Abstract
Telomere 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. We examined the clinical and molecular features of aging and cancer in persons carrying heterozygous loss-of-function mutations in the telomere-related geneand noncarrier relatives. A total of 17mutation 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 themutation carriers with telomere length evaluated (9 of 13) had long telomeres (>99th percentile).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 18mutation 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; somaticandhotspot 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,mutation carriers maintained telomere length over the course of 2 years. 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.).
Overview
- The study examines the clinical and molecular features of aging and cancer in persons carrying heterozygous loss-of-function mutations in the telomere-related gene and noncarrier relatives. The main focus of the study is to investigate whether long telomere length is advantageous or not. The hypothesis being tested is whether long telomere length is associated with a predisposition to clonal hematopoiesis syndrome and a range of benign and malignant solid neoplasms. The methodology used for the experiment includes evaluating telomere length in mutation carriers and noncarrier relatives, and identifying any significant differences or similarities in the results between these conditions. The primary objective of the study is to determine whether long telomere length confers a predisposition to a familial clonal hematopoiesis syndrome and a range of benign and malignant solid neoplasms, and whether this predisposition is mediated by extended cellular longevity and the capacity to maintain telomeres over time. The study aims to answer the question whether long telomere length is advantageous or not.
Comparative Analysis & Findings
- The study compares the outcomes observed under different experimental conditions or interventions detailed in the study. The results show that mutation carriers with long telomeres (>99th percentile) 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 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 and 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, mutation carriers maintained telomere length over the course of 2 years. The key findings of the study are that long telomere length is associated with a predisposition to clonal hematopoiesis syndrome and a range of benign and malignant solid neoplasms, and that this predisposition is mediated by extended cellular longevity and the capacity to maintain telomeres over time. The study supports the hypothesis that long telomere length is advantageous.
Implications and Future Directions
- The study's findings have significant implications for the field of research and clinical practice. The study suggests that long telomere length is associated with a predisposition to clonal hematopoiesis syndrome and a range of benign and malignant solid neoplasms, and that this predisposition is mediated by extended cellular longevity and the capacity to maintain telomeres over time. The study also identifies somatic driver mutations that probably arose in the first decades of life and their lineages that secondarily accumulated a higher mutation burden characterized by a clocklike signature. These findings suggest that long telomere length may be a protective factor against age-related disease and cancer. The study's limitations include the small sample size and the need for further research to validate the findings. Future research directions could include studying the mechanisms underlying the predisposition to clonal hematopoiesis syndrome and the role of long telomere length in cancer development and progression. The study also highlights the importance of genetic counseling and early detection of long telomere length in individuals with a family history of clonal hematopoiesis syndrome and cancer.