Cancer Genetics of Short Telomere Syndromes

短端粒综合征的癌症遗传学

基本信息

批准号：
10434717
负责人：
Mary Y Armanios
金额：
$ 44.67万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-07-03 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10434717
关键词：
Acute Myelocytic Leukemia Adult Affect Animal Model Area Automobile Driving Biogenesis Biology Cancer-Predisposing Gene Candidate Disease Gene Cell Line Cells Clinical Clinical Management Complex DNA Polymerase II Data Diagnosis Disease Dysmyelopoietic Syndromes Enzymes Etiology Family Functional disorder Gene Mutation Generations Genes Genetic Genetic Predisposition to Disease Genetic study Germ-Line Mutation Goals Heterogeneity In Vitro Incidence Individual Knowledge Length Life Lung diseases Malignant Neoplasms Mediating Modeling Molecular Mus Mutation Nuclear RNA Pathway interactions Patient Care Patient-Focused Outcomes Patients Phenotype Population Premature aging syndrome Prevalence Proteins Publishing Pulmonary Fibrosis RNA RNA 3&apos End Processing RNA-Directed DNA Polymerase Registries Regulation Reporting Resources Ribonucleoproteins Risk Role Stem cell transplant Symptoms Syndrome Technology Telomerase Telomerase RNA Component Telomere Length Maintenance Telomere Maintenance Telomere Shortening Time Toxic effect United States Untranslated RNA Work Zinc base cancer diagnosis cancer genetics cancer risk cohort conventional therapy design exosome experience gene discovery gene function genetic linkage analysis genetic risk factor genome sequencing in vivo insight loss of function mutation mutant novel novel strategies precision medicine programs recruit standard care success telomere tool whole genome

项目摘要

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.

项目摘要该应用重点是定义异常短的癌症易于综合症的遗传基础端粒长度。端粒酶成分的突变是其最著名的原因，但在几乎一半常染色体显性遗传，突变基因尚不清楚。我们以前已经表明这些疾病是最常见的过早衰老综合症，大多数人在中期表现出症状到成年晚期。骨髓增生性综合征和急性髓细胞性白血病是最常见的ST癌。他们的端粒综合征较短患者的发病率增加了2000倍，至少包括在该人群中被诊断出的一半癌症。端粒酶基因中的突变也是最大的家族性骨髓增生综合征和急性髓样白血病的普遍原因。认识患者端粒介导的癌症对于临床管理至关重要，因为它们很容易受到毒性的毒性常规疗法。他们也经常依靠从相关供体的干细胞移植作为一种疗法，为了避免供体衍生的并发症，确定遗传病因至关重要。这个建议建立在约翰·霍普金斯（Johns Hopkins）的长期计划的基础上，该计划的重点是定义简短的遗传基础端粒综合征并将这些知识实施到可以推进患者护理的临床范例中。它包括最大，最佳特征的短端粒综合征患者人群之一世界。我们的目标是通过基于家庭研究和了解这些基因在端粒长度维持中的作用。我们的发现与了解癌症的遗传基础，推进骨髓增生的精确医学范式综合征和急性髓样白血病患者，同时加深对端粒酶的基本了解生物学和端粒维护机制。

项目成果

期刊论文数量（2）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Liver Transplantation in Short Telomere-Mediated Hepatopulmonary Syndrome Following Bone Marrow Transplantation Using HCV Positive Allografts: A Case Series.

DOI：
10.1002/lt.26109
发表时间：
2021-12
期刊：
Liver transplantation : official publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society
影响因子：
0
作者：
Oseini AM;Hamilton JP;Hammami MB;Kim A;Oshima K;Woreta T;Rizkalla N;Pustavoitau A;Merlo C;Nguyen MC;King EA;Wesson RN;Garonzik-Wang J;Ottmann S;Philosophe B;Cameron AM;Armanios M;Gurakar A
通讯作者：
Gurakar A

Extrahematopoietic manifestations of the short telomere syndromes.

短端粒综合征的造血外表现。