Researchers uncover 'fundamental' cancer risk link to telomere length

December 14, 2020
Human colorectal cancer cells stained and under a microscope. (National Cancer Institute, Unsplash)

Human colorectal cancer cells stained and under a microscope. (National Cancer Institute, Unsplash)

Humans gain some protection from cancer if nucleic acid segments at the ends of chromosomes are shorter, which helps to limit cell division, according to new research.

In a study published this month in the journal eLife, U.S. and Dutch researchers examined telomeres, repetitive segments of nucleic acids on the ends of chromosomes. Average length of the structures ordinarily gets shorter as a person gets older, a process that has been linked to downturns in stem-cell function, regeneration and organ maintenance late in life. 

People born with abnormally short telomeres have a higher risk of bone-marrow disorders and other diseases. However, telomeres that are too long present other risks. The researchers found that abnormally long telomeres can cause cancer, and they identified a gene that suppresses excessive growth of the structures.

The scientists studied two Dutch families with dense histories of cancer — including in the breast, colon, skin and thyroid — and found that mutations in the TINF2 gene led to their chromosomal tips becoming extremely long.

“We have provided a fundamental insight into how cancer develops and how it's suppressed in us,” said Titia de Lange, a biology professor at Rockefeller University and the lead author of the paper. “You can predict from these families what would have happened to all of us if we didn't have it — we would all look like those families and have five cancers in your lifetime, which we don't.”

Long telomeres allow human cells to multiply more times than the usual limit of about 50, creating more favorable conditions for cancerous tumors to grow, according to the researchers. Cancerous cells also rely on long telomeres, using the enzyme telomerase to constantly expand the chromosomal tips and fuel tumor growth.

The cancer-prone Dutch families exhibited different mutations in the TINF2 gene, which encodes the TIN2 protein. It is one of the six components of shelterin, a protein complex that protects telomeres from being damaged by DNA-repair mechanisms and regulates their growth.

With no evidence that the telomeres were being improperly protected, the researchers concluded that the TINF2 mutations disrupted shelterin’s ability to curb telomere length. They proposed that the gene’s tumor-suppressing influence is imposed in early development, and that the families’ mutated TINF2 genes lengthened their telomeres in the first weeks or months after fertilization.

The study’s most important takeaway is its consequences for members of families with high rates of cancer, de Lange told The Academic Times.

“People need to pay attention to telomere length in their cancer-prone families,” de Lange said. “People will now automatically look for TIN2 mutations in cancer-prone families ... and maybe other components of our shelterin complex.”

Mutations in another shelterin protein, POT1, have also been found to lengthen telomeres and promote cancer. The authors concluded that this telomere-cancer relationship is causative, challenging the findings of previous researchers who cited genome instability caused by POT1 mutations as being its primary driver of cancer.

De Lange, who discovered shelterin’s protective functions and named the complex in 2005, said her lab is continuing to investigate the molecular mechanism of shelterin’s regulation of telomeres and its role in suppressing tumors. 

The causative link between long telomeres and cancer predisposition — a finding that is consistent with previous research — also led the authors to caution against efforts to delay effects of aging by lengthening telomeres.

“I'm not going to take them, and I would suggest others don't either,” de Lange said. “Telomere shortening is a good thing.”

The article, “TINF2 is a haploinsufficient tumor suppressor that limits telomere length,” was published Dec. 1 in eLife.The authors of the study were Isabelle Schmutz, Kaori Takai and Titia de Lange, Rockefeller University; Arjen Mensenkamp, Maaike Haadsma, Liesbeth Spruijt, Richarda de Voer and Marjolijn Jongmans, Radboud University; and Seunga Sara Choo, Franziska Lorbeer, Emma van Grinsven and Dirk Hockemeyer, University of California, Berkeley. The lead author was Titia de Lange.

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