New Computational Method Links One Mammal’s Striking Longevity and Resistance to Cancer With ‘Dark Genome’

All mammals can develop cancer, the rapid growth of harmful cells that can overtake normal cells and compromise their ability to function. Scientists have long observed that a species of nearly-hairless subterranean rodents from eastern Africa are surprisingly long-lived and demonstrate a pronounced resistance to cancer. A new study led by Andrei Gudkov, PhD, DSci, at Roswell Park Comprehensive Cancer Center supports a new understanding of what might be driving the species’ propensity for avoiding cancer — its noteworthy evolutionary stability.

New insights about that species, the naked mole-rat, and the clues its genes may hold for ways to prevent or control cancer’s development in other mammals are reported in a new study in the journal Proceedings of the National Academy of Sciences of the United States of America (PNAS).

Nearly half of our DNA is made up of the “dark genome,” ancient virus-like elements called retrotransposons that reproduce rapidly and were once thought to have no effect on human biology. But extensive evidence now suggests strongly that these once-ignored genes — which Dr. Gudkov collectively calls “the retrobiome” — are implicated in both aging and cancer.

“Normally dormant in healthy cells, these genetic elements often become reactivated in cancer cells, contributing to cancer development and progression,” says Dr. Gudkov, senior author on the new study and Senior Vice President for Research Technology and Innovation/The Garman Family Chair in Cell Stress Biology at Roswell Park. “There is also growing evidence linking the desilencing of the retrobiome to mammalian aging, particularly as a driver of chronic systemic inflammation that underlies many age-related diseases, including cancer.”

Using a new and original computational method, Dr. Gudkov and colleagues tracked the expansion of the retrobiome in 16 mammal species over the last 20 million years. Their analyses revealed that the retrobiome continued to grow in all species except one: the naked mole-rat.

“We learned that the naked mole-rat appears to have completely blocked retrobiome activity, with no new retrotransposon entries for millions of years — suggesting a potential relationship between the suppression of retrobiome activity in this species and its well-documented capacity for both cancer resistance and extraordinary longevity,” says Dr. Gudkov. “This makes the retrobiome an attractive therapeutic target for anticancer and antiaging strategies.”

A clinical study underway at Roswell Park (NCT04696575), led by Roswell Park medical oncologist Grace Dy, MD, explores whether reverse transcriptase inhibitors — drugs originally developed for treating human immunodeficiency virus, or HIV — can extend progression-free survival in patients with advanced small-cell lung cancer by controlling the activity of the retrobiome. Further studies of antiviral drugs in patients with additional cancer types are in consideration.

The research team includes co-first authors Valeria Kogan, PhD, and Ivan Molodtsov, PhD, and collaborators from Roswell Park and the Institute for Personalized and Translational Medicine/Adelson School of Medicine, Ariel University, Ariel, Israel. The work made use of shared resources available through Roswell Park Comprehensive Cancer Center’s Cancer Center Support Grant from the National Cancer Institute (award P30CA16056) as well as a grant from the Roswell Park Alliance Foundation.