Among the 3,000 mutagens in tobacco smoke is benzo[a]pyrene diol epoxide (BPDE). This compound forms bulky adducts on G residues in DNA, leading mainly to G→T mutations, which are much more common in lung cancer than in other cancers. Furthermore, in the p53 ( TP53 ) oncogene, BPDE interacts preferentially with the specific G residues that are frequently mutated in the lung cancers of smokers. So, BPDE stands convicted — an open and shut case — that is, until Rodin and Rodin reopened it.

In their most recent work, the authors examined a weak link in the BPDE story — the p53 mutation spectrum in lung cancers from non-smokers. This has been investigated previously, but with small sample numbers. Rodin and Rodin do report evidence for an overall difference in the p53 mutation spectrum between smokers and non-smokers. However, this difference can be accounted for by DNA strand-specific differences, which could reflect the activities of strand-specific DNA repair mechanisms in smokers versus non-smokers. They find no evidence that G→T mutations arise more frequently in smoke-exposed versus non-exposed cancer tissue. And, strikingly, one particular G→T mutation is prevalent not only in lung cancer but also in other tumours such as colon cancer, suggesting that this mutation is found frequently because it is more tumorigenic than other mutations — not because it arises more often.

Rodin and Rodin conclude that physiological stresses in smoke-exposed tissue lead to selection pressures on cells that, in turn, affect the type of mutations that are identified in lung cancers. So mutagenesis by BPDE seems less important, although it might still have a role in lung cancer — after all, there's no smoke without fire.