Recent research has highlighted a strong correlation between tissue-specific cancer risk and the lifetime number of tissue-specific stem-cell divisions. Whether such correlation implies a high unavoidable intrinsic cancer risk has become a key public health debate with the dissemination of the ‘bad luck’ hypothesis. Here we provide evidence that intrinsic risk factors contribute only modestly (less than ~10–30% of lifetime risk) to cancer development. First, we demonstrate that the correlation between stem-cell division and cancer risk does not distinguish between the effects of intrinsic and extrinsic factors. We then show that intrinsic risk is better estimated by the lower bound risk controlling for total stem-cell divisions. Finally, we show that the rates of endogenous mutation accumulation by intrinsic processes are not sufficient to account for the observed cancer risks. Collectively, we conclude that cancer risk is heavily influenced by extrinsic factors. These results are important for strategizing cancer prevention, research and public health.

Discriminating the contribution of unmodifiable random intrinsic DNA replication errors (‘bad luck’) to cancer development from those of other factors is critical for understanding cancer in humans and for directing public resources aimed at reducing the burden of cancer. Here, we review and highlight the evidence that demonstrates cancer causation is multifactorial, and provide several important examples where modification of risk factors has achieved cancer prevention. Furthermore, we stress the need and opportunities to advance understanding of cancer aetiology through integration of interaction effects between risk factors when estimating the contribution of individual and joint factors to cancer burden in a population. We posit that non-intrinsic factors drive most cancer risk, and stress the need for cancer prevention.

Acid ceramidase inhibition promotes YAP/TAZ degradation to inactivate fibroblasts, decrease matrix stiffness, and reduce fibrosis in mice.