Identification of a signature of evolutionarily conserved stress-induced mutagenesis in cancer
The clustering of mutations observed in cancer cells is reminiscent of the stress-induced mutagenesis (SIM) response in bacteria. Bacteria deploy SIM when faced with DNA double-strand breaks in the presence of conditions that elicit an SOS response. SIM employs DinB, the evolutionary precursor to hu...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2022-09-01
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| Series: | Frontiers in Genetics |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fgene.2022.932763/full |
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| author | Luis H. Cisneros Luis H. Cisneros Charles Vaske Kimberly J. Bussey Kimberly J. Bussey Kimberly J. Bussey |
| author_facet | Luis H. Cisneros Luis H. Cisneros Charles Vaske Kimberly J. Bussey Kimberly J. Bussey Kimberly J. Bussey |
| author_sort | Luis H. Cisneros |
| collection | DOAJ |
| description | The clustering of mutations observed in cancer cells is reminiscent of the stress-induced mutagenesis (SIM) response in bacteria. Bacteria deploy SIM when faced with DNA double-strand breaks in the presence of conditions that elicit an SOS response. SIM employs DinB, the evolutionary precursor to human trans-lesion synthesis (TLS) error-prone polymerases, and results in mutations concentrated around DNA double-strand breaks with an abundance that decays with distance. We performed a quantitative study on single nucleotide variant calls for whole-genome sequencing data from 1950 tumors, non-inherited mutations from 129 normal samples, and acquired mutations in 3 cell line models of stress-induced adaptive mutation. We introduce statistical methods to identify mutational clusters, quantify their shapes and tease out the potential mechanism that produced them. Our results show that mutations in both normal and cancer samples are indeed clustered and have shapes indicative of SIM. Clusters in normal samples occur more often in the same genomic location across samples than in cancer suggesting loss of regulation over the mutational process during carcinogenesis. Additionally, the signatures of TLS contribute the most to mutational cluster formation in both patient samples as well as experimental models of SIM. Furthermore, a measure of cluster shape heterogeneity was associated with cancer patient survival with a hazard ratio of 5.744 (Cox Proportional Hazard Regression, 95% CI: 1.824–18.09). Our results support the conclusion that the ancient and evolutionary-conserved adaptive mutation response found in bacteria is a source of genomic instability in cancer. Biological adaptation through SIM might explain the ability of tumors to evolve in the face of strong selective pressures such as treatment and suggests that the conventional ‘hit it hard’ approaches to therapy could prove themselves counterproductive. |
| first_indexed | 2024-04-11T20:05:34Z |
| format | Article |
| id | doaj.art-1e0096848f4b411d81c206a673f4f554 |
| institution | Directory Open Access Journal |
| issn | 1664-8021 |
| language | English |
| last_indexed | 2024-04-11T20:05:34Z |
| publishDate | 2022-09-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Genetics |
| spelling | doaj.art-1e0096848f4b411d81c206a673f4f5542022-12-22T04:05:20ZengFrontiers Media S.A.Frontiers in Genetics1664-80212022-09-011310.3389/fgene.2022.932763932763Identification of a signature of evolutionarily conserved stress-induced mutagenesis in cancerLuis H. Cisneros0Luis H. Cisneros1Charles Vaske2Kimberly J. Bussey3Kimberly J. Bussey4Kimberly J. Bussey5NantOmics, LLC, Santa Cruz, CA, United StatesThe Beyond Center for Fundamental Concepts in Science, Arizona State University, Tempe, AZ, United StatesNantOmics, LLC, Santa Cruz, CA, United StatesNantOmics, LLC, Santa Cruz, CA, United StatesThe Beyond Center for Fundamental Concepts in Science, Arizona State University, Tempe, AZ, United StatesPrecision Medicine, Midwestern University, Glendale, AZ, United StatesThe clustering of mutations observed in cancer cells is reminiscent of the stress-induced mutagenesis (SIM) response in bacteria. Bacteria deploy SIM when faced with DNA double-strand breaks in the presence of conditions that elicit an SOS response. SIM employs DinB, the evolutionary precursor to human trans-lesion synthesis (TLS) error-prone polymerases, and results in mutations concentrated around DNA double-strand breaks with an abundance that decays with distance. We performed a quantitative study on single nucleotide variant calls for whole-genome sequencing data from 1950 tumors, non-inherited mutations from 129 normal samples, and acquired mutations in 3 cell line models of stress-induced adaptive mutation. We introduce statistical methods to identify mutational clusters, quantify their shapes and tease out the potential mechanism that produced them. Our results show that mutations in both normal and cancer samples are indeed clustered and have shapes indicative of SIM. Clusters in normal samples occur more often in the same genomic location across samples than in cancer suggesting loss of regulation over the mutational process during carcinogenesis. Additionally, the signatures of TLS contribute the most to mutational cluster formation in both patient samples as well as experimental models of SIM. Furthermore, a measure of cluster shape heterogeneity was associated with cancer patient survival with a hazard ratio of 5.744 (Cox Proportional Hazard Regression, 95% CI: 1.824–18.09). Our results support the conclusion that the ancient and evolutionary-conserved adaptive mutation response found in bacteria is a source of genomic instability in cancer. Biological adaptation through SIM might explain the ability of tumors to evolve in the face of strong selective pressures such as treatment and suggests that the conventional ‘hit it hard’ approaches to therapy could prove themselves counterproductive.https://www.frontiersin.org/articles/10.3389/fgene.2022.932763/fullcancerstress induced mutagenesistrans-lesion DNA synthesisevolutionmutational clusterscancer evolution |
| spellingShingle | Luis H. Cisneros Luis H. Cisneros Charles Vaske Kimberly J. Bussey Kimberly J. Bussey Kimberly J. Bussey Identification of a signature of evolutionarily conserved stress-induced mutagenesis in cancer Frontiers in Genetics cancer stress induced mutagenesis trans-lesion DNA synthesis evolution mutational clusters cancer evolution |
| title | Identification of a signature of evolutionarily conserved stress-induced mutagenesis in cancer |
| title_full | Identification of a signature of evolutionarily conserved stress-induced mutagenesis in cancer |
| title_fullStr | Identification of a signature of evolutionarily conserved stress-induced mutagenesis in cancer |
| title_full_unstemmed | Identification of a signature of evolutionarily conserved stress-induced mutagenesis in cancer |
| title_short | Identification of a signature of evolutionarily conserved stress-induced mutagenesis in cancer |
| title_sort | identification of a signature of evolutionarily conserved stress induced mutagenesis in cancer |
| topic | cancer stress induced mutagenesis trans-lesion DNA synthesis evolution mutational clusters cancer evolution |
| url | https://www.frontiersin.org/articles/10.3389/fgene.2022.932763/full |
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