Carcinogen-specific mutations in preferred Ras-Raf pathway oncogenes directed by strand bias

Ross R. Keller, Shelley A. Gestl, Amy Q. Lu, Alicia Hoke, David J. Feith, Edward Gunther

Research output: Contribution to journalArticle

2 Citations (Scopus)

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 carcinogenspecific 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 HrasCAA61CTA mutations. Surprisingly, mammary tumors that followed ENU exposure typically lacked Hras mutations, and instead activated the Ras pathway downstream via BrafGTG636GAG mutations. HrasCAA61CTA mutations involve an A-to-T change on the sense strand, whereas BrafGTG636GAG 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 Apcmin mice. DMBA and ENU each accelerated mammary tumor onset in Apcmin 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 HrasCAA61CTA versus BrafGTG636GAG 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.

Original languageEnglish (US)
Pages (from-to)810-816
Number of pages7
JournalCarcinogenesis
Volume37
Issue number8
DOIs
StatePublished - Aug 1 2016

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Oncogenes
Carcinogens
Mutation
Ethylnitrosourea
9,10-Dimethyl-1,2-benzanthracene
Breast Neoplasms
Mutagenesis
Neoplasms
Carcinogenesis
Breast
History
Genome

All Science Journal Classification (ASJC) codes

  • Cancer Research

Cite this

Keller, Ross R. ; Gestl, Shelley A. ; Lu, Amy Q. ; Hoke, Alicia ; Feith, David J. ; Gunther, Edward. / Carcinogen-specific mutations in preferred Ras-Raf pathway oncogenes directed by strand bias. In: Carcinogenesis. 2016 ; Vol. 37, No. 8. pp. 810-816.
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Carcinogen-specific mutations in preferred Ras-Raf pathway oncogenes directed by strand bias. / Keller, Ross R.; Gestl, Shelley A.; Lu, Amy Q.; Hoke, Alicia; Feith, David J.; Gunther, Edward.

In: Carcinogenesis, Vol. 37, No. 8, 01.08.2016, p. 810-816.

Research output: Contribution to journalArticle

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