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Cited by 22Cancer Genomics and DiagnosticsEvolution and Genetic DynamicsMathematical Biology Tumor Growth

The somatic molecular evolution of cancer: Mutation, selection, and epistasis

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Dasari, Krishna, Somarelli, Jason A., Kumar, Sudhir, Townsend, Jeffrey P.·2021·Progress in Biophysics and Molecular Biology
DOI 10.1016/j.pbiomolbio.2021.08.003PMC PMC8819680
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Abstract

Cancer progression has been attributed to somatic changes in single-nucleotide variants, copy-number aberrations, loss of heterozygosity, chromosomal instability, epistatic interactions, and the tumor microenvironment. It is not entirely clear which of these changes are essential and which are ancillary to cancer. The dynamic nature of cancer evolution in a patient can be illuminated using several concepts and tools from classical evolutionary biology. Neutral mutation rates in cancer cells are calculable from genomic data such as synonymous mutations, and selective pressures are calculable from rates of fixation occurring beyond the expectation by neutral mutation and drift. However, these cancer effect sizes of mutations are complicated by epistatic interactions that can determine the likely sequence of gene mutations. In turn, longitudinal phylogenetic analyses of somatic cancer progression offer an opportunity to identify key moments in cancer evolution, relating the timing of driver mutations to corresponding landmarks in the clinical timeline. These analyses reveal temporal aspects of genetic and phenotypic change during tumorigenesis and across clinical timescales. Using a related framework, clonal deconvolution, physical locations of clones, and their phylogenetic relations can be used to infer tumor migration histories. Additionally, genetic interactions with the tumor microenvironment can be analyzed with longstanding approaches applied to organismal genotype-by-environment interactions. Fitness landscapes for cancer evolution relating to genotype, phenotype, and environment could enable more accurate, personalized therapeutic strategies. An understanding of the trajectories underlying the evolution of neoplasms, primary, and metastatic tumors promises fundamental advances toward accurate and personalized predictions of therapeutic response.

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  • Cancer cells are subjected to high selection pressure due to their highly proliferative nature, favoring the acquisition of mutations that provide further growth advantages.

    “Furthermore, cancer cells are subjected to high selection pressure due to their highly proliferative nature, favoring the acquisition of mutations that provide further growth advantages (89).”

    From G-quadruplex-mediated genomic instability drives SNVs in cancer (2024) · cites this paper as [89]

    The Introduction’s “Genotype-by-environment interactions” section says environmental conditions select for cancer-cell traits that promote survival and proliferation. The “Hallmarks of cancer and cancer fitness landscapes” section also describes mutations that may be selectively advantageous. The cited paper does not establish that cancer cells face high selection pressure *because* they are highly proliferative; it describes proliferation as a trait subject to selection. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

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Cited by

Sorted by citations

Authors
Dasari, K., Somarelli, J. A., Kumar, S., & Townsend, J. P.
Affiliations
  • Yale University (US)
  • Duke Medical Center (US)
  • Temple University (US)
  • Yale Cancer Center (US)
Corresponding author
Townsend, Jeffrey P.
ORCID
Venue
Progress in Biophysics and Molecular Biology
Publisher
Elsevier BV
Published
2021-10
Volume
165
Pages
56-65
ISSN
0079-6107 (ISSN-L)
DOI
10.1016/j.pbiomolbio.2021.08.003
PMC
PMC8819680
OpenAlex
W3193184577
Cited by
22
References
137
Citations by year
2026: 3 · 2025: 6 · 2024: 4 · 2023: 4 · 2022: 5
FWCI
1.29
Type
journal article
Language
en
Open access
Licence
Locations
  • Progress in Biophysics and Molecular Biology (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • Yale University
  • Society for Molecular Biology and Evolution
  • National Science Foundation (1934848, 1934860)
  • National Institutes of Health (1R01LM013385)
  • U.S. Department of Defense (W81XWH-18-1-0189)
  • National Institute of Dental and Craniofacial Research (1P50DE030707)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Evolution and Genetic Dynamics
  • Physical Sciences › Mathematics › Modeling and Simulation › Mathematical Biology Tumor Growth
Keywords
tumor progression, single nucleotide variants, copy number alterations, loss of heterozygosity, chromosomal instability, epistasis, fixation rate, tumor cell migration, tumor microenvironment, fitness landscape, driver mutations, metastasis, precision oncology
MeSH terms
Epistasis, Genetic, Humans, Models, Genetic, Mutation, Neoplasms, Phylogeny, Evolution, Molecular, Tumor Microenvironment

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