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Cancer risk

Debating the odds

Nature Reviews Cancer volume 16, page 68 (2016)Cite this article

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There are many curiosities in cancer incidence rates that cannot be explained by exposure to exogenous carcinogens or inherited susceptibility. For example, cancer of the small intestine is very rare, yet cancers of other regions of the gastrointestinal tract are common. Tomasetti and Vogelstein proposed that DNA replication errors in stem cells, which occur independently of environmental and inherited factors, could be an important intrinsic source of tumour-initiating events. This postulate was based on the argument that stem cells are the only cells in which mutations can cause tumour initiation. The authors identified 31 tissues in which the number of stem cell divisions was satisfactorily quantified. The total number of stem cell divisions over a lifetime was strongly correlated with the lifetime risk of developing cancer in those 31 tissues. Their data suggested that 65% (with a 95% confidence interval of 39–81%) of the variation in cancer risk could be explained by the total number of stem cell divisions in a tissue.

The extra risk score (ERS) was formulated as the lifetime cancer risk plus the total number of stem cell divisions and this was used to classify tumours from the included tissues relative to other tissues. The nine tumour types with the highest ERS were known to be associated with exogenous carcinogens and inherited risk factors. But intrinsic stem cell replication errors were still found to be an important risk factor in these tumours. However, the relative risk of the 22 tumour types with lower ERS was considered to be more strongly affected by intrinsic replication-induced alterations in stem cells than by exogenous factors. These tumours included many paediatric cancers, rarities such as small intestine cancer, but also others that are associated with exogenous risk factors.

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References

  1. Tomasetti, C. & Vogelstein, B. Variation in cancer risk among tissues can be explained by the number of stem cell divisions. Science 347, 78–81 (2015)

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  2. Wu, S. et al. Substantial contribution of extrinsic risk factors to cancer development. Nature 529, 43–47 (2016)

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Authors
  1. Gemma K. Alderton
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Alderton, G. Debating the odds. Nat Rev Cancer 16, 68 (2016). https://doi.org/10.1038/nrc.2016.5

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