Lack of Correlation between Stem-Cell Proliferation and Radiation- or Smoking-Associated Cancer Risk

Background A recent paper by Tomasetti and Vogelstein (Science 2015 347 78–81) suggested that the variation in natural cancer risk was largely explained by the total number of stem-cell divisions, and that most cancers arose by chance. They proposed an extra-risk score as way of distinguishing the effects of the stochastic, replicative component of cancer risk from other causative factors, specifically those due to the external environment and inherited mutations. Objectives We tested the hypothesis raised by Tomasetti and Vogelstein by assessing the degree of correlation of stem cell divisions and their extra-risk score with radiation- and tobacco-associated cancer risk. Methods We fitted a variety of linear and log-linear models to data on stem cell divisions per year and cumulative stem cell divisions over lifetime and natural cancer risk, some taken from the paper of Tomasetti and Vogelstein, augmented using current US lifetime cancer risk data, and also radiation- and tobacco-associated cancer risk. Results The data assembled by Tomasetti and Vogelstein, as augmented here, are inconsistent with the power-of-age relationship commonly observed for cancer incidence and the predictions of a multistage carcinogenesis model, if one makes the strong assumption of homogeneity of numbers of driver mutations across cancer sites. Analysis of the extra-risk score and various other measures (number of stem cell divisions per year, cumulative number of stem cell divisions over life) considered by Tomasetti and Vogelstein suggests that these are poorly predictive of currently available estimates of radiation- or smoking-associated cancer risk–for only one out of 37 measures or logarithmic transformations thereof is there a statistically significant correlation (p