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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：
10199960
负责人：
Mary Y Armanios
金额：
$ 46.94万
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 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10199960
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.

项目总结