Mosaic: post-zygotic mutations in vascular malformations

马赛克：血管畸形的合子后突变

基本信息

批准号：
10646420
负责人：
JAMES T BENNETT
金额：
$ 87.08万
依托单位：
SEATTLE CHILDREN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-02-08 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10646420
关键词：
3-Dimensional Adult Alleles Architecture Area Arteries Arteriovenous malformation Automobile Driving Bar Codes Biology Biopsy Blood Blood Vessels Blood capillaries Cells Child Clinical Data Clinical Trials Congenital Abnormality DNA DNA analysis Data Development Diagnosis Diagnostic Diagnostic Procedure Endothelial Cells Enrollment Functional disorder Gene Expression Gene Expression Profiling Genes Genomic DNA Genotype Goals Health Heterogeneity Image Individual KRAS2 gene Lesion Leukocytes Link Lymph Lymph Node Mapping MAP Kinase Gene MAP2K1 gene Magnetic Resonance Imaging Maps Measures Methods Molecular Diagnosis Morbidity - disease rate Morphogenesis Mosaicism Mutation Mutation Detection Nature Oncogenes Operative Surgical Procedures PIK3CA gene PIK3CG gene Paracrine Communication Pathology Pathway interactions Patients Pericytes Phenotype Plasma Play Population Proto-Oncogene Proteins c-akt Resected Resolution Retrospective cohort Sampling Slide Techniques Technology Testing Tissue Sample Tissues Veins Venous Malformation Visualization Work biobank cell free DNA cell type efficacy evaluation exome sequencing experimental study genetic testing improved in vivo inhibitor liquid biopsy lymphatic malformations lymphatic vessel malformation molecular diagnostics mosaic mosaic variant multidisciplinary multiple omics mutant mutational status noninvasive diagnosis novel novel diagnostics prospective prospective test targeted treatment transcriptome transcriptome sequencing transcriptomics two-dimensional

项目摘要

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.

项目概要动脉、静脉、毛细血管和淋巴管的形态发生缺陷导致血管畸形，一种相对常见的先天性畸形，目前的治疗主要是侵入性的。大多数血管畸形是由于合子后（马赛克）激活引起的。 PI3K-AKT 和 RAS-MAPK 通路中的一些癌基因（PIK3CA、KRAS、MAP2K1 等）发生突变。这些突变从不存在于源自白细胞的 DNA 中，而白细胞是最常见的样本。基因检测使分子诊断具有挑战性。从长远来看，我们的目标是改善血管畸形患者的治疗。实验通过扩大 VM 患者的诊断选择并剖析细胞和使用新颖的尖端技术研究血管畸形的空间异质性。我们的首要目标是确定血浆来源的无细胞 DNA 的非侵入性“液体活检”是否可以检测到患有血管畸形的个体中存在马赛克突变，因为突变驱动血管畸形。通常仅存在于畸形本身，目前需要进行侵入性手术或活检由于需要分子诊断来指导靶向药物治疗（例如 PI3K 或 AKT）。抑制剂，目前正在进行临床试验），开发血管非侵入性诊断畸形会对患者产生直接影响。接下来，我们将研究血管畸形组织中单个细胞的基因表达如何变化以及我们还将使用一种新颖的多组学方法将此信息与每个细胞的突变状态整合起来。使我们能够可视化基因表达在二维和三维空间中如何变化的技术由于血管畸形内通常只有一小部分细胞（1-10%）。拥有驱动突变，这些实验将帮助我们了解小细胞群如何能够产生大的多细胞畸形。我们组建了一支具有不重叠专业领域的多学科团队来完成这些我们的实验将使用来自大型现有血管生物储存库的样本进行。我们期望这项工作能够扩大我们对血管的理解。特别是畸形和血管生物学，以及更一般的镶嵌现象的性质。

项目成果

期刊论文数量（23）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Can topical beta-blockers reduce the size of superficial infantile hemangiomas of the head and neck?

外用β受体阻滞剂可以缩小头颈部浅表婴儿血管瘤的大小吗？

DOI：
发表时间：
2017-01
期刊：
影响因子：
0
作者：
Bly, Randall A;Perkins, Jonathan;Parikh, Sanjay R
通讯作者：
Parikh, Sanjay R

Medical Management of Vascular Anomalies.

血管异常的医疗管理。

DOI：
发表时间：
2018-06
期刊：
影响因子：
0
作者：
Padia, Reema;Bly, Randall;Bull, Catherine;Geddis, Amy E;Perkins, Jonathan
通讯作者：
Perkins, Jonathan

Structural malformations of the brain, eye, and pituitary gland in PHACE syndrome.

PHACE 综合征中大脑、眼睛和垂体的结构畸形。

DOI：
发表时间：
2018
期刊：
影响因子：
0
作者：
Steiner, Jack E;McCoy, Garrett N;Hess, Christopher P;Dobyns, William B;Metry, Denise W;Drolet, Beth A;Maheshwari, Mohit;Siegel, Dawn H
通讯作者：
Siegel, Dawn H

Genotype correlates with clinical severity in PIK3CA-associated lymphatic malformations.

基因型与 PIK3CA 相关淋巴管畸形的临床严重程度相关。

DOI：
10.1172/jci.insight.129884
发表时间：
2019-11-01
期刊：
JCI insight
影响因子：
8
作者：
K. Zenner;C. Cheng;Dana M. Jensen;A. Timms;G. Shivaram;R. Bly;S. Ganti;K. Whitlock;W. Dobyns
通讯作者：
W. Dobyns

Primary targeted medical therapy for management of bilateral head and neck lymphatic malformations in infants.

用于治疗婴儿双侧头颈部淋巴畸形的主要靶向药物治疗。

DOI：
发表时间：
2023-01
期刊：
影响因子：
1.5
作者：
Richardson, Clare M;Perkins, Jonathan N;Zenner, Kaitlyn;Bull, Catherine;Lutsky, Erika;Jensen, Dana M;Dmyterko, Victoria;Bennett, James T;Wenger, Tara L;Dahl, John P;Bonilla;Bly, Randall A;Geddis, Amy E;Perkins, Jonathan A
通讯作者：
Perkins, Jonathan A