May 23, 2023

Long telomeres may heighten cancer risks

At a Glance

  • People with mutations that lead to excessively long chromosome tips, or telomeres, may be at increased risk for a range of cancers.
  • The findings add another dimension to earlier research suggesting that increased telomere length can slow the aging process and prolong life.
Illustration of X-shaped chromosomes with telomere caps at the end of each arm. Telomeres are structures at the ends of chromosomes that protect them from being broken down. / Shutterstock

Telomeres are protective molecular caps at the ends of chromosomes. They keep chromosome tips from being broken down. Telomeres tend to shorten as we get older, because they naturally erode each time cells divide. When telomeres shrink to a certain threshold, the cell stops multiplying or dies.

Shortened telomeres have been linked to age-related disorders and early death in humans. Since long telomeres extend cells’ lifespan, some have suggested that boosting telomere length might help to delay certain age-related illnesses. But longer telomeres might carry their own sets of risks. And the potential health effects of having very long telomeres are poorly understood.

To learn more, a research team led by Dr. Mary Armanios of Johns Hopkins University studied people who have rare mutations that disable a telomere-related gene called POT1. This gene codes for a protein that normally helps to regulate telomere length. Mutations that hinder normal POT1 activity can lead to excessively long telomeres.

The scientists identified 17 people with POT1 mutations from five unrelated families. The people ranged in age from 7 to 83, with most over age 40. Four had died from cancer. The researchers measured telomere length in the participants who were alive. For comparison, they also studied 21 relatives of the participants who didn’t have the POT1 mutations. Findings were described in the New England Journal of Medicine on May 4, 2023.

The team found that all 13 people who were alive had telomeres that were longer on average than those of their relatives without the POT1 mutations. Their telomeres were 90% longer than average. Some of those with the POT1 mutations showed modest signs of slowed aging, such as delayed graying of hair.

However, 15 of the 17 participants with the mutations had some type of abnormal tissue growth, called neoplasms, that ranged from benign to cancerous. Eight had different types of the skin cancer melanoma. Seven had thyroid neoplasms, including thyroid cancer and goiters. The most life-threatening neoplasm was malignant glioma, a type of brain cancer that affected two participants.

In addition, five of the participants with the POT1 mutations had different types of blood-related cancers. Eight of 12 (67%) people analyzed also had an age-related blood condition called CHIP (clonal hematopoiesis of indeterminate potential). CHIP typically affects only about 10 to 20% of adults over the age of 70. It has been linked to an increased risk for blood and other cancers. The team found evidence that faulty POT1 activity can allow cancerous blood cells to grow and proliferate because they’re unchecked by the normal cell death that occurs when telomeres shorten.

These findings challenge the idea that strategies to lengthen telomeres could effectively protect against aging. “Cells with very long telomeres accumulate mutations and appear to promote tumors and other types of growths that would otherwise be put in check by normal telomere shortening processes,” Armanios says.

—by Vicki Contie

Related Links

References: Familial Clonal Hematopoiesis in a Long Telomere Syndrome. DeBoy EA, Tassia MG, Schratz KE, Yan SM, Cosner ZL, McNally EJ, Gable DL, Xiang Z, Lombard DB, Antonarakis ES, Gocke CD, McCoy RC, Armanios M. N Engl J Med. 2023 May 4. doi: 10.1056/NEJMoa2300503. Online ahead of print. PMID: 37140166.

Funding: NIH’s National Cancer Institute (NCI), National Heart, Lung, and Blood Institute (NHLBI), National Institute of General Medical Sciences (NIGMS), and National Human Genome Research Institute (NHGRI); S&R Foundation; Commonwealth Foundation; Godrej Industries; Turock Family Scholars Fund; American Society of Hematology Scholar Award; Vera and Joseph Dresner Foundation.