GENETIC MECHANISM OF CEREBRAL CAVERNOUS ANGIOMA DEVELOPMENT

Cerebral cavernous angiomas (CA) affect more than a million Americans, predisposing them to a lifetime risk of stroke and seizures. We have long known about inherited cavernous angioma gene mutations among the minority of familial cases, but until now we had no idea why lesions formed in the majority sporadic non-familial cases, commonly in vicinity of abnormal appearing veins in the brain (known as developmental venous anomaly or DVA). DVAs alone are largely innocuous, unless they develop a CA nearby. Research teams from the University of Chicago and Duke University have now shown a molecular mutation (PIK3CA gain of function) in the DVA in human lesion specimens sampled at surgery. This is a somatic mutation, occurring in that part of the brain, and not present in the germ line. Cavernous angioma samples were found to harbor the same somatic mutation plus a second hit mutation in another CA signaling pathway gene. The blood of patients with DVA harbors microRNAs interacting with the DVA mutation, the first report of circulating marker of a somatic mutation in the brain. This type of mutation was previously shown by our team to fuel CA growth by tumor-like mechanism (Ren, et al. Nature 2021). The Chicago team collected all the human samples from DVA and CA in conjunction with neurosurgical resection of symptomatic CAs, and all blood samples from patients harboring DVA and cavernous angiomas. Duke team performed mutation screening in the lesions resected in Chicago, and Chicago team performed the microRNA discovery. This paper demonstrates a genetic mechanism for cavernous angioma lesion genesis in the majority cases who do not inherit the disease. It relates to a specific somatic mutation in an abnormal vein, which seeds the subsequent development of the cavernous angioma. Discovery of this mechanism opens novel opportunities for developing blood tests and new therapies for these lesions. Research was published on March 14, 2022  (Snelling, et al.) in the journal NATURE Cardiovascular Research. Senior co-authors are Issam Awad from the University of Chicago and Douglas Marchuk from Duke University.