Study Uncovers Link Between Long Telomere Length, Cancer Predisposition

While there is a known link between shortened telomeres and age-related disease, excessively long telomere length may also have negative health implications, predisposing a person to a range of cancers, according to a new study in this week's New England Journal of Medicine. The length of telomeres — which are made up of tandem sequences at chromosome ends that shorten with cell division — predicts the onset of replicative senescence and functions as a mitotic clock. Short dysfunctional telomeres signal DNA damage, which elicits a cellular response that leads to senescence or apoptosis, and short telomere syndromes are associated with pulmonary and hematopoietic disease. It is unclear, however, whether long telomere length is advantageous. To investigate, a team led by Johns Hopkins University scientists examined the clinical and molecular features of aging and cancer in 17 people with heterozygous loss-of-function mutations in the telomere-related gene POT1, along with 21 relatives without the mutations. They find that mutations that lead to long telomeres 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, the study's authors write, was mediated by extended cellular longevity and by the capacity to maintain telomeres over time. "Overall, our data uncover an inherited cancer-predisposition mechanism that is distinct from that of mutations affecting tumor-suppressor proteins and oncoproteins: an extended cellular lifespan that supports clonal evolution with aging," they conclude.