Wednesday, April 2, 2025
4/2/2025
Cancer Genetics of Long Telomere Syndromes - Abstract This application focuses on understanding the genetic basis of a recently recognized cancer-prone syndrome caused by long telomere length. It is driven by extended cellular longevity, a mechanism that is distinct from tumor suppressor- and oncogene-mediated familial cancer syndromes. Telomere length is constrained in the human population to a relatively narrow range and telomerase elongation is tightly regulated. Recent studies, from multiple lines of evidence from our group and others, have uncovered that genetically-determined short telomere length, at certain thresholds, is protective against most age-related malignancies. Exceptions include squamous cancers that arise in the setting of T cell immune exhaustion, and myelodysplastic syndrome and acute myeloid leukemia that arise in the setting of hematopoietic stem cell failure. These cancers occur at significantly higher rates among individuals with Mendelian short telomere syndromes. The relatively lower risk of other age-related malignancies in the short telomere syndromes has deep mechanistic underpinnings as short telomere length mediates cellular senescence and apoptosis, thus limiting cancer evolution in nearly all tumor-prone animal models. By contrast, there is emerging evidence that long telomere length is associated with significantly increased cancer risk in the human population with common variants in telomere genes increasing the risk for more than 28 malignancies. Our group recently reported on an autosomal dominant long telomere syndrome caused by heterozygous mutations in POT1. Haploinsufficiency of POT1 enhances telomerase elongation in vitro, and we found mediates ultra-long telomere length. POT1 mutation carriers with long telomeres had high cancer penetrance, near 100% by age 60, and were prone to multiple malignancies including melanoma, thyroid cancer, sarcoma, epithelial and hematologic malignancies. Alongside, they shared a predilection to high rates of clonal hematopoiesis, which we phylogenetically inferred arose in the first decade of life and was sustained by the longer telomere length. In more recent work, we found two other mutant telomere genes phenocopy the long telomere syndrome phenotype supporting wide locus heterogeneity. This application aims to advance this new and timely area. We will identify additional novel mechanisms for the long telomere syndrome with the goal of identifying high risk groups who would benefit from screening and surveillance. The proposed studies will define the role of these variants in familial cancer predisposition, and examine how they disrupt normal telomere length regulation in relevant genetic models and in human cancer-prone families. Building on our recently published data, and leveraging unique resources in our group, we will also examine how the long telomere background influences cancer somatic landscapes. The proposed application promises to identify novel large effect size cancer-predisposing variants in children and adults and define their underlying mechanisms of pathogenicity in relevant models, while establishing approaches that will advance patient care through early detection and prevention protocols.
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