Models, Biological
Neoplasm Metastasis - genetics
Neoplasm Seeding
Patients
Phylogenetics
Phylogeny
Trees
Tumors
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Abstract 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. Analysis of metastases using a mathematical framework and multi-region sampling data shows that lymph node metastases have higher levels of intratumor heterogeneity than distant metastases, and that these form via different evolutionary mechanisms.
AbstractList 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.
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.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.
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. Analysis of metastases using a mathematical framework and multi-region sampling data shows that lymph node metastases have higher levels of intratumor heterogeneity than distant metastases, and that these form via different evolutionary mechanisms.
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. Analysis of metastases using a mathematical framework and multi-region sampling data shows that lymph node metastases have higher levels of intratumor heterogeneity than distant metastases, and that these form via different evolutionary mechanisms.
Audience Academic
Author Liu, Gang
Taylor, Martin S.
Farahani, Alexander A.
Hung, Wei-Ting
Naxerova, Kamila
Wassenaar, Emma C. E.
Jeck, William R.
Nagpal, Shriya
Giunta, Peter
Reiter, Johannes G.
Marble, Hetal D.
Knott, Simon
Kranenburg, Onno
Lee, I-Hsiu
Lennerz, Jochen K.
Degner, Sebastian
AuthorAffiliation 10 Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, California, USA
11 Division of Cancer and Imaging, University Medical Center Utrecht, Utrecht, Netherlands
8 Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA
1 Canary Center for Cancer Early Detection, Department of Radiology, Stanford University School of Medicine, Palo Alto, California, USA
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4 Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA
7 Department of Surgery, St. Antonius Hospital, Nieuwegein, Netherlands
6 Center for Applied Mathematics, Cornell University, Ithaca, New York, USA
2 Stanford Cancer Institute, Stanford University School of Medicine, Palo Alto, California, USA
9 Center for Integrated Diagnostics, Massachusetts General Hospital and Harvard Medical School, Boston, M
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BackLink https://www.ncbi.nlm.nih.gov/pubmed/32451459$$D View this record in MEDLINE/PubMed
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ContentType Journal Article
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Author contributions. J.G.R, K.N., W.H., P.G., G.L., I.L., S.D., E.W. analyzed data. J.G.R and S.N. developed the mathematical framework. W.H., P.G., G.L. performed experiments. W.R.J., M.S.T., A.A.F., H.D.M. and J.K.L. obtained and reviewed clinical samples and clinical data. S.K. and O.K. contributed to data interpretation. K.N. and J.G.R. designed the study. K.N., J.G.R and W.H. wrote the manuscript with input from all authors.
contributed equally
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Snippet Genetic diversity among metastases is poorly understood but contains important information about disease evolution at secondary sites. Here we investigate...
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SourceType Open Access Repository
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StartPage 692
SubjectTerms 45/77
631/208
631/67/322
Agriculture
Animal Genetics and Genomics
Biological diversity
Biomedical and Life Sciences
Biomedicine
Biopsy
Cancer Research
Cohort Studies
Colorectal cancer
Colorectal carcinoma
Colorectal Neoplasms - genetics
Colorectal Neoplasms - pathology
Disease Progression
Evolution
Gene Function
Genetic diversity
Genetic Heterogeneity
Genetic Variation
Heterogeneity
Human Genetics
Humans
Lesions
Liver
Lymph nodes
Lymphatic Metastasis - genetics
Lymphatic system
Mastectomy
Metastases
Metastasis
Models, Biological
Neoplasm Metastasis - genetics
Neoplasm Seeding
Patients
Phylogenetics
Phylogeny
Trees
Tumors
Title Lymph node metastases develop through a wider evolutionary bottleneck than distant metastases
URI https://link.springer.com/article/10.1038/s41588-020-0633-2
https://www.ncbi.nlm.nih.gov/pubmed/32451459
https://www.proquest.com/docview/2422405275
https://www.proquest.com/docview/2406950221
https://pubmed.ncbi.nlm.nih.gov/PMC7343611
Volume 52
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