Elucidating the Clonality of Somatic Mutations in Vascular Malformations Arising in Hereditary Hemorrhagic Telangiectasia
Abstract
Hereditary Hemorrhagic Telangiectasia (HHT) is an inherited disease passed on from parent to child, in which patients have abnormal blood vessel formations. These abnormal formations, called arteriovenous malformations (AVMs) are comprised of fragile blood vessels that occur in clumps and can connect arteries directly to veins (which is not normal). Nearly all patients with HHT have small blood vessel abnormalities in the skin and the inside of the nose where they cause recurrent, often severe nose bleeds and blood loss. However, the biggest problems are the abnormal blood vessel formations that occur quite commonly in the liver (70% of patients), the lung (50% of patients), the intestinal tract (60% of patients), and the brain (10% of patients). In these locations the connections between the arteries and the veins can cause the blood to pump ineffectively, leading to heart failure necessitating liver transplant, or allow for bacteria to enter places they shouldn t, like the brain, causing life-threatening infections. In the intestinal tract these lesions can cause intractable intestinal bleeding and its many consequences. Tragically, some patients will die of stroke caused by sudden rupture of these abnormalities in the brain. While people with HHT are born with it and the complications of the disease can start in early childhood, most people start developing problems in their teens and twenties. There are nearly 70,000 HHT patients in the United States, yet very little research is funded in this area. The prevalence (1:5000) in the military/Veteran populations is likely similar to the U.S. population. We know the exact cause of HHT. Namely, it is caused by the inheritance of certain mutations in genes and specifically in any one of four genes that play critical roles in the normal development of blood vessels. However, we do not know what happens next. Our group believes that what happens next is similar to what happens in certain cancer syndromes that are also inherited. We believe that additional genetic mutations (changes to the DNA) occur and lead to further impairment of the genes that are inherited. This then completely eliminates the critical vascular functions provided by these four genes and leads to the development of the skin and organ vessel abnormalities. One very surprising finding is that in patients who undergo liver transplant, the blood vessel abnormalities can reappear in the liver that has been transplanted. Since this new liver has all the normal genes, the only way for this to happen is that the genetically mutated blood vessel cells of the patient spread to the new liver. This also is a remarkable finding, which has great similarities to the nature of how cancer spreads. We are a unique team comprised of experts in the diagnosis and treatment of this disease (Dr. Al-Samkari, Massachusetts General Hospital) and experts in the study of the genetic events that cause and drive cancer (Dr. Getz, Massachusetts General Hospital and Broad Institute, and Dr. Sellers, Broad Institute, Dana-Farber Cancer Institute). In our proposal we plan on using the most cutting-edge DNA and RNA sequencing methods to analyze biopsy samples obtained from patients with HHT. This will include technologies that allow us to look at changes at the single-cell level from human tissues. Overall Goals: Therefore, our goals are to collect biopsy samples and to apply the latest in next-generation sequencing technologies to determine the extent to which additional genetic/mutation events underlie the development of the abnormal blood vessel formations and to use single-cell sequencing of the RNA to probe the interactions between blood vessels and their surrounding cells. We think that we can also determine whether certain events such as UV exposure or smoking that cause damage to the DNA are part of the reason that additional genetic events occur. Finally, if we are right, we will have completely changed
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310892
Entities
People
- Hanny Al-samkari
Organizations
- Massachusetts General Hospital
- United States Army