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 (HR 10 ) 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 HR 10 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 nonreproductive 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.

From zygote to a multicellular soma: body size affects optimal growth strategies under cancer risk

“…Our finding is therefore interesting in the context of macroevolutionary changes in body sizes, where it is known that miniaturization, when it happens, appears to proceed much faster than the (as a whole more common; Kingsolver and Pfennig, 2004) increase in body size over evolutionary time (Evans et al, 2012). It also fits well with findings of intraspecific variation in humans, where size increases associate with heightened cancer risk (Green et al, 2011;Nunney, 2018) while hereditary forms of dwarfism, at least in the context of the so-called Laron syndrome, appear to offer cancer protection (Laron et al, 2017).…”

Functional and structural changes in aorta of mice divergently selected for basal metabolic rate

“…According to previous studies, BMR is strongly correlated with the mass of internal organs such as heart, liver, kidney and small intestine (Brzęk et al 2007;Konarzewski and Książek 2013), and-for example-with a size of cells building those organs (Maciak et al 2014). Therefore, increasing evidence from both, studies on humans and animal models suggest that physiological and anatomical differences in the rate of metabolism can translate into susceptibility to the development of serious illnesses (Ghebre et al 2016;Kathiresan and Srivastava 2012;Maciak and Michalak 2015;Nunney 2018;Sadowska et al 2017).…”

The Evolution of Human Cancer Gene Duplications across Mammals

“…Thus, in both the cellular and organismal contexts, cancer is a phenotype that has evolved under multiple levels of selection since the origins of multicellularity (Domazet-Lošo and Tautz 2010; Aktipis et al 2015). Tumor suppression may be especially challenging in organisms with large bodies and longer lifespans, since cancer is an age-and body size-related disease (Nunney 2018;Seluanov et al 2018). In humans, longer average leg length results in a higher risk of non-smoking-related cancers (Albanes 1998), and greater than average height has been associated with a higher lifetime risk of melanoma (Lahmann et al 2016).…”