For almost as long as scientists have understood how genetic mutations can drive the growth of cancers, they’ve also believed that most of those mutations are acquired over the course of a person’s life. But a new study shows that for breast cancers, small and previously overlooked genetic variations present at birth shape the aggressiveness of a disease that often emerges decades later.
That “invisible hand” guides the tumor’s growth, shifts the immune system’s ability to keep cancer in check, and changes its susceptibility to treatments, according to a new study from Stanford University.
By analyzing the genomes of nearly 6,000 breast cancer patients, the researchers devised a new genetic risk score for how likely cancer is to escape the immune system’s natural defenses and progress to more advanced disease. The study, published Thursday in Science, has implications for diagnostics, treatment selection and cancer vaccine design.
Christina Curtis“We believe it potentially provides a new diagnostic approach to improve risk stratification and to guide more effective interventions,” said Christina Curtis, director of artificial intelligence and cancer genomics at the Stanford Cancer Institute, in an interview with Endpoints News. “And critically, we can obtain this from a routine blood draw.”
Numerous biotech companies are devising complex tests to measure minute amounts of cancer DNA in the blood to catch tumors early. Curtis’ approach could complement those liquid biopsies or more traditional screening methods like mammograms, giving doctors a way to assess the risk of a preinvasive cancer found in the milk ducts spreading into surrounding breast tissue.
“We don’t really have good ways to identify individuals that are at risk of progression versus not. And so they’re kind of treated one-size-fits-all, even though we know that’s not optimal,” Curtis said. “These findings provide clues as to how to find those populations.”
‘The invisible hand’
Although scientists have long suspected that inherited mutations could cause cancer, there have been few smoking guns apart from a handful of infamous mutations, such as those in the BRCA1/2 genes that strongly increase a person’s risk.
Instead of hunting for single genes, the Stanford group focused on molecular signposts called epitopes that cells throw up to help the immune system differentiate the body’s own cells from infected or cancerous ones. Those more subtle clues provide a new way of looking at how genes impact the course of cancer, rather than its occurrence in the first place.
“The variation can nudge someone towards what type of breast cancer they might develop, and that’s quite interesting,” Chad Creighton, a cancer geneticist at Baylor College of Medicine who was not involved in the study, told Endpoints. “It will be interesting to see if there are other cancer types that are driven by some of these key genes.”
Curtis devised a metric to quantify this genetic variation that she called germline-derived epitope burden, or GEB. In preinvasive breast cancers that hadn’t spread beyond the milk ducts, the researchers found that a high GEB score was linked to better outcomes because the cancer cells were more likely to have signaled to immune cells that something was awry.
“The immune system can seemingly see those nascent or early tumor cells and eradicate them,” Curtis said. “We never even see a cancer emerge. So this is the invisible hand.”
But the immune system doesn’t always win the fight. Some tumor cells can escape. If they start spreading, the same genetic diversity that was once protective becomes a liability. In an invasive tumor, which has developed ways to evade the immune system, a high GEB score is linked to immune suppression and poorer prognosis.
Curtis believes the finding raises questions about the optimal timing of giving patients immunotherapies, and hopes it will inspire new ways to make treatments more effective.
The work could also influence the increasingly hot field of cancer vaccines. While companies like Moderna and BioNTech are developing personalized vaccines based on mutations known as neoantigens that arise throughout a tumor’s development, genetic variation present from birth could inform the development of off-the-shelf vaccines for high-risk populations.
Curtis has filed a patent related to her work on germline genetics. When asked if there were plans to translate the diagnostic or therapeutic applications into a biotech company, Curtis declined to answer. “I can’t really comment on that right now. But we’re excited about the implication of this,” she said.