Cancer Genetics of Short Telomere Syndromes

项目摘要 这种应用程序的重点是定义遗传基础的癌症易患综合征所造成的异常短 端粒长度端粒酶成分的突变是其最著名的原因，但在近一半的人中， 常染色体显性遗传家族，突变基因未知。我们之前已经证明，这些疾病 是最常见的早衰综合征，大多数人在中年时表现出症状， 到成年晚期骨髓增生异常综合征和急性髓性白血病是最常见的STS癌症; 它们在短端粒综合征患者中的发病率增加了2000倍， 在这一人群中诊断出的癌症中有一半。端粒酶基因的突变也是 家族性骨髓增生异常综合征和急性髓细胞白血病的流行原因。识别患者， 端粒介导的癌症对于临床管理是至关重要的，因为它们高度倾向于毒性， 传统疗法。他们还经常依赖于从相关捐赠者那里移植干细胞作为治疗， 因此必须鉴定遗传病因以避免供体来源的并发症。这项建议 建立在约翰霍普金斯的一个长期项目之上，该项目专注于定义短的遗传基础。 端粒综合征，并将这些知识应用于临床模式，以促进患者护理。它 包括了世界上最大和最具特征的短端粒综合征患者群体之一， 世界我们的目标是通过以家族为基础的研究来确定新的孟德尔癌症易感基因， 了解这些基因在端粒长度维持中的作用。我们的发现与以下方面有直接关系： 了解癌症的遗传基础，推进骨髓增生异常的精准医学范式 综合征和急性髓系白血病患者，同时加深了对端粒酶的基本认识 生物学和端粒维持机制。

Project Summary This application focuses on defining the genetic basis of cancer prone syndromes caused by abnormally short telomere length. Mutations in telomerase enzyme components are their best known cause, but in nearly half of autosomal dominant families, the mutant gene is not known. We have previously shown that these disorders are the most common premature aging syndromes with a majority of individuals manifesting symptoms in mid to late adulthood. Myelodysplastic syndrome and acute myeloid leukemia are the most common STS cancers; they have a 2000-fold increased incidence in patients with short telomere syndromes and comprise at least half of the cancers diagnosed in this population. Mutations in the telomerase genes are also the most prevalent cause of familial myelodysplastic syndrome and acute myeloid leukemia. Recognizing patients with telomere-mediated cancers is critical for clinical management since they are highly prone to toxicities from conventional therapies. They also often rely on stem cell transplantation from related donors as a therapy, making it essential to identify the genetic etiology in order to avoid donor-derived complications. This proposal builds on a long-standing program at Johns Hopkins that is focused on defining the genetic basis of short telomere syndromes and implementing that knowledge into clinical paradigms that advance patient care. It includes one of the largest and best characterized populations of short telomere syndrome patients in the world. Our goal is to identify new Mendelian cancer predisposing genes through family-based studies and to understand the role of these genes in telomere length maintenance. Our findings have direct relevance for understanding the genetic basis of cancer, advancing precision medicine paradigms for myelodysplastic syndrome and acute myeloid leukemia patients, while deepening the fundamental understanding of telomerase biology and telomere maintenance mechanisms.