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

项目摘要/摘要 我们建议研究罕见的奥利尔病(OD)和Maffucci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 治疗软骨肉瘤和其他恶性肿瘤。我们的中心假设是过量和多发性硬化症- 公认的癌症易感综合征是由干扰少数基因的多个基因变异引起的 这些基因中的致病变异也会导致分离的其他形式的 癌症。 OD的特征是多发内生软骨瘤，起病于儿童早期，通常是单侧的 分布偏向于附肢骨骼。多发性硬化症的特点是多发性软骨瘤。 双侧分布并合并血管异常，约13%的病例明显 在一岁的时候。这两种疾病都会导致四肢多发性肿胀，关节周围畸形， 关节活动受限，脊柱侧弯，骨骼缩短，腿长不等，步态障碍，骨痛， 病理性骨折、面部不对称和脑神经麻痹。罹患软骨肉瘤的风险 OD和MS为~30%。此外，这些患者患神经胶质瘤、幼年颗粒瘤的风险也较高。 卵巢细胞瘤和血管恶性肿瘤。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。 美国国立卫生研究院共同基金的加布里埃拉·米勒儿童首个儿科研究计划使我们能够进行 75例OD或MS患者及其父母的生殖系全基因组测序 霍普金斯大学孟德尔基因组学中心对63个基因组进行了种系全外显子组测序 在这里，我们提出了一种分析方法来分析这些数据并确定 并利用这些信息来研究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.