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

项目总结/摘要 我们建议研究Ollier病（OD）和Maffucci综合征（MS）的分子基础， 以多发性内生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在- 公认的癌症易感性综合征是由多个基因的变异引起的， 这些基因中的致病变异也会导致其他疾病的孤立形式。 癌的 OD的特点是多发性内生软骨瘤，发病于儿童早期，通常为单侧， 分布与一个preelection为appropriular骨骼。多发性硬化症的特征是多发性内生软骨瘤 双侧分布，并合并血管异常，约13%的病例中，该疾病是明显的 在第一年的年龄。这两种疾病都可能导致四肢多发性肿胀，关节周围畸形， 关节活动受限、脊柱侧凸、骨缩短、下肢不等长、步态障碍、骨痛， 病理性骨折、面部不对称和脑神经麻痹。患软骨肉瘤的风险 OD和MS约为30%。此外，这些患者也有较高的风险发展胶质瘤，青少年颗粒 卵巢细胞瘤和血管恶性肿瘤。OD和MS的分子基础尚未完全理解。 目前，OD和MS患者的唯一治疗方法是手术;没有药物治疗。 美国国立卫生研究院共同基金的加布里埃拉米勒儿童第一儿科研究计划使我们能够执行 对75名OD或MS患者及其父母进行生殖系全基因组测序，并通过Baylor- 霍普金斯孟德尔基因组学中心，我们已经对63个 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，并利用这些信息来调查孤立的胶质瘤的原因。

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.