Cancer Genetics of Short Telomere Syndromes

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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.