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Long telomeres may mean higher cancer risk, UCSF team says

telomeres genetics cancer

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#1 APBT

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Posted 11 June 2014 - 03:19 PM


http://www.sfgate.co...CSF-5543260.php

Long telomeres may mean higher cancer risk, UCSF team says

It was a cliche, maybe, but seemed to be true: Bigger is better when it comes to telomeres. For a long time, that was what the evidence suggested, anyway.

Telomeres are the protective sheaths at the end of chromosomes that help delay cellular aging and fend off disease. Multiple studies have shown that people with long telomeres tend to be healthier and live longer, by five years or so, than those with short telomeres.

Long telomeres have been associated with lower incidences of diabetes and heart disease and lower levels of stress. People with long telomeres tend to eat better and exercise more than those with short telomeres.

But increasingly scientists have begun to wonder if there might be a downside - if bigger isn't always necessarily better.

Scientists have hypothesized that long telomeres may contribute to cancer development, and earlier studies have found links between telomere maintenance and breast, prostate and colon cancer.

Now, a team of UCSF researchers has produced some of the strongest evidence that having long telomeres, while certainly protective in many ways, may leave people vulnerable to certain types of cancer.

In a paper released this week, the UCSF scientists reported that people who are genetically predisposed to having long telomeres also have an increased risk - by about 30 to 40 percent - of developing gliomas, a deadly brain tumor. The actual risk of cancer is still very small - less than 1 percent of people with the genetic predisposition will develop gliomas - but the findings show that telomere length is not as black and white as the earliest studies might have suggested.

"People have thought there might be paradoxical effects of telomeres, but this study is a really vivid demonstration of that," said Margaret Wrensch, an author of the new report who runs a glioma study at UCSF.

With telomeres, as with most areas of human biology and behavior, that gray area known as "moderation" may be the key to overall health, added Kyle Walsh, also an author, who is a cancer genetics scientist at UCSF.

"We've operated under the assumption that long telomeres are good and short telomeres are bad," Walsh said. "But telomeres are a little more complex than perhaps we've been thinking about them."

Telomeres are short chains of chemical coding that cap off the ends of chromosomes, the double-stranded strings of DNA that contain our genetic material in the nucleus of every cell. UCSF molecular biologist Elizabeth Blackburn, along with two other scientists, won the Nobel Prize in 2009 for discovering telomeres in the 1970s and later identifying the enzyme called telomerase that builds and maintains the protective caps.

Scientists often compare telomeres to the plastic tips at the end of shoelaces - they protect the laces and keep them from unraveling. But that's just one piece of their job.
 

Stabilizing DNA

Telomeres also help stabilize DNA during replication. Without telomeres, the strings of DNA would shorten each time a cell divided and reproduced. As long as there's a healthy strip of telomere at the end of a chromosome, a cell can keep dividing, providing new material to grow blood, bone, muscle and other tissues that must be replenished over a lifetime.

Eventually, telomeres do shorten, but the longer a telomere is, the longer a cell can safely reproduce. Scientists believe that short telomeres not only shorten the reproductive lives of cells but also weaken them, leaving them prone to damage that can eventually lead to disease.

And so, naturally, scientists also believed that long telomeres were a marker of good health.

"Telomeres are something that we've known were associated with youth and with healthful aging," Walsh said. "All these healthful things were associated with them."

The UCSF study looked at genomic data from 1,644 patients with glioma, many of them participants in Wrensch's glioma study, and 7,736 healthy people. Earlier work by Wrensch and other colleagues had found that people with genetic variations in a gene called TERT had a higher risk of developing glioma. The new study found that variants in the gene called TERC also increased the risk.

What piqued the scientists' interest was that both TERT and TERC are necessary for the release of telomerase, which controls production of telomeres. But they couldn't tell from their study results what the gene variants did - whether they increased the release of telomerase, reduced it, or had some other effect.

So Walsh reached out to scientists at the University of Leicester in Britain, where they had collected data on gene variants and telomere length for 40,000 people. The Leicester data showed that the same TERT and TERC variants that increased the risk of glioma also predisposed people to have long telomeres.

The results showed a very strong connection between glioma risk and telomere length, Wrensch said.

"It's rare in epidemiology to get such clarity," she said. "There had been theories about possibly increasing carcinogenesis with telomere length. We haven't had the tools and techniques until recently to really nail down these hypotheses."

What that relationship may mean is still unclear, though. Walsh suggested that it's possible that long telomeres that allow cells more time to divide may also leave them more open to acquiring mutations, which can lead to cancer. Long telomeres may also mean that the cancer cells are able to spread longer and faster - tumors are, after all, built on cells that divide and spread out of control.

Another possibility is that telomerase production is the link between long telomeres and cancer risk. Perhaps the gene variants cause increased production of telomerase, which in turn leads to long telomeres while also giving a boost to cancer cells, said Dr. Steven Artandi, a Stanford oncologist who studies telomerase and cancer.

In other words, long telomeres aren't necessarily causing cancer.

"Long telomeres might just be a biomarker or indication of what the gene variant is actually doing," Artandi said.

The UCSF study, he said, adds to the increasing complexity of telomeres and the role they play in health and aging. Short telomeres are undoubtedly bad - aside from being associated with an increased risk of diseases like diabetes, they are very closely connected to conditions like pulmonary fibrosis, anemia and even certain types of cancer, Artandi said.
 

Improving treatments

And long telomeres - even if they may leave people vulnerable to cancers - are undoubtedly also associated with other signs of good health, Walsh said.

"I've talked to neuro-oncologists who have said that these glioma patients are much healthier than the general population," he said. "Very frequently these are very virile, robust, healthy people, who have taken good care of themselves and haven't been sick a day in their life. And then they're diagnosed with this malignant brain tumor."

Research that better defines the associations between long and short telomeres, telomerase production and overall health may lead to improved treatments for diseases like glioma or even therapies to prevent illness, Artandi said.

"I think it depends on where you are on the telomere curve," he said.

Somewhere in the middle is probably about right, but no one knows where the middle is, just yet, scientists said.

"It's the extremes of the distribution that cause problems. Most of us are in the middle," Walsh said. "But it does make you question this idea that, 'Oh, if we just lengthened telomeres, that would be great.' Everything turns out to be more complicated."



#2 Darryl

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Posted 11 June 2014 - 05:39 PM

A confirmation of Judith Campisi's theory of limited telomeres being tumor suppressors, dating back to 1996.


Edited by Darryl, 11 June 2014 - 05:39 PM.


#3 GreenPower

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Posted 11 June 2014 - 07:56 PM

My first reaction is that the article is a bit confused. First it implies they have proved the hyphothesis that long telomere length increase the risk for glioma. Then they correctly state that correlation does not necessary imply causation and that they have proved nothing. Then they end the article by implying long telomeres might be dangerous anyway.

 

The confusion might however be the fault of the journalist. Have anyone read the actual study? It would be interesting to see if the persons with long telomeres and glioma developed glioma at a young or advanced age.


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#4 xEva

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Posted 11 June 2014 - 10:37 PM

My first reaction is that the article is a bit confused. First it implies they have proved the hyphothesis that long telomere length increase the risk for glioma. Then they correctly state that correlation does not necessary imply causation and that they have proved nothing. Then they end the article by implying long telomeres might be dangerous anyway.
 
The confusion might however be the fault of the journalist. Have anyone read the actual study? It would be interesting to see if the persons with long telomeres and glioma developed glioma at a young or advanced age.


+1

The other thing is that people born with various genetic mishaps that affect TERT and lead to short, or quickly shortening teolmeres, have a much higher incidence of cancer than average. I don't recall the exact numbers (they differ per syndrome), but it is definitely more than 1% mentioned in this article -- much more.

#5 APBT

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Posted 11 June 2014 - 11:08 PM

Link to the abstract and some additional graphs of the study quoted in the article; gotta pay for the full text:

http://www.nature.co...ll/ng.3004.html

 

 

Glioma, the most common central nervous system cancer in adults, has poor prognosis. Here we identify a new SNP associated with glioma risk, rs1920116 (near TERC), that reached genome-wide significance (Pcombined = 8.3 × 10−9) in a meta-analysis of genome-wide association studies (GWAS) of high-grade glioma and replication data (1,644 cases and 7,736 controls). This region has previously been associated with mean leukocyte telomere length (LTL). We therefore examined the relationship between LTL and both this new risk locus and other previously established risk loci for glioma using data from a recent GWAS of LTL (n = 37,684 individuals)1. Alleles associated with glioma risk near TERC and TERT were strongly associated with longer LTL (P = 5.5 × 10−20 and 4.4 × 10−19, respectively). In contrast, risk-associated alleles near RTEL1 were inconsistently associated with LTL, suggesting the presence of distinct causal alleles. No other risk loci for glioma were associated with LTL. The identification of risk alleles for glioma near TERC and TERT that also associate with telomere length implicates telomerase in gliomagenesis.

 



#6 APBT

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Posted 11 June 2014 - 11:12 PM

http://www.ucsf.edu/...sk-brain-cancer

 

Longer Telomeres Linked to Risk of Brain Cancer
A Double-Edged Sword, Gene Variants May Promote Overall Health while Increasing Risk of Gliomas

 

New genomic research led by UC San Francisco scientists reveals that two common gene variants that lead to longer telomeres, the caps on chromosome ends thought by many scientists to confer health by protecting cells from aging, also significantly increase the risk of developing the deadly brain cancers known as gliomas.

The genetic variants, in two telomere-related genes known as TERT and TERC, are respectively carried by 51 percent and 72 percent of the general population. Because it is somewhat unusual for such risk-conferring variants to be carried by a majority of people, the researchers propose that in these carriers the overall cellular robustness afforded by longer telomeres trumps the increased risk of high-grade gliomas, which are invariably fatal but relatively rare cancers.

The research was published online in Nature Genetics on June 8, 2014.

“There are clearly high barriers to developing gliomas, perhaps because the brain has special protection,” said Margaret Wrensch, MPH, PhD, the Stanley D. Lewis and Virginia S. Lewis Endowed Chair in Brain Tumor Research at UCSF and senior author of the new study. “It’s not uncommon for people diagnosed with glioma to comment, ‘I’ve never been sick in my life.’”

In a possible example of this genetic balancing act between risks and benefits of telomere length, in one dataset employed in the current study—a massive genomic analysis of telomere length in nearly 40,000 individuals conducted at the University of Leicester in the United Kingdom—shorter telomeres were associated with a significantly increased risk of cardiovascular disease.

“Though longer telomeres might be good for you as a whole person, reducing many health risks and slowing aging, they might also cause some cells to live longer than they’re supposed to, which is one of the hallmarks of cancer,” said lead author Kyle M. Walsh, PhD, assistant professor of neurological surgery and a member of the Program in Cancer Genetics at UCSF’s Helen Diller Family Comprehensive Cancer Center.

In the first phase of the new study, researchers at UCSF and The Mayo Clinic College of Medicine analyzed genome-wide data from 1,644 glioma patients and 7,736 healthy control individuals, including some who took part in The Cancer Genome Atlas project sponsored by the National Cancer Institute and National Human Genome Research Institute. This work confirmed a link between TERT and gliomas that had been made in previous UCSF research, and also identified TERC as a glioma risk factor for the first time.

Since both genes have known roles in regulating the action of telomerase, the enzyme that maintains telomere length, the research team combed the University of Leicester data, and they found that the same TERT and TERC variants associated with glioma risk were also associated with greater telomere length.

UCSF’s Elizabeth Blackburn, PhD, shared the 2009 Nobel Prize in Physiology or Medicine for her pioneering work on telomeres and telomerase, an area of research she began in the mid-1970s. In the ensuing decades, untangling the relationships between telomere length and disease has proved to be complex.

In much research, longer telomeres have been considered a sign of health—for example, Blackburn and others have shown that individuals exposed to chronic stressful experiences have shortened telomeres. But because cancer cells promote their own longevity by maintaining telomere length, drug companies have searched for drugs to specifically target and block telomerase in tumors in the hopes that cancer cells will accumulate genetic damage and die.

Walsh said the relevance of the new research should extend beyond gliomas, since TERTvariants have also been implicated in lung, prostate, testicular and breast cancers, and TERCvariants in leukemia, colon cancer and multiple myeloma. Variants in both TERT and TERChave been found to increase risk of idiopathic pulmonary fibrosis, a progressive disease of the lungs.

In some of these cases, the disease-associated variants promote longer telomeres, and in others shorter telomeres, suggesting that “both longer and shorter telomere length may be pathogenic, depending on the disease under consideration,” the authors write.

In addition to the Mayo Clinic and Leicester University teams, Wrensch and Walsh were joined by colleagues from University Medical Center Groningen in the Netherlands. Other UCSF authors include Ivan V. Smirnov, PhD; Terri Rice, MPH; Helen M. Hansen; Annette M. Molinaro, PhD; Lucie S. McCoy, MPH; Paige M. Bracci, PhD, MPH; Belinda S. Cabriga; Melike Pekmezci, MD; Shichun Zheng, MD; Joseph L. Wiemels, PhD; Tarik Tihan, MD, PhD; Mitchel S. Berger, MD; Susan M. Chang, MD; Michael D. Prados, MD; and John K. Wiencke, PhD.Alexander R. Pico, PhD, of the Gladstone Institutes also took part in the research, as did members of the ENGAGE Consortium Telomere Group.

Research conducted at UCSF was supported by the National Institutes of Health; the National Brain Tumor Foundation; the UCSF Lewis Chair in Brain Tumor Research; the UCSF Robert Magnin Newman chair in Neuro-Oncology; and by donations from families and friends of John Berardi, Helen Glaser, Elvera Olsen, Raymond E. Cooper and William Martinusen.


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#7 APBT

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Posted 12 June 2014 - 03:16 AM

Here's a link to the FULL STUDY (thanks to Darryl no less):  Variants near TERT and TERC influencing telomere length are associated with high-grade glioma risk



#8 Brafarality

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Posted 12 June 2014 - 11:49 PM

My 2 cents is that medium length telomeres that are lengthened in small but constant increments throughout the lifespan (whether by increased telomerase or by other means) will end up being the best version of things.


Edited by Brafarality, 12 June 2014 - 11:49 PM.


#9 hav

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Posted 19 June 2014 - 10:25 PM

I think summaries of the study are a little misleading.  What the study actually says is that certain gene mutations are associated with both glioma and telomerase activation:

 

 

In summary, we identify a new susceptibility locus for high-grade glioma near TERC and demonstrate that the alleles for glioma risk near TERC and TERT might also influence telomere length.

 

Which makes allot of sense if telomerase activation is a requirement for cancer to flourish.  See:  

 

TERT promoter mutations occur frequently in gliomas and a subset of tumors derived from cells with low rates of self-renewal.

 

Malignant cells, like all actively growing cells, must maintain their telomeres, but genetic mechanisms responsible for telomere maintenance in tumors have only recently been discovered.

 

These findings may be relevant to taking a telomerase activator if you are born with the mutation.  The suggestion is that at best, it won't help. But it seems to me that if you are not born with the bad alleles, longer telomeres might avert dna damage that could cause such a mutation spontaneously.

 

Howard

 


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#10 Skypp

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Posted 22 July 2014 - 07:15 PM

Has anyone connected Telomere "lengtheners" such as Ta-65 or Product B, with any higher incidence of cancer?



#11 Darryl

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Posted 22 July 2014 - 08:51 PM

The TA-65 mice studies found no higher tumor incidence, and in both mice and humans TA-65 selectively acted on short telomeres, with little effect on mean telomere length.

 

de Jesus, B. B., Schneeberger, K., Vera, E., Tejera, A., Harley, C. B., & Blasco, M. A. (2011). The telomerase activator TA‐65 elongates short telomeres and increases health span of adult/old mice without increasing cancer incidenceAging cell10(4), 604-621.

Harley, C. B., Liu, W., Blasco, M., Vera, E., Andrews, W. H., Briggs, L. A., & Raffaele, J. M. (2011). A natural product telomerase activator as part of a health maintenance programRejuvenation research14(1), 45-56.

 

 


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#12 Skypp

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Posted 23 July 2014 - 07:04 AM

Thanks for the reply and help information.



#13 seivtcho

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Posted 23 July 2014 - 09:16 AM

Cnacer has too complex ethiology. Moreover, each type of cancer has a very complex ethiology.

 

The telomeres are not the main factor.

 

To develope cancer, you need cancerogenes, genetic predispository and others.

 

One may has long telomeres and never to develope a cancer.

 

"In other words, long telomeres aren't necessarily causing cancer"



#14 pleb

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Posted 24 July 2014 - 08:41 AM

They use the same warning for igf-1 as it also upregulates telomerase. whilst admitting that proof of a definite  link has not been found. I tend to look at it from a different perspective.

Teenagers have longer telomeres and presumably more Telomerase and the chance of getting cancer at that age is 100 to 1. Whilst at my age it's 4 to 1 .  


Edited by pleb, 24 July 2014 - 08:47 AM.


#15 Skypp

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Posted 24 July 2014 - 07:32 PM

They use the same warning for igf-1 as it also upregulates telomerase. whilst admitting that proof of a definite  link has not been found. I tend to look at it from a different perspective.

Teenagers have longer telomeres and presumably more Telomerase and the chance of getting cancer at that age is 100 to 1. Whilst at my age it's 4 to 1 .  

 

Many thanks, Pleb, as I have also seen those warnings about igf-1 and wondered if they were accurate, or just unsubstantiated conjecture based on limited evidence. Personally, I really like the Telomere product I've been taking and I though of adding igf-1 to my regime as well. As I read through the material on Telomere length, it seemed the "danger" only refered to a type of rare brain cancer. I thought the "research" was really sketchy. Some people, who were already susceptible to that type of cancer, had a somewhat higher risk if they had long Telomeres (or increased them?). At least that is what I gleaned from what I read.



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#16 pleb

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Posted 24 July 2014 - 09:14 PM

Body builders take it as it builds musclecells through hyperplasia but presumably in larger amounts than would be needed to upregulate telomerase. finding out the amount the body produces through the HGH pathway via the liver in our late teens would be of interest it may be a minor amount as 1iu of HGH takes the amount of HGH up to the level when we were about 19 or 20 years old and presumably the liver produces a much lower amount of igf 1 although that's conjecture on my part.


Edited by pleb, 24 July 2014 - 09:15 PM.






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