International group of scientists identifies cancer-resistance genes across species

Cancer is a leading cause of human disease and death worldwide, but it's also common in animals. Can we learn something about the genetic mutations associated with cancer in animals that sheds light on the origins of human cancer and how to prevent and treat it?

An international group of scientists used comparative genomics to investigate genes involved with cancer resistance across 193 vertebrates. The scientists were from the Hebrew University of Jerusalem, the University of Maryland, and the National Cancer Institute of the National Institutes of Health. Their work appears in Science Advances, Aug. 3, 2022. 

Current Science Daily asked professor Yuval Tabach, a co-author, to discuss the research. Tabach noted that some humans are more resistant to cancer than others, "but in animals the situation is even more drastic. While some species can develop cancer after a few months others can live more than 100 years without getting cancer." 

"Overall today it's clear that certain species are evolved sophisticated mechanisms and their cells are 10 to 1,000 times more resistant to cancer than human cells," he said.

Tabach is a member of the Faculty of Medicine at Hebrew University in Jerusalem and directs its Deep Genomics Lab. The lab aims to unravel "the deep secrets of life and the species around us to fight today’s challenges."

A unique study

In this study, Tabach said, "the researchers aim to find for the first time genes that correlated with resistance to cancer across a wide range of vertebrates. These genes show different evolution in species that are more resistant to cancer. They potentially evolved to mediate cancer risk across animal species, including cancer in humans."

The study characterized genes as being positively or negatively conserved with estimates of cancer resistance across species. Conserved here refers to whether the gene has remained basically unchanged throughout evolution, indicating that the gene is essential to protect against cancer. Thus, negatively conserved means that the gene has had more mutations and evolved faster in organisms that are resistant to cancer.

Negatively conserved genes are associated with removal of harmful mutations and are "enriched for metabolic functions," while positively conserved genes are enriched in "cell cycle regulation, DNA repair, and immune response," the researchers state. Further, they write, the positively conserved genes "are less tolerant to loss-of-function mutations, are enriched in cancer driver genes, and are associated with germline mutations that increase human cancer risk."

Genes that mediate human cancer risk

The researchers hypothesized that cancer resistance evolved through increased selection of genes functionally relevant to cancer, positively or negatively. They "estimated the protein conservation scores across species including mammals, birds, and fish, identifying genes whose conservation levels are associated with cancer resistance estimated based on the species’ life span and body size."

Both longevity and body size are expected to be correlated with cancer. "Bigger animals are expected to have more cells that over time can become cancer cells. In humans, for example, cancer risk is associated with body height and weight, but most important cancer risk is dramatically increased with age," Tabach said.

"However," he added, "this correlation is not kept cross-species, and human cancer risk is actually lower than that of much smaller mice, despite the existence of 100 more cells. Furthermore, the huge long-lived bowhead whale (it can live more than 200 years) is cancer resistant."

A genomics based predictor

Using these data, the researchers built a genomics-based predictor of cancer resistance that could be used with any species. They write: "We show that the biological processes associated with cancer resistance vary across taxonomic groups (classes and orders of species), pointing to the diversity in the evolutionary paths and mechanisms for resisting cancer." 

The researchers were able to test their data in comparison to experiments with mice that "knocked out" particular genes. They also used data from a study of cancer mortality in 110,148 adult zoo animals. 

The study found that the genes associated with cancer resistance "are enriched in cell cycle, DNA repair, immune response, and different metabolic pathways." Their results also showed that their method of predicting cancer resistance correlated with long-lived species that are known to be cancer resistant, such as "the bowhead whale, the African elephant, the chimpanzee, the Brandt's bat, the naked mole rat," among others.

The researchers identified specific positively conserved genes that were known to be associated with human cancers, for example the BRCA1 and BRCA2 genes associated with breast cancer. 

The article concludes: "In summary, this study presents a systematic species comparison identifying key genes and pathways associated with cancer resistance across species. Many of the genes identified are implicated in human cancers, and their further study may increase our understanding of human cancer development, prevention, and treatment."

The research results could change future cancer treatment, Tabach said: "A new company, Cavos Biotech, is using cancer-resistant species to develop novel drugs based on naturally occurring resistance mechanisms--basically, using `natural anticancer mechanisms' instead of chemotherapy."

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Nishanth Ulhas Nair et al. "Cross-species identification of cancer resistance–associated genes that may mediate human cancer risk." Science Advances, Aug. 3, 2022.

DOI: 10.1126/sciadv.abj7176