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

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 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 bi...
Source: Carcinogenesis - Category: Cancer & Oncology Authors: Tags: Original Manuscript Source Type: research