Long telomeres linked to higher lymphoma risk in families
· News-MedicalResearchers at the Johns Hopkins Kimmel Cancer Center and the Telomere Clinic at Johns Hopkins have identified a genetic syndrome in which unusually long telomeres - the protective caps at the ends of chromosomes - allow immune cells to remain biologically "younger" for longer than normal, predisposing affected individuals to lymphoma and other cancers.
The research, published May 7 in Blood, and funded in part by the National Institutes of Health, shows that inherited loss-of-function mutations in the POT1 gene disrupt the normal aging of lymphocytes, sustaining long-lived cells that can accumulate cancer-associated changes over time.
POT1 normally helps keep telomere length in check. When one of the two copies of the gene is inactivated, telomeres become excessively long. While long telomeres have often been viewed as protective of aging, the new study, which builds on prior work, shows that, in this inherited setting, extended cellular longevity may come at a cost of increased risk of blood cancers.
In the study, investigators examined cancer histories and biological samples from 51 individuals across 24 families who carried POT1 variants. After melanoma skin cancer, known to be associated with POT1 mutations, the most common cancers were hematologic malignancies and thyroid cancer. Three-quarters of the blood cancers arose from lymphocytes, the immune cells responsible for fighting infection.
Mary Armanios, M.D., professor of oncology and genetic medicine and director of the Telomere Center at Johns HopkinsThe spectrum of lymphoid cancers was striking. 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."
To test whether these findings extended beyond affected families, the researchers analyzed data from 210 adults with POT1 variants in the UK Biobank, a large population study that included nearly 500,000 persons. They found an eightfold higher risk of lymphoma, with 45% developing a lymphoid cancer by age 80.
To understand how lymphoma risk develops, the team studied individuals who had not yet been diagnosed with lymphoma. Even in these people, the researchers found evidence of early lymphocyte clonality, a slow-growing precursor to lymphoma. After age 60, nearly all POT1 mutation carriers showed expanded lymphocyte clones, and most harbored mutations commonly associated with lymphoma.
While 60% of individuals with POT1 mutations had ultra-long telomere length in the top 1% of the human population, others had shorter telomere length potentially reflecting the lymphoid clonal state.
Normally, telomeres shorten with age, helping limit the lifespan of cells that accumulate damage. In contrast, lymphocytes from POT1 mutation carriers did not show this expected shortening. Instead, telomere length remained stable, and in some cases, appeared to lengthen, allowing mutations that would typically be lost with aging to persist.
Telomerase, the enzyme that lengthens telomeres, is tightly regulated in most cells but is noted for its activity in lymphocytes. In the absence of normal POT1 function, this regulation is disrupted, increasing opportunities for telomere elongation as immune cells divide. Although lymphoid cancers were most commonly seen, the researchers also observed rarer slow-growing myeloid blood cancers, sometimes occurring alongside lymphoma in the same individual.
"Our findings point to a new mechanism of lymphoma susceptibility that is linked to extended cellular longevity," says Armanios. "In this setting, lymphocytes retain a kind of youthfulness that allows cancer-associated mutations to persist and expand over time."
There are about 1 million people in the U.S. living with lymphoma, according to the National Cancer Institute's SEER database. The study also helps explain why some people with lymphoma are at increased risk for developing other malignancies, such as melanoma, and offers insight into why telomere shortening with aging - long viewed only as a limitation - may serve a protective role by pruning damaged cells.
Armanios says "Our data suggest that, for now, telomere length clinical testing should be reserved for individuals with variants in the gene that have unclear significance."
There are currently no established screening protocols for lymphoma, and the optimal cancer surveillance strategies for individuals with POT1 mutations are uncertain. Some experts favor careful clinical monitoring, while others consider more proactive approaches. Further research is needed to better understand how these findings should inform clinical care, says Armanios.
In addition to Armanios, other researchers participating in the study were Hannah Davidson-Swinton, Sheila Iyer, Anna Kolchinski, Jasmine Salem, Emily DeBoy, Andrew Kilada, Jisoo Hwang, Tania Jain, Christopher Gocke, Ying Zou, and Kristen Schratz from Johns Hopkins, and Sioban Keel from the University of Washington.
The research was supported by the National Institutes of Health grants R01CA29812 K08HL163468, and P30CA006973 and the Commonwealth Foundation.
Armanios has a pending patent application for the use of telomere length in assessing cancer risk.
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