Genome-wide Sequencing to Identify the Genes Responsible for Enchondromatoses and Related Malignant Tumors

全基因组测序以确定导致软骨瘤病和相关恶性肿瘤的基因

基本信息

批准号：
10302664
负责人：
Nara Sobreira
金额：
$ 16.38万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-08 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10302664
关键词：
Adolescent Affect Age-Years Astrocytoma Atlases Benign Bilateral Biology Blood Vessels Bone Pain Brain Neoplasms CDKN2A gene Cancer Patient Candidate Disease Gene Child Childhood Brain Neoplasm Chondrogenic Neoplasm Chondroma Chondrosarcoma Clinical Cranial nerve palsies Data Deformity Development Disease Enchondromatosis Facial asymmetry Family Frequencies Funding Gait abnormality Genes Genetic Genome Genomics Germ-Line Mutation Glioma Goals HIF1A gene Health Care Costs Individual Isocitrate Dehydrogenase Joints Leg Length Limb structure Maffucci Syndrome Malignant - descriptor Malignant Neoplasms Medical Molecular Mutation Neoplasms in Vascular Tissue Operative Surgical Procedures Outcome Ovarian Granulosa Cell Tumor Parents Pathogenesis Pathogenicity Pathological fracture Pathway interactions Patients Pediatric Research Pharmacology Predisposition Quality of life Rare Diseases Recovery Resources Risk Role Skeleton Somatic Mutation Swelling Syndrome Testicular Neoplasms Testing United States National Institutes of Health Variant Work alpha ketoglutarate base bone cancer therapy causal variant data resource early childhood effective therapy exome sequencing gain of function gene discovery genetic variant genome sequencing genome-wide high risk hypoxia inducible factor 1 improved joint mobilization melanoma mutant ovarian neoplasm pediatric patients prevent proband programs scoliosis skeletal tumor whole genome

项目摘要

Project Summary/Abstract We propose to investigate the molecular bases of Ollier disease (OD) and Maffucci syndrome (MS), rare diseases characterized by multiple enchondromas leading to severe skeletal deformities and an increased risk for chondrosarcomas and other malignancies. Our central hypothesis is that OD and MS are under- recognized cancer susceptibility syndromes caused by variants in multiple genes that disrupt few connected pathways and that pathogenic variants in these genes also cause isolated forms of other cancers. OD is characterized by multiple enchondromas with onset in early childhood, typically unilateral in distribution with a predilection for the appendicular skeleton. MS is characterized by multiple enchondromas distributed bilaterally and combined with vascular anomalies and in ~13% of the cases the disease is noticeable in the first year of age. Both disorders can cause multiple swellings on the extremity, deformity around the joints, limitations in joint mobility, scoliosis, bone shortening, leg-length discrepancy, gait disturbances, bone pain, pathological fractures, facial asymmetry and cranial nerve palsies. The risk of developing a chondrosarcoma in OD and MS is ~ 30%. In addition, these patients also have a higher risk of developing gliomas, juvenile granulosa cell tumor of ovary and vascular malignancies. The molecular bases of OD and MS is not completely understood. Currently, the only treatment for patients with OD and MS is surgical; there is no pharmacologic therapy. The NIH- Common Fund's Gabriella Miller Kids First Pediatric Research Program enabled us to perform germline whole genome sequencing in 75 individuals with OD or MS and their parents and through the Baylor- Hopkins Center for Mendelian Genomics we have performed germline whole exome sequencing on 63 individuals with OD or MS. Here, we propose an analytical approach to analyze this data and identify the molecular bases of OD and MS and to use this information to investigate the cause of isolated gliomas.

项目摘要/摘要我们建议研究Ollier病（OD）和Maffucci综合征（MS）的分子碱基，罕见以多种膜状瘤为特征的疾病导致严重的骨骼畸形和风险增加用于软骨肉瘤和其他恶性肿瘤。我们的中心假设是OD和MS不足由多个基因中的变异引起的公认的癌症易感性综合征连接的途径和这些基因中的致病变异也引起其他其他形式的其他形式癌症。 OD的特征是多个邻肌瘤，在幼儿时期发作，通常是单方面的分布依赖阑尾骨骼。 MS的特征是多个inosonondromas 双侧分布并与血管异常结合，在约13％的病例中，疾病是显而易见的在第一年。两种疾病都会在肢体上引起多个肿胀，关节周围的畸形，关节迁移率，脊柱侧弯，骨骼缩短，腿长差异，步态干扰，骨痛，病理骨折，面部不对称和颅神经麻痹。在 OD和MS约为30％。此外，这些患者还具有较高的胶质瘤，少年颗粒的风险卵巢和血管恶性肿瘤的细胞肿瘤。 OD和MS的分子碱基尚未完全了解。目前，对OD和MS患者的唯一治疗方法是手术。没有药理疗法。 NIH-普通基金的Gabriella Miller儿童第一儿科研究计划使我们能够表演在75个患有OD或MS及其父母的人中，通过Baylor-种系整个基因组测序霍普金斯孟德尔基因组学中心我们在63上进行了种系整个外显病测序具有OD或MS的个人。在这里，我们提出了一种分析方法来分析这些数据并确定 OD和MS的分子碱基，并使用此信息研究分离的神经胶质瘤的原因。