Tug-of-war between driver and passenger mutations in cancer and other adaptive processes
Cancer progression is an example of a rapid adaptive process where evolving new traits is essential for survival and requires a high mutation rate. Precancerous cells acquire a few key mutations that drive rapid population growth and carcinogenesis. Cancer genomics demonstrates that these few driver...
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| Format: | Article |
| Language: | en_US |
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National Academy of Sciences (U.S.)
2015
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| Online Access: | http://hdl.handle.net/1721.1/96468 https://orcid.org/0000-0002-0785-5410 |
| _version_ | 1811072845221986304 |
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| author | McFarland, Christopher D. Mirny, Leonid A. Korolev, Kirill Sergeevich |
| author2 | Institute for Medical Engineering and Science |
| author_facet | Institute for Medical Engineering and Science McFarland, Christopher D. Mirny, Leonid A. Korolev, Kirill Sergeevich |
| author_sort | McFarland, Christopher D. |
| collection | MIT |
| description | Cancer progression is an example of a rapid adaptive process where evolving new traits is essential for survival and requires a high mutation rate. Precancerous cells acquire a few key mutations that drive rapid population growth and carcinogenesis. Cancer genomics demonstrates that these few driver mutations occur alongside thousands of random passenger mutations—a natural consequence of cancer’s elevated mutation rate. Some passengers are deleterious to cancer cells, yet have been largely ignored in cancer research. In population genetics, however, the accumulation of mildly deleterious mutations has been shown to cause population meltdown. Here we develop a stochastic population model where beneficial drivers engage in a tug-of-war with frequent mildly deleterious passengers. These passengers present a barrier to cancer progression describable by a critical population size, below which most lesions fail to progress, and a critical mutation rate, above which cancers melt down. We find support for this model in cancer age–incidence and cancer genomics data that also allow us to estimate the fitness advantage of drivers and fitness costs of passengers. We identify two regimes of adaptive evolutionary dynamics and use these regimes to understand successes and failures of different treatment strategies. A tumor’s load of deleterious passengers can explain previously paradoxical treatment outcomes and suggest that it could potentially serve as a biomarker of response to mutagenic therapies. The collective deleterious effect of passengers is currently an unexploited therapeutic target. We discuss how their effects might be exacerbated by current and future therapies. |
| first_indexed | 2024-09-23T09:16:40Z |
| format | Article |
| id | mit-1721.1/96468 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T09:16:40Z |
| publishDate | 2015 |
| publisher | National Academy of Sciences (U.S.) |
| record_format | dspace |
| spelling | mit-1721.1/964682022-09-26T11:09:53Z Tug-of-war between driver and passenger mutations in cancer and other adaptive processes McFarland, Christopher D. Mirny, Leonid A. Korolev, Kirill Sergeevich Institute for Medical Engineering and Science Massachusetts Institute of Technology. Department of Physics Massachusetts Institute of Technology. School of Engineering Mirny, Leonid A. Korolev, Kirill Sergeevich Cancer progression is an example of a rapid adaptive process where evolving new traits is essential for survival and requires a high mutation rate. Precancerous cells acquire a few key mutations that drive rapid population growth and carcinogenesis. Cancer genomics demonstrates that these few driver mutations occur alongside thousands of random passenger mutations—a natural consequence of cancer’s elevated mutation rate. Some passengers are deleterious to cancer cells, yet have been largely ignored in cancer research. In population genetics, however, the accumulation of mildly deleterious mutations has been shown to cause population meltdown. Here we develop a stochastic population model where beneficial drivers engage in a tug-of-war with frequent mildly deleterious passengers. These passengers present a barrier to cancer progression describable by a critical population size, below which most lesions fail to progress, and a critical mutation rate, above which cancers melt down. We find support for this model in cancer age–incidence and cancer genomics data that also allow us to estimate the fitness advantage of drivers and fitness costs of passengers. We identify two regimes of adaptive evolutionary dynamics and use these regimes to understand successes and failures of different treatment strategies. A tumor’s load of deleterious passengers can explain previously paradoxical treatment outcomes and suggest that it could potentially serve as a biomarker of response to mutagenic therapies. The collective deleterious effect of passengers is currently an unexploited therapeutic target. We discuss how their effects might be exacerbated by current and future therapies. National Cancer Institute (U.S.) (Grant U54CA143874) MIT Department of Physics Pappalardo Program 2015-04-08T18:47:06Z 2015-04-08T18:47:06Z 2014-10 2014-03 Article http://purl.org/eprint/type/JournalArticle 0027-8424 1091-6490 http://hdl.handle.net/1721.1/96468 McFarland, Christopher D., Leonid A. Mirny, and Kirill S. Korolev. “Tug-of-War Between Driver and Passenger Mutations in Cancer and Other Adaptive Processes.” Proceedings of the National Academy of Sciences 111, no. 42 (October 2, 2014): 15138–15143. https://orcid.org/0000-0002-0785-5410 en_US http://dx.doi.org/10.1073/pnas.1404341111 Proceedings of the National Academy of Sciences of the United States of America Article is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use. application/pdf National Academy of Sciences (U.S.) National Academy of Sciences (U.S.) |
| spellingShingle | McFarland, Christopher D. Mirny, Leonid A. Korolev, Kirill Sergeevich Tug-of-war between driver and passenger mutations in cancer and other adaptive processes |
| title | Tug-of-war between driver and passenger mutations in cancer and other adaptive processes |
| title_full | Tug-of-war between driver and passenger mutations in cancer and other adaptive processes |
| title_fullStr | Tug-of-war between driver and passenger mutations in cancer and other adaptive processes |
| title_full_unstemmed | Tug-of-war between driver and passenger mutations in cancer and other adaptive processes |
| title_short | Tug-of-war between driver and passenger mutations in cancer and other adaptive processes |
| title_sort | tug of war between driver and passenger mutations in cancer and other adaptive processes |
| url | http://hdl.handle.net/1721.1/96468 https://orcid.org/0000-0002-0785-5410 |
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