Cancer Genetics of Short Telomere Syndromes

项目摘要 这个应用程序的重点是定义由异常矮小引起的癌症易发综合征的遗传基础 端粒长度。端粒酶成分的突变是他们最知名的原因，但在近一半的 常染色体显性家系中，突变基因尚不清楚。我们之前已经证明，这些障碍 是最常见的早衰综合症，大多数人在年中出现症状。 到了成年后期。骨髓增生异常综合征和急性髓系白血病是最常见的STS癌症； 它们在短端粒综合征患者中的发病率增加了2000倍，并且至少包括 在这个人群中被诊断出的癌症有一半。端粒酶基因的突变也是最多的 家族性骨髓增生异常综合征和急性髓系白血病的流行原因。识别患有以下疾病的患者 端粒介导的癌症对于临床治疗至关重要，因为它们极易受到 传统疗法。他们还经常依靠亲属捐赠者的干细胞移植作为治疗方法， 因此有必要确定遗传病因，以避免供体衍生的并发症。这项建议 建立在约翰·霍普金斯大学一个长期项目的基础上，该项目专注于定义矮小的遗传基础 端粒综合征，并将这一知识应用到促进患者护理的临床范例中。它 包括最大和最具特征的短端粒综合征患者群体之一 世界。我们的目标是通过基于家庭的研究识别新的孟德尔癌症易感基因，并 了解这些基因在维持端粒长度中的作用。我们的发现与 了解癌症的遗传基础，推进骨髓增生异常的精准医学范式 综合征与急性髓系白血病患者，同时加深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.