Analysis of Mutations and Dysregulated Pathways Unravels Carcinogenic Effect and Clinical Actionability of Mutational Processes
Somatic mutations accumulate over time in cancer cells as a consequence of mutational processes. However, the role of mutational processes in carcinogenesis remains poorly understood. Here, we infer the causal relationship between mutational processes and somatic mutations in 5,828 samples spanning...
Guardado en:
| Autores principales: | , , , , , , , , , , , |
|---|---|
| Formato: | article |
| Lenguaje: | EN |
| Publicado: |
Frontiers Media S.A.
2021
|
| Materias: | |
| Acceso en línea: | https://doaj.org/article/887b25e876c84bf39e9988d4dc05e387 |
| Etiquetas: |
Agregar Etiqueta
Sin Etiquetas, Sea el primero en etiquetar este registro!
|
| id |
oai:doaj.org-article:887b25e876c84bf39e9988d4dc05e387 |
|---|---|
| record_format |
dspace |
| spelling |
oai:doaj.org-article:887b25e876c84bf39e9988d4dc05e3872021-11-30T18:39:50ZAnalysis of Mutations and Dysregulated Pathways Unravels Carcinogenic Effect and Clinical Actionability of Mutational Processes2296-634X10.3389/fcell.2021.768981https://doaj.org/article/887b25e876c84bf39e9988d4dc05e3872021-11-01T00:00:00Zhttps://www.frontiersin.org/articles/10.3389/fcell.2021.768981/fullhttps://doaj.org/toc/2296-634XSomatic mutations accumulate over time in cancer cells as a consequence of mutational processes. However, the role of mutational processes in carcinogenesis remains poorly understood. Here, we infer the causal relationship between mutational processes and somatic mutations in 5,828 samples spanning 34 cancer subtypes. We found most mutational processes cause abundant recurrent mutations in cancer genes, while exceptionally ultraviolet exposure and altered activity of the error-prone polymerase bring a large number of recurrent non-driver mutations. Furthermore, some mutations are specifically induced by a certain mutational process, such as IDH1 p.R132H which is mainly caused by spontaneous deamination of 5-methylcytosine. At the pathway level, clock-like mutational processes extensively trigger mutations to dysregulate cancer signal transduction pathways. In addition, APOBEC mutational process destroys DNA double-strand break repair pathway, and bladder cancer patients with high APOBEC activity, though with homologous recombination proficient, show a significantly longer overall survival with platinum regimens. These findings help to understand how mutational processes act on the genome to promote carcinogenesis, and further, presents novel insights for cancer prevention and treatment, as our results showing, APOBEC mutagenesis and HRD synergistically contributed to the clinical benefits of platinum-based treatment.Zedong JiangGaoming LiaoYiran YangYujia LanLiwen XuMin YanYao ZhouJiali ZhuWei LiuJing BaiJing BaiYun XiaoYun XiaoXia LiXia LiFrontiers Media S.A.articlemutational processmutational signaturemutationhomologous recombination proficientAPOBEC mutational signatureBiology (General)QH301-705.5ENFrontiers in Cell and Developmental Biology, Vol 9 (2021) |
| institution |
DOAJ |
| collection |
DOAJ |
| language |
EN |
| topic |
mutational process mutational signature mutation homologous recombination proficient APOBEC mutational signature Biology (General) QH301-705.5 |
| spellingShingle |
mutational process mutational signature mutation homologous recombination proficient APOBEC mutational signature Biology (General) QH301-705.5 Zedong Jiang Gaoming Liao Yiran Yang Yujia Lan Liwen Xu Min Yan Yao Zhou Jiali Zhu Wei Liu Jing Bai Jing Bai Yun Xiao Yun Xiao Xia Li Xia Li Analysis of Mutations and Dysregulated Pathways Unravels Carcinogenic Effect and Clinical Actionability of Mutational Processes |
| description |
Somatic mutations accumulate over time in cancer cells as a consequence of mutational processes. However, the role of mutational processes in carcinogenesis remains poorly understood. Here, we infer the causal relationship between mutational processes and somatic mutations in 5,828 samples spanning 34 cancer subtypes. We found most mutational processes cause abundant recurrent mutations in cancer genes, while exceptionally ultraviolet exposure and altered activity of the error-prone polymerase bring a large number of recurrent non-driver mutations. Furthermore, some mutations are specifically induced by a certain mutational process, such as IDH1 p.R132H which is mainly caused by spontaneous deamination of 5-methylcytosine. At the pathway level, clock-like mutational processes extensively trigger mutations to dysregulate cancer signal transduction pathways. In addition, APOBEC mutational process destroys DNA double-strand break repair pathway, and bladder cancer patients with high APOBEC activity, though with homologous recombination proficient, show a significantly longer overall survival with platinum regimens. These findings help to understand how mutational processes act on the genome to promote carcinogenesis, and further, presents novel insights for cancer prevention and treatment, as our results showing, APOBEC mutagenesis and HRD synergistically contributed to the clinical benefits of platinum-based treatment. |
| format |
article |
| author |
Zedong Jiang Gaoming Liao Yiran Yang Yujia Lan Liwen Xu Min Yan Yao Zhou Jiali Zhu Wei Liu Jing Bai Jing Bai Yun Xiao Yun Xiao Xia Li Xia Li |
| author_facet |
Zedong Jiang Gaoming Liao Yiran Yang Yujia Lan Liwen Xu Min Yan Yao Zhou Jiali Zhu Wei Liu Jing Bai Jing Bai Yun Xiao Yun Xiao Xia Li Xia Li |
| author_sort |
Zedong Jiang |
| title |
Analysis of Mutations and Dysregulated Pathways Unravels Carcinogenic Effect and Clinical Actionability of Mutational Processes |
| title_short |
Analysis of Mutations and Dysregulated Pathways Unravels Carcinogenic Effect and Clinical Actionability of Mutational Processes |
| title_full |
Analysis of Mutations and Dysregulated Pathways Unravels Carcinogenic Effect and Clinical Actionability of Mutational Processes |
| title_fullStr |
Analysis of Mutations and Dysregulated Pathways Unravels Carcinogenic Effect and Clinical Actionability of Mutational Processes |
| title_full_unstemmed |
Analysis of Mutations and Dysregulated Pathways Unravels Carcinogenic Effect and Clinical Actionability of Mutational Processes |
| title_sort |
analysis of mutations and dysregulated pathways unravels carcinogenic effect and clinical actionability of mutational processes |
| publisher |
Frontiers Media S.A. |
| publishDate |
2021 |
| url |
https://doaj.org/article/887b25e876c84bf39e9988d4dc05e387 |
| work_keys_str_mv |
AT zedongjiang analysisofmutationsanddysregulatedpathwaysunravelscarcinogeniceffectandclinicalactionabilityofmutationalprocesses AT gaomingliao analysisofmutationsanddysregulatedpathwaysunravelscarcinogeniceffectandclinicalactionabilityofmutationalprocesses AT yiranyang analysisofmutationsanddysregulatedpathwaysunravelscarcinogeniceffectandclinicalactionabilityofmutationalprocesses AT yujialan analysisofmutationsanddysregulatedpathwaysunravelscarcinogeniceffectandclinicalactionabilityofmutationalprocesses AT liwenxu analysisofmutationsanddysregulatedpathwaysunravelscarcinogeniceffectandclinicalactionabilityofmutationalprocesses AT minyan analysisofmutationsanddysregulatedpathwaysunravelscarcinogeniceffectandclinicalactionabilityofmutationalprocesses AT yaozhou analysisofmutationsanddysregulatedpathwaysunravelscarcinogeniceffectandclinicalactionabilityofmutationalprocesses AT jializhu analysisofmutationsanddysregulatedpathwaysunravelscarcinogeniceffectandclinicalactionabilityofmutationalprocesses AT weiliu analysisofmutationsanddysregulatedpathwaysunravelscarcinogeniceffectandclinicalactionabilityofmutationalprocesses AT jingbai analysisofmutationsanddysregulatedpathwaysunravelscarcinogeniceffectandclinicalactionabilityofmutationalprocesses AT jingbai analysisofmutationsanddysregulatedpathwaysunravelscarcinogeniceffectandclinicalactionabilityofmutationalprocesses AT yunxiao analysisofmutationsanddysregulatedpathwaysunravelscarcinogeniceffectandclinicalactionabilityofmutationalprocesses AT yunxiao analysisofmutationsanddysregulatedpathwaysunravelscarcinogeniceffectandclinicalactionabilityofmutationalprocesses AT xiali analysisofmutationsanddysregulatedpathwaysunravelscarcinogeniceffectandclinicalactionabilityofmutationalprocesses AT xiali analysisofmutationsanddysregulatedpathwaysunravelscarcinogeniceffectandclinicalactionabilityofmutationalprocesses |
| _version_ |
1718406337234206720 |