Abstract
Carcinogenesis is an evolutionary process whereby cells accumulate multiple mutations. Besides the ‘driver mutations’ that cause the disease, cells also accumulate a number of other mutations with seemingly no direct role in this evolutionary process. They are called passenger mutations. While it has been argued that passenger mutations render tumours more fragile due to reduced fitness, the role of passenger mutations remains understudied. Using evolutionary computational models, we demonstrate that in the context of tumour suppressor gene inactivation (and hence fitness valley crossing), the presence of passenger mutations can accelerate the rate of evolution by reducing overall population fitness and increasing the relative fitness of intermediate mutants in the fitness valley crossing pathway. Hence, the baseline rate of tumour suppressor gene inactivation might be faster than previously thought. Conceptually, parallels are found in the field of turbulence and pattern formation, where instabilities can be driven by perturbations that are damped (disadvantageous), but provide a richer set of pathways such that a system can achieve some desired goal more readily. This highlights, through a number of novel parallels, the relevance of physical sciences in oncology.
| Original language | English (US) |
|---|---|
| Article number | 20170967 |
| Journal | Journal of the Royal Society Interface |
| Volume | 15 |
| Issue number | 143 |
| DOIs | |
| State | Published - Jan 1 2018 |
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Keywords
- Evolutionary theory
- Fitness valley
- Mathematical models
- Tumour evolution
ASJC Scopus subject areas
- Biotechnology
- Biophysics
- Bioengineering
- Biomaterials
- Biochemistry
- Biomedical Engineering
Cite this
Passenger mutations can accelerate tumour suppressor gene inactivation in cancer evolution. / Wodarz, Dominik; Newell, Alan C; Komarova, Natalia L.
In: Journal of the Royal Society Interface, Vol. 15, No. 143, 20170967, 01.01.2018.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Passenger mutations can accelerate tumour suppressor gene inactivation in cancer evolution
AU - Wodarz, Dominik
AU - Newell, Alan C
AU - Komarova, Natalia L.
PY - 2018/1/1
Y1 - 2018/1/1
N2 - Carcinogenesis is an evolutionary process whereby cells accumulate multiple mutations. Besides the ‘driver mutations’ that cause the disease, cells also accumulate a number of other mutations with seemingly no direct role in this evolutionary process. They are called passenger mutations. While it has been argued that passenger mutations render tumours more fragile due to reduced fitness, the role of passenger mutations remains understudied. Using evolutionary computational models, we demonstrate that in the context of tumour suppressor gene inactivation (and hence fitness valley crossing), the presence of passenger mutations can accelerate the rate of evolution by reducing overall population fitness and increasing the relative fitness of intermediate mutants in the fitness valley crossing pathway. Hence, the baseline rate of tumour suppressor gene inactivation might be faster than previously thought. Conceptually, parallels are found in the field of turbulence and pattern formation, where instabilities can be driven by perturbations that are damped (disadvantageous), but provide a richer set of pathways such that a system can achieve some desired goal more readily. This highlights, through a number of novel parallels, the relevance of physical sciences in oncology.
AB - Carcinogenesis is an evolutionary process whereby cells accumulate multiple mutations. Besides the ‘driver mutations’ that cause the disease, cells also accumulate a number of other mutations with seemingly no direct role in this evolutionary process. They are called passenger mutations. While it has been argued that passenger mutations render tumours more fragile due to reduced fitness, the role of passenger mutations remains understudied. Using evolutionary computational models, we demonstrate that in the context of tumour suppressor gene inactivation (and hence fitness valley crossing), the presence of passenger mutations can accelerate the rate of evolution by reducing overall population fitness and increasing the relative fitness of intermediate mutants in the fitness valley crossing pathway. Hence, the baseline rate of tumour suppressor gene inactivation might be faster than previously thought. Conceptually, parallels are found in the field of turbulence and pattern formation, where instabilities can be driven by perturbations that are damped (disadvantageous), but provide a richer set of pathways such that a system can achieve some desired goal more readily. This highlights, through a number of novel parallels, the relevance of physical sciences in oncology.
KW - Evolutionary theory
KW - Fitness valley
KW - Mathematical models
KW - Tumour evolution
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UR - http://www.scopus.com/inward/citedby.url?scp=85048321586&partnerID=8YFLogxK
U2 - 10.1098/rsif.2017.0967
DO - 10.1098/rsif.2017.0967
M3 - Article
C2 - 29875280
AN - SCOPUS:85048321586
VL - 15
JO - Journal of the Royal Society Interface
JF - Journal of the Royal Society Interface
SN - 1742-5689
IS - 143
M1 - 20170967
ER -