Today's open access paper merges discussion of a number of related topics. Firstly mutation rate in cancer tissue and its relationship to success in immunotherapy, secondly mutation rate in normal tissues as a risk factor for the development of cancer, and thirdly the radically different cancer risks exhibited by different mammalian species. It is well known that long-lived, large species have a much reduced cancer risk relative to short-lived, small species, and as researchers note here, this relationship is better mapped to mutation rates rather than to size or life span. Separately, within a species, cancer is clearly an age-related condition, where risk relates to the accumulated burden of somatic mutations within tissues.
Can the comparative biology of cancer and DNA damage lead to novel approaches to treat cancer or reduce cancer risk in humans? As for all aspects of comparative biology, it is entirely unclear as to whether even the discovery of an influential single genetic difference could give rise to a useful basis for therapy in the near term. On some time scale humanity will engineer itself, create better genomes. We stand a fair way removed from the ability to safely adopt even single gene differences at this time, however. Delivery of gene therapies to desired tissues in adults is a challenge, understanding second order effects is a challenge, and we don't know what we don't know.
The somatic mutation theory predicts that cancer risk should scale proportionally with lifetime cell divisions; yet large-bodied and long-lived species exhibit lower-than-expected cancer incidence - a long-standing contradiction termed Peto's paradox. Although Peto's paradox has puzzled scientists for nearly half a century, its underlying mechanisms remain incompletely understood. This study clarifies this enigma by presenting novel evidence: larger-bodied animals generally exhibit a lower-than-expected cancer incidence relative to their body mass, whereas life expectancy only weakly correlates with cancer risk across species. In sharp contrast, cancer incidence in humans is strongly age-dependent, rising exponentially after the age of 40, indicating that chronological aging contributes to the majority (more than 80%) of lifetime cancer risk.
Through comparative analysis of cross-species mutation rates, this study reconciles the conflict between the age-dependent cancer risk in humans and the inter-species variability encapsulated in Peto's paradox. As an iconic example, elephants have evolved enhanced DNA repair mechanisms, notably through expanded copies of the TP53 gene, to curb mutagenesis and preserve genomic integrity, effectively suppressing mutational accumulation within a tolerable amount despite their massive body size and long lifespans. Conversely, smaller and short-lived animals like mice accumulate mutations at a much faster rate, which corresponds to their higher-than-expected cancer incidence.
Notably, this study unifies these observations by identifying a universal pattern: both somatic mutation rate and cumulative lifetime mutation burden correlate strongly with cancer risk across species, positioning mutational burden as a fundamental and evolutionarily conserved hallmark of cancer, transcending species boundaries.
View the full article at FightAging
