Cross-species identification of cancer-resistance associated genes uncovers their relevance to human cancer risk

Abstract

Cancer is an evolutionarily conserved disease that occurs in a wide variety of species. We applied a comparative genomics approach to systematically characterize the genes whose conservation levels significantly correlates positively (PC) or negatively (NC) with a broad spectrum of cancer-resistance estimates, computed across almost 200 vertebrate species. PC genes are enriched in pathways relevant to tumor suppression including cell cycle, DNA repair, and immune response, while NC genes are enriched with a host of metabolic pathways. The conservation levels of the PC and NC genes in a species serve to build the first genomics-based predictor of its cancer resistance score. We find that PC genes are less tolerant to loss of function (LoF) mutations, are enriched in cancer driver genes and are associated with germline mutations that increase human cancer risk. Furthermore, their expression levels are associated with lifetime cancer risk across human tissues. Finally, their knockout in mice results in increased cancer incidence. In sum, we find that many genes associated with cancer resistance across species are implicated in human cancers, pointing to several additional candidate genes that may have a functional role in human cancer.

Comparative analysis of genome-scale, base-resolution DNA methylation profiles across 580 animal species

“…Finally, we investigated potential associations between DNA methylation and cancer risk, as it had been suggested previously that DNA methylation could be one of many factors that contribute to cancer suppression in large, long-lived species 76 – for example by suppressing repetitive DNA elements that threaten genome integrity or by constraining developmental plasticity in differentiated cells. We observed a positive correlation between genome-wide DNA methylation levels and theoretical, unmitigated cancer risk of the investigated species (which we estimated based on each species’ body weight and longevity 77 ). This positive association was most pronounced in birds (r=0.53) and remained statistically significant after correcting for phylogeny (p=0.01) ( Supplementary Figure 5d ).…”

“…The seven most frequent tissues are shown.(b) Boxplot showing mean non-CpG methylation levels, aggregated by taxonomic groups and tissues. The seven most frequent tissues are shown.(c) Histograms of genome-wide DNA methylation, non-CpG methylation, and DNA methylation erosion (measured by PDR) for vertebrates and invertebrates to compare to lamprey as a jawless vertebrate (represented as dot).(d) Scatterplot relating genome-wide DNA methylation levels, non-CpG methylation levels, and DNA methylation erosion (measured by PDR) with theoretical cancer risk estimated by the MLTAW metric 77 , which is calculated as log( Maximum longevity (years) ^6 * Adult weight (g) . Pearson’s correlation coefficient and the corresponding significance are indicated.…”

“…(d) Scatterplot relating genome-wide DNA methylation levels, non-CpG methylation levels, and DNA methylation erosion (measured by PDR) with theoretical cancer risk estimated by the MLTAW metric 77 , which is calculated as log( Maximum longevity (years) ^6 * Adult weight (g) . Pearson’s correlation coefficient and the corresponding significance are indicated.…”