SHORT TELOMERES AND CANCER RISK

July 9, 2010 — The first prospective population-based study to examine telomere length and subsequent cancer risk has confirmed animal data suggesting that short telomeres are associated with higher cancer risk and worse cancer survival. The study appears in the July 7 issue of JAMA.

"The key message that the aging of cells may contribute to cancer manifestation and dissemination has been postulated before, based on several lines of evidence. Our study provides the first large-scale support of this notion," senior author Stefan Kiechl, MD, from the Department of Neurology at Innsbruck Medical University in Austria, told Medscape Medical News.

The researchers suggest that this might be because some cells that have lost bits of telomere over many cell cycles reactivate telomerase in a bid to recover their lost youth, but wind up with uncontrolled cell division instead.

Telomeres are nucleoprotein complexes at the ends of chromosomes that shorten a bit with each cell division, and thus constitute a sort of internal cell clock. Once telomeres shorten to nubs, their associated chromosomes become unstable, and the cell is headed for senescence and death. Experimental work in animals has suggested that short telomeres might also contribute to malignant cell transformation.

The research team, led by Peter Willeit, MD, from Innsbruck Medical University, report that short telomere length was associated with a 60% increased risk for subsequent cancer, independent of other risk factors, in 787 subjects in the Bruneck Study in Italy. All were cancer-free at baseline in 1995, when leukocyte telomere length was measured by quantitative polymerase chain reaction.

Subjects with the shortest telomeres had more than triple the incident cancer risk of those with the longest telomeres. Hazard ratio for incident cancer was 1.60 for every 1-standard-deviation (1-SD) decrease in telomere length. Compared with subjects in the group with the longest telomeres, incident cancer risk was 3.11 for those in the group with the shortest telomeres and 2.15 for those in the group with mid-length telomeres.

The researchers also found a doubling of cancer mortality with every 1-SD decrease in telomere length, that the association between telomere length and cancer risk applied to both males and females, and that short telomeres were particularly associated with cancer subtypes with high fatality rates.

Dr. Kiechl said that the study could have implications for clinical trial design. "However, a step to be taken is to prove whether telomere length at the time of cancer diagnosis is a predictor of cancer mortality as well; preliminary unpublished data form our group indicate that this is the case. In the current JAMA publication, we have measured telomere length well in advance of cancer onset," Dr. Kiechl said.

Dr. Kiechl expects telomere length to be useful in cancer screening. "We are confident that telomere length, in addition to other recent advances like microRNA profiling, may become components of future risk scores for cancer manifestation — at least for some types of cancer," he said. "I think that it may also become useful in the estimation of tumor prognosis, which again can influence the choice of therapy."

Dr. Kiechl also said that the researchers were surprised to find that individuals with the shortest telomeres at baseline showed an increase in telomere length over the 10-year follow-up. "This may eventually indicate that aged cells at risk of cell senescence are capable of reactivating telomerase to prolong telomeres," he said.

The researchers have disclosed no relevant financial relationships.

JAMA. 2010;304:69-75. Abstract