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Telomere Length Linked to Genomic Alterations in 31 Cancers

NEW YORK (GenomeWeb) – Cancer cells use a variety of mechanisms to survive cellular crisis, including through telomere maintenance processes. By activating telomerase, cancer cells can counteract telomere shortening, and therefore avoid tumor-suppressing senescence and crisis.

In a paper published today in Nature Genetics, a team led by researchers at the Jackson Laboratory and the University of Texas MD Anderson Cancer Center showed the links between telomerase activity, genomic abnormalities, and telomere length in 31 different cancer types.

"The telomerase enzymatic subunit, encoded by [telomerase reverse transcriptase] TERT, is transcriptionally silent in most non-neoplastic cells, but reactivation may endow a small population of cells with the ability to survive crisis, at which point they become immortalized," the authors wrote.

"It has been proposed that up to 90 percent of human cancers reactivate telomerase," they added, and "alternative lengthening of telomeres is frequently observed in tumors lacking telomerase activity and manifests with long but highly variable telomeres. Deactivating mutations in ATRX and its binding partner DAXX were found to be tightly correlated with long telomeres in pancreatic neuroendocrine tumors and gliomas."

The researchers analyzed 18,430 unique samples — 9,065 tumors, 7,643 blood controls, and 1,722 solid tissue controls — from 9,127 patients, and reported the telomere lengths of all the samples, including tumors and non-neoplastic tissue.

They found that telomeres were shorter in tumors than in normal tissues, and longer in sarcomas and gliomas than in other cancers.

From 6,835 of the cancers they analyzed, the researchers found that 73 percent expressed TERT. Of these TERT-expressing samples, 32 percent carried at least one of three TERT abnormalities — promoter mutation, amplification, or chromosomal rearrangement.

A further 5 percent of the cases were characterized by undetectable TERT expression and alterations in ATRX or DAXX, and had both elongated telomeres and increased telomeric repeat-containing RNA (TERRA). The remaining 22 percent of tumors didn't express TERT and had no alterations in ATRX or DAXX, but had telomere lengths that positively correlated with TP53 and RB1 mutations.

"Our results suggested a positive correlation between TERT expression and telomerase activity, corroborating recent findings in bladder cancer," the team noted. "We also observed a positive correlation between TERC expression and telomerase activity, as well as increased telomerase activity in TERT-expressing tumors compared to tumors with ATRX or DAXX alterations and WT/WT tumors. This gene signature may serve as a useful proxy for estimating telomerase activity using transcriptional profiles."

The findings also provide insight on the telomere biology of tumors that lack common alterations, and open "avenues for functional studies of how to target this crucial pathway in oncogenesis," the researchers added.