Researchers identify genetic mutations behind sporadic cavernous angiomas

More than a million Americans live with cavernous angiomas—tangled clusters of abnormal blood vessels in the brain that can bleed without warning, triggering strokes and seizures at any point in a person's life. For decades, doctors understood that some families inherited these lesions through genetic mutations passed down across generations. But the majority of cases appeared randomly, with no clear explanation. Until now, no one knew why.

Researchers at the University of Chicago Medicine, Duke University, and the University of Pennsylvania have finally identified the genetic mechanism behind these sporadic cases. The discovery, published in March 2022 in Nature Cardiovascular Research, reveals a two-step mutation process that seeds and then fuels the growth of these dangerous brain malformations. The finding opens a path toward blood tests that could identify at-risk patients and toward drugs that might prevent or shrink the lesions before they cause harm.

The mechanism works like this: A mutation in the gene PIK3CA creates what doctors call a developmental venous anomaly—an abnormal pattern of blood vessels in the brain. These DVAs are actually common; somewhere between 6 and 10 percent of people have one, and most never develop any problems from it. But in rare cases, a second mutation occurs in one of several genes—MAP3K3, KRIT1, CCM2, or PDCD10—specifically within the area of that abnormal vein. When this second mutation takes root, the cavernous angioma forms and begins to grow. "We'd previously observed that these lesions often grow near a preexisting abnormal vein," said Issam Awad, the John Harper Seeley Professor of Neurological Surgery and Director of Neurovascular Surgery at UChicago Medicine. "But we've never known why. In this study, we were finally able to use mutation analysis on the vein itself to see why it seems predisposed to these angiomas."

The researchers were able to examine the genetics of both the angioma and its connected abnormal vein because of the delicate surgical technique required to repair bleeding lesions. The procedure involves removing small portions of the veins to untangle them from the cavernous angioma. This gave the team access to tissue they could analyze, leading them to discover the PIK3CA mutation in the vein and the realization that the same mutation co-occurs with a second mutation within the angioma itself. "This is very novel," Awad said, "because we can now explain why the DVA forms in the first place. Along with a second mutation, it is the genetic seed for the formation and growth of the cavernous angioma."

Beyond identifying the genetic mechanism, the team made another breakthrough: they discovered molecules circulating in the blood that are associated with the key brain mutation. This marks the first time that a blood test has been described for detecting a focal somatic mutation in the brain—a finding that could transform how doctors identify and monitor these lesions. "Now we can develop blood tests that can identify these mutations in the brain," Awad said. "Some of the genes we've identified can be inhibited by drugs that are already on the market."

The next phase of research will focus on finding biomarkers that distinguish benign abnormal veins from those carrying the genetic seeds of future angiomas. If successful, a simple blood test could tell a patient whether their vein abnormality is harmless or destined to develop into a dangerous lesion. The team also plans to test existing pharmaceutical inhibitors against the mutations they've identified to see whether they can stabilize or even shrink the brain lesions. "A mechanism is not just about scientific curiosity," Awad emphasized. "It should motivate us to change patient care. If we don't know the mechanism, we can't have a truly rational therapy."