Mosaic: post-zygotic mutations in vascular malformations

PROJECT SUMMARY
Defective morphogenesis of arteries, veins, capillaries, and lymphatic vessels results in vascular
malformations, a relatively common congenital malformation. Current therapies are primarily invasive and can
produce significant morbidity. Most vascular malformations are due to post-zygotic (mosaic) activating
mutations in a few oncogenes (PIK3CA, KRAS, MAP2K1, others) in the PI3K-AKT and RAS-MAPK pathways.
These mutations are never present in DNA derived from white blood cells, the most common sample for
genetic testing, making molecular diagnosis challenging.
Long-term, our goal is to improve treatment of individuals with vascular malformations. The proposed
experiments advance that goal by expanding diagnostic options for VM patients and dissecting cellular and
spatial heterogeneity in vascular malformations, using novel, cutting edge technologies.
Our first aim is to determine if non-invasive “liquid biopsies” of plasma derived cell-free DNA can detect
mosaic mutations in individuals with vascular malformations. Since mutations driving vascular malformations
are typically present only in the malformation itself, an invasive surgery or biopsy is currently required for
diagnosis. Since a molecular diagnosis is required to guide targeted drug therapies (such as PI3K or AKT
inhibitors, for which clinical trials are currently open), developing non-invasive diagnostics for vascular
malformations would have immediate patient impact.
Next, we will study how gene expression changes in single cells in vascular malformation tissues and
integrate this information with each cell's mutation status, using a novel, multi-omics method. We will also use
techniques that allow us to visualize how gene expression changes in two and three dimensional space within
vascular malformations. Since only a small fraction (1-10%) of cells inside vascular malformations typically
possess the driving mutation, these experiments will help us understand how small cell populations can
produce large, multicellular malformations.
We have assembled a multidisciplinary team with non-overlapping areas of expertise to accomplish these
goals. Our experiments will be performed using samples from a large, pre-existing biorepository of vascular
malformation samples rich in clinical data. We expect this work to expand our understanding of vascular
malformations and vascular biology specifically, and the nature of mosaicism more generally.

Grant Number: 5R01HL130996-09
NIH Institute/Center: NIH
Principal Investigator: JAMES BENNETT