Familial Clonal Hematopoiesis in Individuals With a Mutation in Telomere-Related Gene POT1

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In a study reported in The New England Journal of Medicine, DeBoy et al found that individuals carrying germline heterozygous loss-of-function mutations in the telomere-related gene POT1 had long telomeres and may be at risk for benign and malignant neoplasms as part of a familial clonal hematopoiesis syndrome.

Study Details

The study enrolled 17 POT1 mutation carriers and 21 noncarrier relatives at Johns Hopkins University School of Medicine, with 6 additional carriers subsequently added to the cohort.

Key Findings

Among 13 evaluable POT1 mutation carriers, all had a mean telomere length > 90th percentile and 9 had a mean telomere length > 99th percentile (P < .001 for both comparisons with noncarrier relatives). Noncarrier relatives exhibited typical telomere shortening with age, whereas POT1 mutation carriers maintained their telomere length over the course of 2 years of follow-up.

POT1 mutation carriers exhibited a range of benign and malignant neoplasms involving epithelial, mesenchymal, and neuronal tissues, in addition to B- and T-cell lymphoma and myeloid cancers. For example, neoplasms of melanocyte origin included dysplastic nevi in four, melanoma in situ in three, and invasive melanoma in seven. Other neoplasms included: renal cell carcinoma, colorectal adenocarcinoma, and urothelial carcinoma of the bladder in one patient each; goiter in four and papillary thyroid cancer in three; and malignant glioma in two. Overall, among evaluable mutation carriers, 5 (28%) of 18 had T-cell clonality and 8 (67%) of 12 had clonal hematopoiesis of indeterminate potential.

Predisposi­tion to clonal hematopoiesis exhibited an autosomal dominant pattern of inheritance and penetrance that increased with age; somatic DNMT3A and JAK2 hotspot mutations were the most commonly identified mutations. As stated by the investigators, “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 (ie, an increasingly early onset of disease).”

The investigators concluded, “POT1 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.”

Mary Armanios, MD, of the Depart­ment of Oncology, Johns Hopkins Uni­versity School of Medicine, is the corresponding author for The New England Journal of Medicine article.

Disclosure: The study was funded by the National Institutes of Health and others. For full disclosures of the study authors, visit

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