Cross-species identification of cancer resistance–associated genes that may mediate human cancer risk

Abstract

Cancer is a predominant disease across animals. We applied a comparative genomics approach to systematically characterize genes whose conservation levels correlate positively (PC) or negatively (NC) with cancer resistance estimates across 193 vertebrates. Pathway analysis reveals that NC genes are enriched for metabolic functions and PC genes in cell cycle regulation, DNA repair, and immune response, pointing to their corresponding roles in mediating cancer risk. 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. Their relevance to cancer risk is further supported via the analysis of mouse functional genomics and cancer mortality of zoo mammals’ data. In sum, our study describes a cross-species genomic analysis pointing to candidate genes that may mediate human cancer risk.

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 prevention in large, long-lived species 78 -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 the theoretical, unmitigated cancer risk of the investigated species (which we estimated based on each species' body weight and longevity 79 ). This positive association was most pronounced in birds (r = 0.53) and remained statistically significant after correcting for phylogeny (p = 0.01) (Supplementary Fig.…”

Bridging clinic and wildlife care with AI-powered pan-species computational pathology

“…Finally, comparative oncology also brings tremendous benefits to human cancer research 5 , 9 , 43 , 66 , 67 . The understanding of cancer in model animals is crucial for the selection of the right animal models 68 for human diseases and the pre-clinical development of drugs 69 .…”

Wild animals as an underused treasure trove for studying the genetics of cancer

“…The median age of cancer-related genes predates the divergence between humans and other vertebrate animals by a large margin, allowing for comparative genomic studies to understand the role and evolution of oncogenes and tumour-suppressor genes. [15,17,21,22,23,30] Animal figures indicate vertebrate classes (mammals, birds, reptiles, amphibians, fish), position of the figure denotes the last common ancestor between Homo sapiens and a representative of different vertebrate classes (Lofodonta africana for mammals, Gallus gallus for birds, Danio rerio for fish, Bufo bufo for amphibians, Chelonoidis niger for reptiles) based on timetree.org. The divergence times of different groups are based on timetree.org.…”

“…[ 13 ] However, these studies have also highlighted the differences between species, for example in the vulnerabilities to different types of cancer, or in their responsiveness to treatment methods. [ 14,15 ] These findings, pinpointing to the differences between animal species in cancer defences and vulnerabilities, encourage the field to move forward to the levels of the genomes, to understand the genetic basis of these differences, and the evolutionary/ecological reasons for them.…”

“…As an example, the recent comparative genetics study of 193 vertebrates including mammals, birds, fish, and reptiles revealed that genes that were more conserved in species with higher cancer rates were mostly linked to metabolic functions, while genes that were more conserved in species with low cancer rates were linked with cell cycle regulation, DNA repair, and immune response. [ 15 ] Comparative genomics studies depend on the availability of high‐quality genome sequences for wild species, but as the number of the latter is expected to increase quickly in the coming years, acknowledging the potential of comparative cancer genomics becomes an urgent future perspective.…”