Researchers at the Johns Hopkins Kimmel Cancer Center and the Telomere Clinic at Johns Hopkins have identified an inherited cancer predisposition syndrome that results in unusually long telomeres that allow lymphocytes to stay in a biologically more youthful state for extended periods, increasing the risk of lymphoid malignancies. The findings, published the journal Blood, showed that inherited loss-of-function mutations in the POT1 gene disrupt normal telomere regulation and alter the aging dynamics of immune cells. The investigators found that because of this longer cellular lifespan cancer-associated mutations are persistent and expand over time, creating favorable conditions for the development of lymphoma and related blood cancers.
“The spectrum of lymphoid cancers was striking,” said senior author Mary Armanios, MD, a professor of medicine at Johns Hopkins. “Family members developed childhood leukemia, multiple forms of lymphoma, and adult-onset chronic lymphocytic leukemia—cancers often considered biologically distinct and associated with different inherited risks. Yet within the same families, multiple lymphoid malignancies appeared across generations. Some individuals developed melanoma before lymphoma, while others developed as many as five cancers over a lifetime. The good news is the cancers tended to be slow-growing and usually curable.”
Telomeres are protective caps at the ends of chromosomes that normally shorten with age and as a result of cell division, which limits the lifespan of cells that accumulate damage. POT1, or protection of telomeres 1, normally regulates telomere length by binding single-stranded telomeric DNA and restricting telomerase-mediated elongation. The researchers said that “POT1 binds single-stranded telomeric DNA and is essential for telomere protection, but POT1 heterozygous loss of function is permissive of telomerase elongation in the absence of a detectable DNA damage response.”
For their initial research the investigators focused on 51 people from 24 families that were know to carry mutant POT1 variants. The surveyed the participants to evaluate family cancer histories and collected biological samples to define the range of cancers associated with the mutations with the aim of examining how telomeres influenced lymphocyte aging. The data showed that among this small cohort, hematologic malignancies were the second most common cancers after melanoma, occurring in 27% of participants, with lymphoid cancers accounting for approximately three-quarters of blood malignancies found.
As a result, the researchers noted that “our data identify extended cellular longevity due to long TL as an inherited risk factor for lymphoma, explaining its syndromic association with solid tumors and, in some cases, myeloproliferative neoplasms.”
The investigators also found that telomeres responded differently that is typically observed as people aga. In those people with the POT1 mutation telomere length remained stable over time and in some cases lengthened rather than shortening with age. The findings indicated that lymphocytes retained prolonged replicative capacity, allowing cells with oncogenic mutations to survive instead of being eliminated through senescence.
To find out whether these findings extended beyond the studied families, the researchers then analyzed data from 210 adults with POT1 variants enrolled in the UK Biobank and found that people carrying pathogenic POT1 variants had an eightfold increased risk of lymphoma, and 45% developed lymphoid malignancies by age 80.
The research also examined asymptomatic POT1 mutation carriers to understand how lymphoma develops before clinical diagnosis. Among carriers without lymphoma, 12 of 20 had evidence of B-cell or T-cell clonality, a precursor state associated with lymphoma development. After age 65, all studied carriers showed detectable clonality. Sequencing and cytogenetic analyses revealed lymphoma-associated mutations in nearly all mutation carriers older than 60 years.
The study was prompted by earlier research which has shown evidence linking long telomeres to tumor development. Work in animal models had shown that long telomere length can bypass cellular senescence checkpoints and increase tumor incidence. Other research had also found POT1 mutations in melanoma, papillary thyroid cancer, glioma, sarcoma, and chronic lymphocytic leukemia. But, the prevalence and natural history of these mutations across hematologic malignancies had remained uncertain.
The findings may influence future approaches to cancer surveillance and genetic evaluation in individuals with POT1 variants. The researchers said that ultralong lymphocyte telomere length could help identify pathogenic variants and distinguish variants of uncertain significance. They noted, however, that telomere length testing may have limitations because advanced clonality can interview with the ability to accurately measure baseline telomeres.
“Our data suggest that, for now, telomere length clinical testing should be reserved for individuals with variants in the gene that have unclear significance,” Armanios said.
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