Size matters: height, cell number and a person's risk of cancer

Abstract

The multistage model of carcinogenesis predicts cancer risk will increase with tissue size, since more cells provide more targets for oncogenic somatic mutation. However, this increase is not seen among mammal species of different sizes (Peto's paradox), a paradox argued to be due to larger species evolving added cancer suppression. If this explanation is correct, the cell number effect is still expected within species. Consistent with this, the hazard ratio for overall cancer risk per 10 cm increase in human height (HR₁₀) is about 1.1, indicating a 10% increase in cancer risk per 10 cm; however, an alternative explanation invokes an indirect effect of height, with factors that increase cancer risk independently increasing adult height. The data from four large-scale surveillance projects on 23 cancer categories were tested against quantitative predictions of the cell-number hypothesis, predictions that were accurately supported. For overall cancer risk the HR₁₀ predicted versus observed was 1.13 versus 1.12 for women and 1.11 versus 1.09 for men, suggesting that cell number variation provides a null hypothesis for assessing height effects. Melanoma showed an unexpectedly strong relationship to height, indicating an additional effect, perhaps due to an increasing cell division rate mediated through increasing IGF-I with height. Similarly, only about one-third of the higher incidence of non-reproductive cancers in men versus women can be explained by cell number. The cancer risks of obesity are not correlated with effects of height, consistent with different primary causation. The direct effect of height on cancer risk suggests caution in identifying height-related SNPs as cancer causing.

Keywords: GWAS and cancer; Peto's paradox; cancer and BMI; cancer and height; cell number; multistage carcinogenesis.

Figure 1.

The multistage model of carcinogenesis. In the simplest form of the multistage model, cancer originates following the accumulation in a single cell of a cancer-specific set of driver mutations. These mutations may be a mix of DNA mutations, epigenetic reprogramming and/or chromosomal alterations. The probability of cancer depends upon the number of dividing cells, the number of divisions that each cell lineage undergoes, the somatic mutation rate, and the number of driver mutations required.

Figure 2.

A comparison of the observed and predicted effect of height on the risk of specific cancers: the observed hazard ratio (HR₁₀) and 95% confidence interval linking a 10 cm increase in height to the increased risk of specific cancers, showing only cancers included in at least two of the target studies (for women [–25]; for men [–25]). The vertical lines illustrate: no effect of height (HR₁₀ = 1.00; solid line); the average HR₁₀ predicted from the multistage model based on the allometry of human height to overall body mass, which is used as a proxy for cell number (dashed line); and (3) the predicted effect based on the expected extremes of organ cell number allometry to height: linear, b = 1 (lower dotted line); and volumetric, b = 3 (upper dotted line). For data sources, see electronic supplementary material, table S1.