Carcinogen-specific mutations in preferred Ras-Raf pathway oncogenes directed by strand bias
| Autor: | Ross R. Keller, Edward J. Gunther, Amy Q. Lu, Alicia Hoke, David J. Feith, Shelley A. Gestl |
|---|---|
| Rok vydání: | 2016 |
| Předmět: |
Proto-Oncogene Proteins B-raf
0301 basic medicine Cancer Research Genotype Carcinogenesis 9 10-Dimethyl-1 2-benzanthracene DMBA Mutagenesis (molecular biology technique) Original Manuscript Mammary Neoplasms Animal Wnt1 Protein Biology medicine.disease_cause Proto-Oncogene Proteins p21(ras) Mice 03 medical and health sciences Biomarkers Tumor medicine Animals Humans HRAS Mammary tumor Mutation Oncogene Cancer General Medicine medicine.disease Molecular biology Gene Expression Regulation Neoplastic 030104 developmental biology Sense strand Ethylnitrosourea Carcinogens Cancer research Female |
| Zdroj: | Carcinogenesis. 37:810-816 |
| ISSN: | 1460-2180 0143-3334 |
| DOI: | 10.1093/carcin/bgw061 |
| Popis: | Carcinogen exposures inscribe mutation patterns on cancer genomes and sometimes bias the acquisition of driver mutations toward preferred oncogenes, potentially dictating sensitivity to targeted agents. Whether and how carcinogen-specific mutation patterns direct activation of preferred oncogenes remains poorly understood. Here, mouse models of breast cancer were exploited to uncover a mechanistic link between strand-biased mutagenesis and oncogene preference. When chemical carcinogens were employed during Wnt1-initiated mammary tumorigenesis, exposure to either 7,12-dimethylbenz(a)anthracene (DMBA) or N-ethyl-N-nitrosourea (ENU) dramatically accelerated tumor onset. Mammary tumors that followed DMBA exposure nearly always activated the Ras pathway via somatic Hras(CAA61CTA) mutations. Surprisingly, mammary tumors that followed ENU exposure typically lacked Hras mutations, and instead activated the Ras pathway downstream via Braf(GTG636GAG) mutations. Hras(CAA61CTA) mutations involve an A-to-T change on the sense strand, whereas Braf(GTG636GAG) mutations involve an inverse T-to-A change, suggesting that strand-biased mutagenesis may determine oncogene preference. To examine this possibility further, we turned to an alternative Wnt-driven tumor model in which carcinogen exposures augment a latent mammary tumor predisposition in Apc(min) mice. DMBA and ENU each accelerated mammary tumor onset in Apc(min) mice by introducing somatic, "second-hit" Apc mutations. Consistent with our strand bias model, DMBA and ENU generated strikingly distinct Apc mutation patterns, including stringently strand-inverse mutation signatures at A:T sites. Crucially, these contrasting signatures precisely match those proposed to confer bias toward Hras(CAA61CTA) versus Braf(GTG636GAG) mutations in the original tumor sets. Our findings highlight a novel mechanism whereby exposure history acts through strand-biased mutagenesis to specify activation of preferred oncogenes. |
| Databáze: | OpenAIRE |
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