Telomeres are essential for the maintenance of genomic integrity. Dyskeratosis congenita (DC) is a cancer- prone syndrome characterized by short telomeres. Affected patients have an increased risk for developing hematologic malignancies, specifically myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). While DC is an inherited Mendelian disorder, germline mutations in telomerase and telomere components are identifiable in only two-thirds of families, leaving the causal mutations in the remaining cases uncharacterized. Mutations in DC genes also underlie inheritance in a subset of MDS and AML families. This fact, along with the observation that MDS-AML patients have short telomeres, has suggested an intimate role for telomere length in the genetics of these disorders. This project examines two aspects of DC genetics and biology of relevance to understanding MDS-AML pathogenesis.
We aim to identify novel genes that are critical for telomere maintenance by studying genetically uncharacterized DC families in a registry we have established. Given the known limitations of traditional linkage approaches in small kindreds, the cohort we have compiled provides an ideal setting to apply next-generation sequencing technologies for the purpose of gene discovery.
In Aim 2, we examine the biology by which short telomeres promote MDS-AML in an animal model of DC we have characterized. This murine model uniquely recapitulates human telomere length dynamics. The proposed studies in DC have particular significance for understanding the biology of MDS-AML since the telomere defect found in DC patients is universally acquired with aging, and the biology that underlies the increasing incidence of MDS-AML with age is not understood. Broadly, they have implications for understanding fundamental questions regarding the role of telomere length in cancer risk and progression.
This proposal aims to understand the genetics that predispose to myelodysplastic syndromes and acute myeloid malignancies. Both disorders account for as many as 20,000 deaths in the United States alone and treatment options are limited and toxic. Our goal is to improve the understanding of the inherited factors that predispose to these disorders with aging with the goal of improving their prevention and treatment.
|Parry, Erin M; Gable, Dustin L; Stanley, Susan E et al. (2017) Germline Mutations in DNA Repair Genes in Lung Adenocarcinoma. J Thorac Oncol 12:1673-1678|
|Lee, Melissa; Roos, Patrick; Sharma, Neeraj et al. (2017) Systematic Computational Identification of Variants That Activate Exonic and Intronic Cryptic Splice Sites. Am J Hum Genet 100:751-765|
|Stanley, Susan E; Gable, Dustin L; Wagner, Christa L et al. (2016) Loss-of-function mutations in the RNA biogenesis factor NAF1 predispose to pulmonary fibrosis-emphysema. Sci Transl Med 8:351ra107|
|Stanley, Susan E; Merck, Samantha J; Armanios, Mary (2016) Telomerase and the Genetics of Emphysema Susceptibility. Implications for Pathogenesis Paradigms and Patient Care. Ann Am Thorac Soc 13:S447-S451|
|You, Jing; Sobreira, Nara L; Gable, Dustin L et al. (2016) A Syndromic Intellectual Disability Disorder Caused by Variants in TELO2, a Gene Encoding a Component of the TTT Complex. Am J Hum Genet 98:909-918|
|Stanley, Susan E; Rao, Avani Dholakia; Gable, Dustin L et al. (2015) Radiation Sensitivity and Radiation Necrosis in the Short Telomere Syndromes. Int J Radiat Oncol Biol Phys 93:1115-7|
|Alder, Jonathan K; Stanley, Susan E; Wagner, Christa L et al. (2015) Exome sequencing identifies mutant TINF2 in a family with pulmonary fibrosis. Chest 147:1361-1368|
|Stanley, Susan E; Armanios, Mary (2015) The short and long telomere syndromes: paired paradigms for molecular medicine. Curr Opin Genet Dev 33:1-9|
|Gorgy, Amany I; Jonassaint, Naudia L; Stanley, Susan E et al. (2015) Hepatopulmonary syndrome is a frequent cause of dyspnea in the short telomere disorders. Chest 148:1019-1026|
|Stanley, Susan E; Chen, Julian J L; Podlevsky, Joshua D et al. (2015) Telomerase mutations in smokers with severe emphysema. J Clin Invest 125:563-70|
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