• Emily A DeBoy, Michael G Tassia, Kristen E Schratz, Stephanie M Yan, Zoe L Cosner, Emily J McNally, Dustin L Gable, Zhimin Xiang, David B Lombard, Emmanuel S Antonarakis, Christopher D Gocke, Rajiv C McCoy, and Mary Armanios.
• From the Departments of Oncology (E.A.D., K.E.S., Z.L.C., E.J.M., Z.X., E.S.A., C.D.G., M.A.), Pathology (C.D.G., M.A.), and Genetic Medicine (M.A.), the Medical Scientist Training Program (E.A.D.), the Telomere Center (E.A.D., K.E.S., Z.L.C., E.J.M., Z.X., M.A.), and Sidney Kimmel Comprehensive Cancer Center (K.E.S., E.S.A., C.D.G., M.A.), Johns Hopkins University School of Medicine, and the Department of Biology, Krieger School of Arts and Sciences, Johns Hopkins University (M.G.T., S.M.Y., R.C.M.) - both in Baltimore; the Child Neurology Residency Program, Boston Children's Hospital, Boston (D.L.G.); the Department of Pathology and Laboratory Medicine, Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami (D.B.L.); and the Division of Hematology, Oncology, and Transplantation, University of Minnesota Masonic Cancer Center, Minneapolis (E.S.A.).
• N. Engl. J. Med. 2023 Jun 29; 388 (26): 242224332422-2433.

BackgroundTelomere shortening is a well-characterized cellular aging mechanism, and short telomere syndromes cause age-related disease. However, whether long telomere length is advantageous is poorly understood.MethodsWe examined the clinical and molecular features of aging and cancer in persons carrying heterozygous loss-of-function mutations in the telomere-related gene POT1 and noncarrier relatives.ResultsA total of 17 POT1 mutation carriers and 21 noncarrier relatives were initially included in the study, and a validation cohort of 6 additional mutation carriers was subsequently recruited. A majority of the POT1 mutation carriers with telomere length evaluated (9 of 13) had long telomeres (>99th percentile). POT1 mutation carriers had a range of benign and malignant neoplasms involving epithelial, mesenchymal, and neuronal tissues in addition to B- and T-cell lymphoma and myeloid cancers. Five of 18 POT1 mutation carriers (28%) had T-cell clonality, and 8 of 12 (67%) had clonal hematopoiesis of indeterminate potential. A predisposition to clonal hematopoiesis had an autosomal dominant pattern of inheritance, as well as penetrance that increased with age; somatic DNMT3A and JAK2 hotspot mutations were common. These and other somatic driver mutations probably arose in the first decades of life, and their lineages secondarily accumulated a higher mutation burden characterized by a clocklike signature. Successive generations showed genetic anticipation (i.e., an increasingly early onset of disease). In contrast to noncarrier relatives, who had the typical telomere shortening with age, POT1 mutation carriers maintained telomere length over the course of 2 years.ConclusionsPOT1 mutations associated with long telomere length conferred a predisposition to a familial clonal hematopoiesis syndrome that was associated with a range of benign and malignant solid neoplasms. The risk of these phenotypes was mediated by extended cellular longevity and by the capacity to maintain telomeres over time. (Funded by the National Institutes of Health and others.).Copyright © 2023 Massachusetts Medical Society.

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