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.

项目概要/摘要我们建议研究罕见的奥利尔病 (OD) 和马夫奇综合征 (MS) 的分子基础以多发性软骨瘤为特征的疾病，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 不足公认的癌症易感性综合症是由多个基因变异引起的，这些变异破坏了少数基因连接的途径，并且这些基因中的致病变异也会导致其他形式的孤立形式癌症。 OD 的特点是多发性软骨瘤，在儿童早期发病，通常为单侧分布以附肢骨骼为主。 MS 的特点是多发性软骨瘤双侧分布并伴有血管异常，约 13% 的病例疾病明显在第一年。这两种疾病都会导致四肢多处肿胀、关节周围畸形、关节活动受限、脊柱侧凸、骨质缩短、腿长不等、步态障碍、骨痛、病理性骨折、面部不对称和颅神经麻痹。患软骨肉瘤的风险 OD 和 MS 约为 30%。此外，这些患者患神经胶质瘤、幼年颗粒细胞瘤的风险也较高卵巢细胞肿瘤和血管恶性肿瘤。 OD 和 MS 的分子基础尚不完全清楚。目前，OD 和 MS 患者的唯一治疗方法是手术治疗。没有药物治疗。 NIH 共同基金的 Gabriella Miller Kids First 儿科研究计划使我们能够执行贝勒大学对 75 名 OD 或 MS 患者及其父母进行种系全基因组测序霍普金斯孟德尔基因组学中心我们对 63 例进行了种系全外显子组测序患有 OD 或 MS 的个体。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 的分子基础，并利用这些信息来研究孤立性神经胶质瘤的原因。