A deterministic model for the occurrence and dynamics of multiple mutations in hierarchically organized tissues.

Benjamin Werner, David M Dingli, Arne Traulsen

Research output: Contribution to journalArticle

25 Citations (Scopus)

Abstract

Cancers are rarely caused by single mutations, but often develop as a result of the combined effects of multiple mutations. For most cells, the number of possible cell divisions is limited because of various biological constraints, such as progressive telomere shortening, cell senescence cascades or a hierarchically organized tissue structure. Thus, the risk of accumulating cells carrying multiple mutations is low. Nonetheless, many diseases are based on the accumulation of such multiple mutations. We model a general, hierarchically organized tissue by a multi-compartment approach, allowing any number of mutations within a cell. We derive closed solutions for the deterministic clonal dynamics and the reproductive capacity of single clones. Our results hold for the average dynamics in a hierarchical tissue characterized by an arbitrary combination of proliferation parameters. We show that hierarchically organized tissues strongly suppress cells carrying multiple mutations and derive closed solutions for the expected size and diversity of clonal populations founded by a single mutant within the hierarchy. We discuss the example of childhood acute lymphoblastic leukaemia in detail and find good agreement between our predicted results and recently observed clonal diversities in patients. This result can contribute to the explanation of very diverse mutation profiles observed by whole genome sequencing of many different cancers.

Original languageEnglish (US)
Pages (from-to)20130349
Number of pages1
JournalJournal of the Royal Society, Interface / the Royal Society
Volume10
Issue number85
StatePublished - Aug 6 2013

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Tissue
Mutation
Telomere Shortening
Genes
Cells
Cell Aging
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Cell Division
Neoplasms
Clone Cells
Cell Count
Genome
Population

ASJC Scopus subject areas

  • Medicine(all)

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A deterministic model for the occurrence and dynamics of multiple mutations in hierarchically organized tissues. / Werner, Benjamin; Dingli, David M; Traulsen, Arne.

In: Journal of the Royal Society, Interface / the Royal Society, Vol. 10, No. 85, 06.08.2013, p. 20130349.

Research output: Contribution to journalArticle

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