title: Carcinogen-specific mutations in preferred Ras-Raf pathway oncogenes directed by strand bias.
abstract: 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.
authors.affiliation: Jake Gittlen Laboratories for Cancer Research and.|Penn State Hershey Cancer Institute, Pennsylvania State University College of Medicine, Hershey, PA 17033, USA.
authors.forename: Ross R
authors.initials: RR
authors.lastname: Keller
authors.affiliation: Jake Gittlen Laboratories for Cancer Research and.|Penn State Hershey Cancer Institute, Pennsylvania State University College of Medicine, Hershey, PA 17033, USA.
authors.forename: Shelley A
authors.initials: SA
authors.lastname: Gestl
authors.affiliation: Jake Gittlen Laboratories for Cancer Research and.|Penn State Hershey Cancer Institute, Pennsylvania State University College of Medicine, Hershey, PA 17033, USA.
authors.forename: Amy Q
authors.initials: AQ
authors.lastname: Lu
authors.affiliation: Jake Gittlen Laboratories for Cancer Research and.|Penn State Hershey Cancer Institute, Pennsylvania State University College of Medicine, Hershey, PA 17033, USA.
authors.forename: Alicia
authors.initials: A
authors.lastname: Hoke
authors.affiliation: Division of Hematology and the Cancer Center, University of Virginia School of Medicine, Charlottesville, VA 22908, USA and.
authors.forename: David J
authors.initials: DJ
authors.lastname: Feith
authors.affiliation: Jake Gittlen Laboratories for Cancer Research and.|Penn State Hershey Cancer Institute, Pennsylvania State University College of Medicine, Hershey, PA 17033, USA.|Department of Medicine (Hematology/Oncology), Pennsylvania State University College of Medicine, Hershey, PA 17033, USA.
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Gunther
mesh_terms: D015127:9,10-Dimethyl-1,2-benzanthracene / Q000633:toxicity; D000818:Animals; D014408:Biomarkers, Tumor / Q000096:biosynthesis / Q000235:genetics; D063646:Carcinogenesis / Q000187:drug effects*; D002273:Carcinogens / Q000633:toxicity*; D005038:Ethylnitrosourea / Q000633:toxicity; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D005838:Genotype; D006801:Humans; D015674:Mammary Neoplasms, Animal / Q000139:chemically induced / Q000235:genetics*; D051379:Mice; D009154:Mutation / Q000187:drug effects; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics*; D051155:Wnt1 Protein / Q000235:genetics
chemical_list: D014408:Biomarkers, Tumor; D002273:Carcinogens; D051155:Wnt1 Protein; C495246:Wnt1 protein, mouse; D015127:9,10-Dimethyl-1,2-benzanthracene; C482120:Braf protein, mouse; D048493:Proto-Oncogene Proteins B-raf; C495971:Hras protein, mouse; D016283:Proto-Oncogene Proteins p21(ras); D005038:Ethylnitrosourea