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Regarding cancer cells and telomeres

Regarding cancer cells and telomeres


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If cancer cells have telomeres are they different than the telomeres in non-cancerous cells? Would cancer cell telomeres be somehow 'set-up' to function almost indefinitely; in other words are 'they' very 'robust' or 'durable'? If these cancer cell telomeres are 'durable could their functioning cause any apoptosis mechanisms to 'shut down'?


In a normal cell, during each replication the telomere is shortened slightly due to the end replication problem, as you probably know. As mutations occur and a normal cell begins to exhibit cancerous characteristics, it needs a way to stop the self-destruction which happens when the telomeres become too short. In fact it is the cancer cells themselves which 'short-circuit' the shortening process and cause the telomeres to stay long enough.

90% of tumors do this by activating telomerase, an enzyme complex which elongates telomeres and keeps them from getting too short, so that the cell is effectively immortal from this sort of destruction. Usually telomerase is not active in most cells, except for stem, germ, and hair follicle cells, but cancer cells use this to their advantage and activate it to stay immortal. The other 10% or so employ a method called ALT, or Alternative Telomere Lengthening, a not yet thoroughly understood process which involves the recombination of tandem repeats between sister chromatids.

This page explains how cancer cells bypass the telomere shortening process well, and also provides a series of further reading on telomeres and telomere shortening.


In cancer cells, the telomerase is not "formed" but activated, mainly due to an amplification and a gain of copy of the 5p chromosome arm, containing the gene coding for TERT. For example, a very common way to immortalize primary cells to establish a cell line is to stably express TERT.

Shortened telomeres initiates DNA damage response pathways, resulting in the activation of ATM and ATR, and downstream kinases CHK1 and CHK2, and phosphorylation of p53. Once activated, p53 upregulates genes that mediate cellular senescence and/or apoptosis.


Telomeres, biology and cancer

Prof Blackburn speaks to ecancertv at IARC 2016 about the shortening of telomeres, its genetic and non-genetic influences and the possible tumourigenic outcomes.

She outlines molecular and behavioural causes for altered telomere degeneration, including chronic stress, diet, and how these predictably influence overall mortality.

Prof Blackburn notes that any purported telomere-preserving or extending medicines do not extend survival in a straightforward fashion, but in fact increase the chances of developing cancer.

IARC 50th Anniversary Conference

Telomeres, biology and cancer

Prof Elizabeth Blackburn - The Salk Institute of Biological Studies, La Jolla, USA


Telomeres are simply the ends of chromosomes and the molecular structure is a very specific DNA sequence which is sheathed by a group of protective proteins, all of which have been well defined at the molecular level. The repeated DNA sequences, normally we&rsquore born with about ten kilobases at the ends on each of our chromosomes but that can dwindle down to about half on average as we go through aging. That dwindling down means that a fraction of telomeres no longer function.

What factors are influencing these processes?

Telomere length is inherited to a fairly large degree but we don&rsquot know how much of that is genetic and how much is simply the telomeric DNA itself carried through on the chromosomes through the parental gametes. So we do know that there are many non-genetic influences on telomere length which show both dose dependency and severity dependency in how much they wear telomeres down during life.

What do you already know about telomeres and their influence?

What we know is at the cellular level if the telomeres wear down too much then they no longer protect the ends of chromosomes and that can lead to chromosome instabilities and hence has a role in cancer aetiology because of chromosome instabilities. Very importantly though, when the telomeres get too short a normal cell will set up a response: sometimes it will go into a senescent state, sometimes it will die and sometimes it will have a transcriptional programme change that makes it more pro-inflammatory. So it can have effects where cells no longer regenerate themselves but also have adverse effects systemically because of the pro-inflammatory factors.

What are the known molecular mediators of the wearing down of telomeres?

There are probably more hundreds of molecular mechanisms than you can ever imagine because every mechanism one has looked at affects both the wearing down and in addition the ability of the telomeres to be regenerated by the enzyme telomerase which we discovered can add back telomeric DNA to chromosome ends. But in humans that typically doesn&rsquot keep up with the wearing down in our somatic tissues, although it seems to be able to regenerate from one generation to another in the normal range of telomere lengths. However, what we do know is that the non-genetic effects include many malleable effects and, in particular, chronic psychological stress which, of course, we know the brain has clear physiological read-outs when it&rsquos under chronic stress such as dysregulation of cortisol that has major effects. We find chronic stress has major quantifiable effects on accelerating the wearing down of telomeres throughout the body but usually measured in blood cells. That in turn clearly increases risks of common diseases of aging, they include cardiovascular and some cancers. Cancer is more complicated because some cancers are actually spurred on by having better telomere maintenance determined genetically. These are weak but discernible effects.

Aside from stress, what other factors can influence telomere durability?

So the converse of stress, if you will, is if one has exercise and social support and sees that that ameliorates the sort of average wearing down. One also sees some effects that can now be pinned down to certain dietary effects. So in large studies omega-3 measured amounts of DHA and EPA in people predicts less telomere wearing down and longitudinal studies that in turn has been related to cardiovascular disease effects as well as mortality from cardiovascular and other causes. So we see telomere length is statistically a predictor of all cause mortality and a predictor of overall cancer risks but within the groups of cancers, of course cancer is hundreds of diseases, there are differences where there are some cancers which are adversely affected by having&hellip that is risks go up when the telomere shortening is greatest, particularly clear in Mendelian diseases of telomere genes that are mutated and haploinsufficiency leads to very accelerated telomere shortening and very greatly increased risks of cancers for certain subsets of cancers.

Are there any &ldquodos and don&rsquots&rdquo coming out of your research so far?

Yes, but they&rsquore everything your mother told you. So get a good night&rsquos sleep, have a good attitude, get good exercise, even moderate exercise, cope with stress if you can possibly do it and some dietary&hellip we&rsquove certainly seen, we meaning large cohort studies, effects that are related to, for example, the Mediterranean diet versus processed food, clear effects of smoking in dose dependent fashion based on history, clear effects of alcohol consumption and clear effects of sugared sodas in dose dependent fashion. Exercise turns out the more categories of exercise one does the longer ones telomeres are, this is in very large population studies. So one sees essentially it&rsquos essentially everything your mother told you but probably don&rsquot take quack medicine that purports to increase telomerase because there&rsquos good biological reasons and good cancer genetic reasons that argue that that could push one into higher risks for certain cancers.

Regarding cancer prevention, how strong is the message regarding influencing telomeres versus smoking and lung cancer?

I can&rsquot give you really good numbers as to the relative contribution of the risks but they all go in the same directions. The very interesting challenge is to understand what fraction of the risk which is clearly caused by things, by tobacco, smoking, lack of exercise and other factors. We don&rsquot know much about stress factors in cancer aetiology but those effects of stress on telomeres are somewhat comparable in magnitude to the effects of these other well-known cancer risk factors. I&rsquod very much like to know if that is a role that may be played in cancer aetiology or not. It&rsquos simply not known at the moment but now there&rsquos a strong pointer that one should at least look based on this particular biomarker.

Could one take a pill to keep telomeres in good shape?

Yes, if you&rsquore prepared to risk cancers and we do not know in which cell types and so forth the increased action of telomerase which has been shown genetically to increase risks for melanomas, gliomas and non-smoker lung cancers, small changes genetically that increase telomere maintenance increase those risks. So we don&rsquot know which tissue types that&rsquos critical in. So the bottom line is I would strongly advise against taking any pill that purports on the internet to push your telomere maintenance up because the biological long-term effects of this on cancer risks are simply unknown but there&rsquos very good biological reason to think that that might push one into statistical risks. However, there&rsquos very good guidance from all of the other factors that telomere measures can give you a kind of quantifiable read-out into some of these interventions that one would look at, such as exercise, dietary interventions and even perhaps looking at how coping with stress could be useful in terms of certainly other disease relationships and potentially in cancers, we just don&rsquot know.

What is the interrelationship between telomerase and telomeres?

Telomerase is one factor that can elongate telomeres. Its action on telomeres, if you&rsquore in the clinically important zone where you have haploinsufficiency for telomerase, that 50% level of telomerase compared with the normal 100% is extremely drastic and you get a clear set of diseases including very high incidence of some cancers. However, in the middle zone of telomere length, telomere maintenance and telomerase, it&rsquos one of hundreds of factors that molecularly control telomere length. So it&rsquos not a simple relationship in the normal range although there&rsquos generally a positive effect of higher telomerase base level and telomere length but that is not necessarily simple, it&rsquos a very highly controlled maintenance system.

What is your take-home message?

For telomere maintenance what we&rsquove found is that all of the health practices that are very simple kinds of practices that traditionally one&rsquos mother tells one to do &ndash exercise, get a good night&rsquos sleep, stress reduction, eat sensibly and so forth, don&rsquot do too many diet sodas and do not smoke or have excessive alcohol &ndash all of those quantifiably in dose dependent ways relate to adverse effects on telomere maintenance. So some of those will play into cancer prevention modes but they probably interact with a lot of other factors as well and that&rsquos where there&rsquos a lot to be learned in the interactions.


Dual roles

As de Lange explained it, the shortening of telomeres plays a dual role in cancer development and progression. Each time a cell divides, its telomeres shorten a little bit. After a while, the telomeres become too short to hold the group of proteins that shield it from the cellular machinery that recognizes breaks in DNA.

The DNA damage response then kicks in, causing cells to stop growing or perhaps even die. Based on these findings, scientists like de Lange believe telomere shortening functions as a biological pathway that suppresses tumor formation.

&ldquoHowever, this tumor suppressor pathway sometimes fails, particularly when p53 or RB [genes that induce cell cycle arrest in response to DNA damage] are lost,&rdquo said de Lange.

When that happens, the cells continue to divide unchecked, their telomeres becoming shorter and shorter. Eventually, the telomeres become so short that they start fusing together and create a cellular state called telomere crisis.

Then, telomere shortening takes on the role of tumor promotion. Recent work from the de Lange lab has shown that this telomere crisis prompts several genetic changes that are associated with cancer.

One is the phenomenon in which dozens of chromosomal rearrangements occur in one or a few chromosomes, called chromothripsis.

Another example is characterized by a large number of mutations in a small region of DNA, called kataegis.

de Lange spoke to a standing-room&minusonly crowd in the conference room that serves as the alternate location for the Distinguished Lecture Series during the renovation of Rodbell Auditorium. (Photo courtesy of Steve McCaw)

&ldquoThe idea is that perhaps some of the genomic events that happen during telomere crisis contribute to the rearrangements that one observes in the cancer genome,&rdquo de Lange said. &ldquoWe are very interested in understanding what the consequences are of this telomere crisis.&rdquo

To address that question, de Lange seeks to identify patterns of genomic changes that indicate a telomere crisis has occurred. If one has, researchers can see whether the changes result in a cancer-related phenomenon like chromothripsis.

Citations:
de Lange T . 2005. Shelterin: the protein complex that shapes and safeguards human telomeres. Genes Dev 19(18):2100&minus2110.

de Lange T, Shiue L, Myers RM, Cox DR, Naylor SL, Killery AM, Varmus HE . 1990. Structure and variability of human chromosome ends. Mol Cell Biol 10(2):518&minus527.

Maciejowski J, Li Y, Bosco N, Campbell PJ, de Lange T . 2015. Chromothripsis and kataegis induced by telomere crisis. Cell 163(7):1641&minus1654.

(Marla Broadfoot, Ph.D., is a contract writer for the NIEHS Office of Communications and Public Liaison.)

The role of telomeres in aging

In a Q&A following the lecture, Natalya Degtyareva, Ph.D., a staff scientist in the NIEHS Mutagenesis and DNA Repair Regulation Group, asked de Lange about the role of telomeres in aging and age-related diseases.

&ldquoDo you think telomere shortening by itself, particularly when considered in the context of aging, is dangerous for cellular health?&rdquo she asked.

A whole cottage industry has emerged to look at that topic, de Lange responded. &ldquoI will declare right away that I am not a fan, though I think the data are probably correct,&rdquo she said. &ldquoThey say things like telomeres are shorter in older people, people who don&rsquot exercise, or people who are stressed.&rdquo

Such thinking follows what de Lange termed the gray hair model. Gray hair is highly correlated with almost every age-related disease, she explained, and yet no one will say that gray hair causes any one of those diseases.

In addition, she said that studies in humans indicate that telomere shortening does not mimic the effects of aging completely. Some age-related illnesses could be blamed on shortened telomeres, whereas others likely have different causes.

&ldquoWe won&rsquot know for sure until somebody makes that pill that elongates telomeres, and I&rsquom not going to take it!&rdquo she said.

Titia de Lange: Telomeres and human disease

Titia de Lange: How telomeres solve the end-protection problem

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Recent advances in telomere biology: implications for human cancer

Purpose of review: Research into the basic biology of telomeres continues to reveal details relevant to fundamental aspects of human cancer. The goal of this review is to highlight discoveries made within the last year, with emphasis on their relevance to cancer prevention, diagnosis, prognostics, and treatment.

Recent findings: Increasing evidence indicates that dysfunctional telomeres likely play a causal role in the process of malignant transformation, in at least a fraction of human cancers, by initiating chromosomal instability. Telomeres form protective capping structures composed of telomeric DNA complexed with a multitude of associated proteins, the loss of which can have profound effects on telomeric stability. Critical telomeric shortening can lead to telomere "uncapping" and may occur at the earliest recognizable stages of malignant transformation in epithelial tissues. The widespread activation of the telomere synthesizing enzyme telomerase in human cancers not only confers unlimited replicative potential but also prevents intolerable levels of chromosomal instability. Several details regarding telomere structure and telomerase regulation have recently been elucidated, providing new targets for therapeutic exploitation. Various therapeutic strategies aimed at either telomerase or its telomeric substrate are showing promise and may synergize with established anti-cancer agents. Further support for anti-telomerase approaches comes from recent studies indicating that telomerase may possess additional functions, beyond telomere maintenance, that support the growth and survival of tumor cells.

Summary: Substantial progress has been made in understanding the complex relationships that exist between telomeres and cancer. However, important issues, such as transient activation of telomerase in normal cells and the potential for tumor cell immortalization via telomerase independent means, remain to be clarified.


New Discovery on Telomeres and Cancer's Immortality

Cellular aging is thought to be controlled, in part, by the chromosomes&rsquo telomeres &ndash end caps that protect our DNA. But the relationship may be much more complex than scientists thought, as new evidence suggest a mechanism for cancer to bypass aging entirely.

At the end of our chromosomes are protective caps called telomeres. These structures get shorter and shorter with each successive cell division. And when the telomeres get to a critical short length, the cell is signaled to die. In this way, telomeres act as a built-in timer for cell death.

However, in the case of cancer cells, the telomeres seem to escape the usual shortening, and cancer cells can divide past their expiry status. Thus, abnormal functioning telomeres imbue cancer its characteristic immortality.

But how do the telomeres of cancer cells, with their constant growing and dividing, not be susceptible to shortening? As it turns out, scientists at the University of Pittsburgh showed that cancer cells seem to make more of telomerase &ndash the enzyme that lengthens telomeres.

Furthermore, the team found something startling about this process. Whereas factors, like oxidative stress, would damage DNA and shorten the telomeres, telomeres in cancer cells seemed to thrive in this condition. "Much to our surprise, telomerase could lengthen telomeres with oxidative damage," said Patricia Opresko, the study&rsquos senior author. "In fact, the damage seems to promote telomere lengthening."


Oxidative stress also doesn&rsquot seem to affect the process of adding building blocks on to telomeres in the same way that scientists thought. Under damaging conditions, the team found that telomerase can add damaged DNA precursor molecules to the end of the chromosomes, but was unable to add damaged DNA molecules. "We also found that oxidation of the DNA building blocks is a new way to inhibit telomerase activity, which is important because it could potentially be used to treat cancer, said Opresko.

"The new information will be useful in designing new therapies to preserve telomeres in healthy cells and ultimately help combat the effects of inflammation and aging. On the flip side, we hope to develop mechanisms to selectively deplete telomeres in cancer cells to stop them from dividing," said Dr. Opresko.

"Using this exciting new technology, we'll be able to learn a lot about what happens to telomeres when they are damaged, and how that damage is processed," she said.


Telomeres, telomerase, and cancer

The cell cycle includes the orderly sequence of events that ensure the faithful duplication of all the cellular components in their correct sequence and the partitioning of these components into two daughter cells. Two classes of genes and their protein products are used to accomplish this process: genes whose products are obligatory for progress through the cell cycle phases, and genes whose proteins act as checkpoints for monitoring the efficacy and completion of these obligatory events and stopping the progression through the cell cycle if conditions are not satisfactory. The loss of cell cycle control generally leads to cell death but can also result in abnormal cells that continue to replicate and eventually form a tumor (for a review, see ( 29)). The theory of carcinogenesis suggests that unlimited cell proliferation is required for development of malignant disease, and cancer cells must attain immortality for progression to malignant states. As shown above, shortening of telomeres may contribute to the control of the proliferative capacity of normal cells, and the enzyme telomerase may be essential for unlimited cell proliferation.

The length of telomeres in cancer cells depends on a balance between the telomere shortening at each cell cycle and the telomere elongation resulting from telomerase activity. Tumors with shorter telomeres than in the original tissue have been detected in many cancer types (for a review, see ( 30)). In neuroblastoma, endometrial cancer, breast cancer, leukemias, and lung cancer, a correlation between decreasing telomere lengths and an increasing severity of disease has been described ( 31)( 32)( 33)( 34)( 35). Short telomeres seem to be a primary cause for karyotype instability in malignant cells. According to the above-described theory of telomere dynamics during cell progression, tumor cells with shortened telomeres can be considered to have undergone many cell divisions, with an accumulation of various genetic alterations. After a point of critical telomere shortening, telomerase might be reactivated to stabilize or elongate the telomeric DNA.

Tumors with telomeres just as long as or even longer than in the original tissue seem to be rarer but have been described in some human malignant tissues, e.g., intracranial tumors, basal cell carcinomas of the skin, and renal cell carcinomas ( 36)( 37)( 38)( 39). There are two possible explanations for this phenomenon: Either an activated telomerase has elongated the once-shortened telomeres back to former length, or the tumor cells have not yet undergone enough cell divisions to induce significant shortening of telomeres.

Telomerase is absent in most human somatic cells (see Table 1 ) but, as Rhyu reports ( 40), was detected in ∼85% of 400 tumor tissue samples. Low amounts of telomerase activity in normal human tissues were found only in hematopoietic progenitor cells and activated T- and B-lymphocytes ( 41) in germ cells, ovaries, and testes ( 42) and in physiologically regenerating epithelial cells ( 43). Results from examinations of normal tissues and benign cancers as well as malignant primary and metastatic tumors permit several conclusions. As in most normal tissues, telomerase activity is not expressed in somatic tissues adjacent to the tumor tissue. Accordingly, telomerase activity has proved to be a reliable marker for detecting tumor cells in resection margins.

In benign and premalignant tumors, including breast fibrocystic disease and fibroadenomas, benign prostatic hyperplasia, colorectal adenomas, anaplastic astrocytomas, and benign meningiomas and leiomyomas, in general no telomerase activity was detected however, it was found in malignant tumor stages ( 44)( 45)( 46)( 47). In this way, telomerase activity is associated with the acquisition of malignancy. The detection of telomerase activity at preneoplastic or benign growth stages may signify disease progression and be of diagnostic value. For example, telomerase activity has been found in some cases of benign prostate hyperplasia and of benign giant tumors of the bone ( 45)( 48)—all tissues that may progress to malignant tumors.

As shown by Hiyama et al. ( 44) in breast cancer, telomerase provides a useful diagnostic tumor marker: Among samples obtained by fine-needle aspiration, 14 of 14 patients whose aspirates contained detectable telomerase activity, and who subsequently underwent surgery, were confirmed to have breast cancer.

Certain tumor types, such as neuroblastoma, display a lower telomerase activity in early-stage cancers, whereas expression in late-stage cases is higher ( 49). Neuroblastomas of a special stage (stage IV), which had short telomeres and no or weak telomerase activity, tended to regress spontaneously ( 49)—possible proof of a correlation between an enzyme activity too weak to remain in an immortal tumor status and a favorable outcome for the patient.

Another example of telomerase activity in cancer diagnosis and as a prognostic indicator of clinical outcome is the results found in gastric cancers. Hiyama et al. ( 50) showed that the survival rate of patients with tumors with detectable telomerase activity in their study was shorter than that of those without telomerase activity.

Although a reliable tumor marker, telomerase activity is not an all-or-none phenomenon. To understand the regulation of telomerase during tumorigenesis, Greider et al. analyzed the concentrations of telomerase RNA components and discussed the differential regulation of enzyme activity according to the concentration of the RNA component ( 51)( 52).

Further prospective and retrospective clinical studies must be carried out to assess the validity of telomere dynamics and telomerase as a diagnostic or prognostic marker in many cancer types.


Telomeres, Crisis and Cancer

Author(s): R. A. Greenberg Department of Cancer Biology, Dana Farber Cancer Institute, Boston, Massasuchsetts, USA.

Affiliation:

Journal Name: Current Molecular Medicine

Volume 5 , Issue 2 , 2005




Abstract:

Eukaryotic chromosomes terminate in specialized nucleic acid-protein complexes known as telomeres. Disruption of telomere structure by erosion of telomeric DNA or loss of telomere binding protein function activates a signal transduction program that closely resembles the cellular responses generated upon DNA damage. Telomere dysfunction in turn induces a permanent proliferation arrest known as senescence. Senescence is postulated to perform a tumor suppressor function by limiting cellular proliferative capacity, thus imposing a barrier to cellular immortalization. Genetic or epigenetic silencing of components of the DNA damage pathway, allows cells to proliferate beyond senescence limits. However, these cells eventually reach a stage of extreme telomere dysfunction known as crisis that is characterized by cell death and the concomitant appearance of cytogenetic abnormalities. Telomeric crisis produces significant chromosomal instability, a hallmark of human cancer, and may thus be relevant to carcinogenesis by increasing the occurrence of genetic alterations that would favor neoplastic transformation. The following review examines the relationship of telomere function during crisis in accelerating chromosomal instability and cancer.

Current Molecular Medicine

Title: Telomeres, Crisis and Cancer

VOLUME: 5 ISSUE: 2

Author(s):R. A. Greenberg

Affiliation:Department of Cancer Biology, Dana Farber Cancer Institute, Boston, Massasuchsetts, USA.

Abstract: Eukaryotic chromosomes terminate in specialized nucleic acid-protein complexes known as telomeres. Disruption of telomere structure by erosion of telomeric DNA or loss of telomere binding protein function activates a signal transduction program that closely resembles the cellular responses generated upon DNA damage. Telomere dysfunction in turn induces a permanent proliferation arrest known as senescence. Senescence is postulated to perform a tumor suppressor function by limiting cellular proliferative capacity, thus imposing a barrier to cellular immortalization. Genetic or epigenetic silencing of components of the DNA damage pathway, allows cells to proliferate beyond senescence limits. However, these cells eventually reach a stage of extreme telomere dysfunction known as crisis that is characterized by cell death and the concomitant appearance of cytogenetic abnormalities. Telomeric crisis produces significant chromosomal instability, a hallmark of human cancer, and may thus be relevant to carcinogenesis by increasing the occurrence of genetic alterations that would favor neoplastic transformation. The following review examines the relationship of telomere function during crisis in accelerating chromosomal instability and cancer.


Long telomeres and cancer risk: the price of cellular immortality

4 McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

Address correspondence to: Mary Armanios, 1650 Orleans Street, CRB 1 Room 186, Baltimore, Maryland 21287, USA. Phone: 410.502.2817 Email: [email protected]

Find articles by McNally, E. in: JCI | PubMed | Google Scholar

3 Sidney Kimmel Comprehensive Cancer Center, and

4 McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

Address correspondence to: Mary Armanios, 1650 Orleans Street, CRB 1 Room 186, Baltimore, Maryland 21287, USA. Phone: 410.502.2817 Email: [email protected]

Find articles by Luncsford, P. in: JCI | PubMed | Google Scholar

3 Sidney Kimmel Comprehensive Cancer Center, and

4 McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

Address correspondence to: Mary Armanios, 1650 Orleans Street, CRB 1 Room 186, Baltimore, Maryland 21287, USA. Phone: 410.502.2817 Email: [email protected]

Find articles by Armanios, M. in: JCI | PubMed | Google Scholar

The distribution of telomere length in humans is broad, but it has finite upper and lower boundaries. Growing evidence shows that there are disease processes that are caused by both short and long telomere length extremes. The genetic basis of these short and long telomere syndromes may be linked to mutations in the same genes, such as the telomerase reverse transcriptase (TERT), but through differential effects on telomere length. Short telomere syndromes have a predominant degenerative phenotype marked by organ failure that most commonly manifests as pulmonary fibrosis and are associated with a relatively low cancer incidence. In contrast, insights from studies of cancer-prone families as well as genome-wide association studies (GWAS) have identified both rare and common variants that lengthen telomeres as being strongly associated with cancer risk. We have hypothesized that these cancers represent a long telomere syndrome that is associated with a high penetrance of cutaneous melanoma and chronic lymphocytic leukemia. In this Review, we will synthesize the clinical and human genetic observations with data from mouse models to define the role of telomeres in cancer etiology and biology.

Telomeres may at first glance simply appear as geographic boundaries at chromosome ends. However, there is mounting evidence that disturbances in telomere length, at short and, as we will discuss here, long extremes, are linked to disease susceptibility. Telomere DNA is a repetitive hexamer of TTAGGGs that is bound by a specialized protein complex known as shelterin ( 1 – 3 ). Telomerase synthesizes new telomere DNA to offset the shortening that normally occurs during DNA replication ( 4 , 5 ). Telomerase has two essential components: the telomerase reverse transcriptase (TERT) uses a template within an intrinsic telomerase RNA component, TR (also known as TERC), to add telomere repeats onto the 3′ ends of chromosomes ( 6 – 9 ). Shelterin proteins prevent chromosome ends from fusing and from being recognized as double-strand breaks ( 3 ). They also regulate telomerase access to the telomere, and promote telomere repeat addition processivity by allowing TERT to use a relatively short template in TR to iteratively synthesize longer telomere tracks ( 10 – 12 ). As we will discuss here, disorders of telomere length are increasingly appreciated as causing clinically recognizable disease processes ( 13 ). The short telomere syndromes are now phenotypically and genetically well characterized ( 14 – 19 ). This knowledge is increasingly integrated into clinical algorithms, especially for patients with lung disease and bone marrow failure ( 20 , 21 ). Here, we focus on emerging evidence, from cancer-prone families as well as from population-based studies, linking germline variants that promote telomere lengthening to cancer susceptibility. We contrast the genetic basis of the two extreme telomere length phenotypes and highlight how recent human-focused studies provide critical insights into the fundamentals of cancer etiology.

The foundational understanding of the role of telomeres and telomerase in disease has been rooted in curiosity-driven science, in simple systems and model organisms ( 22 ). One major theme that emerges at the intersection between this fundamental science and disease genetics is that relatively small, subtle changes affecting telomerase abundance or function can influence telomere length and, in turn, disease risk ( 23 ). The exquisite sensitivity of telomere length to these small changes is related to the fact that telomerase is in very low abundance and its activity is tightly regulated. In yeast, mice, and humans, the number of telomere ends exceeds the number of telomerase molecules (refs. 24 , 25 , and reviewed in refs. 23 , 26 ). The low levels of telomerase set up a system wherein not all telomeres are elongated during a given cell cycle even when telomerase is normally expressed ( 27 ). There are at least three additional limits on telomerase activity. The first is that the essential telomerase components, TERT and TR, are expressed at very low levels relative to other proteins and RNAs (e.g., refs. 24 , 28 ). Even other factors involved in telomerase biogenesis, such as nuclear assembly factor 1 (NAF1), which promotes shuttling of TR to the nucleolus for assembly with TERT, show haploinsufficiency for telomere length ( 28 ). Thus, although only 10% of human genes are estimated to show haploinsufficiency, many of the telomerase and related genes that have been heretofore linked to Mendelian disease, including TERT, TR, and NAF1, do so ( 14 , 28 – 30 ). A second limit is that telomerase expression is also tightly regulated. After early embryonic development, the TERT promoter is repressed in most somatic cells, likely through promoter hypomethylation ( 31 – 33 ). The repressive effect of this hypomethylation on TERT expression is counter to effects in most other contexts. The timing of TERT silencing leaves a small window during early development for telomeres to be elongated ( 34 ), and makes telomere length highly heritable and, in great part, influenced by parental telomere length ( 27 , 35 , 36 ). A third check on telomere elongation is that even when expressed, the timing for telomere repeat addition is cell cycle–regulated and restricted to late S phase (reviewed in ref. 37 ). For all these reasons, telomeres shorten even in telomerase-expressing somatic cells, such as hematopoietic progenitors and T cells ( 26 ). These checks favor a system where telomere shortening is an overall general default, and as we discuss here, evidence linking long telomeres to the risk of multiple cancers underscores the tumor-suppressive advantages of these checks.

One of the major advances in understanding the role of telomere length in human disease has been the standardization of telomere length measurement methods that more robustly define absolute “short” and “long” telomere thresholds ( 20 , 38 ). Relying on a method that measures telomere length in distinct leukocyte lineages using combined flow cytometry and fluorescence in situ hybridization (flowFISH), there is outstanding concordance and reproducibility across laboratories ( 20 , 38 , 39 ). These flowFISH telomere length measurements show that human telomere length has a definable normal range with discrete upper and lower boundaries ( 20 ). This type of telomere length analysis has the advantage of establishing age-, percentile-adjusted values rather than relative comparisons of “longer” and “shorter” descriptors. This advance has made interpretation of telomere length for precision medicine use possible and analogous to other clinical measurements (e.g., white blood cell count) wherein the normal range is broad, but extreme values, relative to healthy controls, may be associated with the risk of certain pathologies. For this Review, “telomere length” refers to the mean length as measured in leukocytes by flowFISH and reported as an age-adjusted percentile. Within each cell, the shortest telomere(s) signal the DNA damage response associated with cellular senescence and apoptosis ( 40 ). Remarkably, however, the mean telomere length, in defined and limited clinical contexts, is an outstanding surrogate and can generally distinguish individuals with germline defects in telomere maintenance from their relatives ( 15 , 41 ). As such, the mean telomere length as measured in leukocyte subsets by flowFISH is used widely as a diagnostic and prognostic tool in patients suspected to have short telomere syndromes ( 18 , 20 , 42 ).

The cancer-prone state associated with telomere lenghtening contrasts with that of short telomere syndromes. To facilitate these comparisons, we will first briefly review the better-described short telomere diseases. Short telomere syndromes encompass a continuum of clinical presentations that manifest from infancy to late adulthood ( 26 ). They are caused by mutations in telomerase and telomere maintenance genes. Their onset is determined in great part by the severity of the short telomere defect ( 20 , 43 ). Short telomere syndromes generally have two primary clinical presentations. A more severe form manifests in infants and children it causes disease in high-turnover tissues and primarily recognized as immunodeficiency, bone marrow failure, and enteropathy ( 16 , 19 , 20 , 44 ). Adult-onset short telomere syndromes are more common and account for at least 90% of presentations ( 45 ). They manifest most frequently as idiopathic pulmonary fibrosis (IPF) and other telomere-related lung disease ( 45 ). These telomere-related lung disorders in the vast majority show autosomal dominant inheritance and may appear as emphysema in smokers ( 45 , 46 ). IPF affects 100,000 individuals in the United States alone, and at least 50% of IPF patients have telomere length in the lowest decile of the population ( 45 ). In one-third of families with pulmonary fibrosis, a mutation in telomerase or telomere-related genes is detectable ( 45 ). The high frequency of telomere defects in IPF and the prevalence of this disease make IPF the most common of the human short telomere phenotypes. A subset of adult IPF patients show extrapulmonary short telomere syndrome features including bone marrow failure, immunodeficiency, and liver disease their recognition is critical for the diagnosis and management of these patients ( 18 , 21 , 41 – 43 , 47 ).

Cancer is an overall relatively rare complication of short telomere syndromes and affects approximately 10% to 15% of patients ( 48 ). This rate is far lower than in other common cancer-prone syndromes, such as Li-Fraumeni, which have lifetime risks around 90% ( 49 ). The short telomere cancer spectrum is also restricted to mostly hematologic cancers, the most common being myelodysplastic syndrome, an age-associated clonal disease of the bone marrow. This low cancer incidence lies in contrast to predictions from cell-based models, which reported spontaneous immortalization and transformation of cells after short telomere–induced senescence ( 50 ). These clinical observations suggest that, in the presence of an intact DNA damage response, as is the case in most patients with short telomere syndromes, degenerative disease is the predominant phenotype and leads to progressive failure of hematopoiesis, T cell immunity, and end-stage lung-liver disease. Below we will highlight how these clinical findings support what has been documented in nearly all tumor-prone mouse models.

Understanding the genetic mechanisms by which short telomere syndromes arise is particularly relevant for our Review, because mutations in some of the same genes have also been linked to a cancer-prone state, which we hypothesize is long-telomere mediated. Thirteen genes have been implicated to date in Mendelian short telomere syndrome genetics they explain 50% to 70% of cases (Figure 1A). Two of these genes are also mutated in cancer-prone families. In general, the vast majority of mutations cause telomere shortening by depleting the abundance of telomerase, disturbing its catalytic functions/processivity, or interfering with its recruitment to the telomere. They affect the telomerase holoenzyme itself (TERT, TR, DKC1), adaptors of the dyskerin complex (NHP2, NOP10), genes that affect TR biogenesis and localization (PARN, NAF1, TCAB1), and regulation of telomerase recruitment to the telomere as well as processivity by shelterin (TPP1, also known as ACD, and likely TINF2 ref. 51 ). There are also mutations in genes that are thought to affect telomere replication (RTEL1) and telomere lagging strand synthesis (CTC1, STN1). The genetic basis of short telomere syndromes has been reviewed elsewhere ( 13 , 28 ). As further discussed below, for TERT and TPP1, mutations that predict telomere lengthening are also associated with high-penetrance familial cancer syndromes ( 13 ).

Schematic of mutant telomerase and telomere genes in Mendelian short and long telomere syndromes and model for TPP1 allele–specific effects on telomere length. (A) Components with known mutations are shown in color, and their telomere function is indicated above each group. Thirteen genes have been identified, with the short telomere syndrome associations marked by a subscript S. Four genes are associated with long telomere syndrome phenotypes and are marked by a superscript L. Adapted with permission from Current Opinion in Genetics & Development ( 13 ). (B) The left panel shows the state of telomere length maintenance normally. The middle panel shows how in-frame deletions in the TEL patch interfere with TERT recruitment and processivity, provoking telomere shortening. The right panel shows a model for how cancer-associated mutations may promote telomere maintenance in cancer-prone families. TPP1 deletions or missense mutations in the POT1-interating domain are predicted to affect POT1’s telomere-binding capacity, allowing TERT to elongate more efficiently. The latter is hypothesized to have a net effect of telomere lengthening and/or telomere maintenance.

Evidence that long telomere length confers a longevity advantage came initially from studies of primary cultured fibroblasts in which cells with longer telomeres had longer replicative potentials ( 52 ). Moreover, exogenous TERT expression was sufficient to bypass cellular senescence and immortalize primary cells ( 53 ). In humans, evidence that telomerase upregulation confers a risk of familial cancer was first documented in a five-generation autosomal dominant family with cutaneous malignant melanoma (CMM) that was found to carry a mutation in the TERT promoter ( 54 ). This gain-of-function mutation upregulates TERT transcription ( 54 ). The mutation, located 57 bases upstream of the TERT transcriptional start site, functions similarly to two other common recurrent somatic TERT promoter mutations ( 54 , 55 ). These promoter mutations create a de novo E26 transformation–specific (ETS) transcription factor family binding site that removes the repressive state on TERT by allowing interaction with an abundant GA-binding protein (GABP) transcription factor to promote TERT transcription ( 54 , 56 , 57 ). A second melanoma family was recently found to carry another TERT promoter mutation ( 58 ), but overall, the prevalence of germline TERT promoter mutations in familial melanoma is less than 1% ( 58 ). The importance of telomere maintenance to melanoma susceptibility is, however, highlighted in the fact that germline heterozygous mutations in three other telomere genes, POT1, TPP1, and RAP1 (also known as TERF2IP), all shelterin components, have been linked to familial melanoma (Table 1). POT1 mutations are most common, and they account for 2% to 4% of CDKN2A/CDK4-negative CMM families (60% of familial CMM cases fall into this category refs. 59 – 61 ). Mutations in TPP1 and RAP1 account for another 2% of this familial CMM subset ( 62 ). Table 1 summarizes these associations.

Telomerase and shelterin genes mutated in familial melanoma

Beyond melanoma, there is also evidence of shelterin gene mutations in other cancer-prone families. Among chronic lymphocytic leukemia (CLL) multigenerational families, mutations in POT1, TPP1, and RAP1 are found in nearly 10% of cases ( 63 ). Rare POT1 mutations have also been reported in families with glioma (<1% ref. 64 ) cardiac angiosarcoma and Li-Fraumeni–like syndrome (27%, 6 of 22 TP53-negative families refs. 65 , 66 ) colorectal cancer (0.3%, 3 of 1051 families ref. 67 ) and Hodgkin lymphoma (5%, 2 of 41 families ref. 68 ). These are generally loss-of-function mutations and are predicted to cause telomere lengthening. While these mutations were identified in familial forms of a single cancer, mutation carriers showed other malignancies, suggesting they confer a broader cancer-prone state ( 54 , 58 , 66 ). In support of this idea, a recent study reported an Ashkenazi founder POT1 mutation that interfered with POT1’s DNA-binding capacity it simultaneously conferred susceptibility to both melanoma and CLL ( 69 ). Because the most prevalent cancers in patients with these TERT and shelterin mutations are melanoma and CLL, we propose that these cancers define core long telomere cancer phenotypes.

How do mutations in the TERT promoter and shelterin genes promote the risk of melanoma and other cancers? Some studies have suggested that the effect is because of telomere deprotection ( 65 ), but this model would not explain the fact that these cancers develop in phenotypically intact adults who show no evidence of genome instability during development. We propose that the single shared consequence of TERT promoter and shelterin mutations is a longer telomere and/or a telomere-lengthening capacity (Table 1). Several pieces of clinical data support this interpretation. The first is that TERT promoter and POT1 mutation carriers have longer telomeres than their unaffected relatives ( 65 , 70 ). The second is that families with POT1 and TPP1 mutations often show genetic anticipation, for both cancer onset and cancer mortality ( 13 , 59 , 60 , 65 ). We have proposed before that this pattern of anticipation is likely because of successive telomere lengthening ( 13 ). In one POT1 mutant family, telomere lengthening was observed across generations, although the telomere length measurements were not age-corrected and were performed by nonstandard methods ( 65 ). As discussed in detail below, there is an additional independent body of genetic epidemiology showing that long telomere length alone is associated with increased risk of the same cancers (i.e., melanoma, glioma, CLL) that are seen in cancer-prone families with TERT promoter and shelterin mutations.

The delicate regulation of telomere length is particularly highlighted in the case of TPP1 mutations, where two distinct types of heterozygous, haploinsufficient mutations show opposing disease phenotypes. Mutations in the TEL patch, which is required for both TERT recruitment and processivity, cause an autosomal dominant short telomere syndrome phenotype ( 11 , 71 , 72 ). By contrast, mutations identified in cancer-prone families fall in the POT1-interacting domain and are predicted to interfere with POT1 binding to the telomere ( 10 , 73 ). This would have the functional effect of removing the negative regulation on telomere elongation, making the telomere more accessible, and have a net effect of telomere lengthening. A schematic of these TPP1 allele–specific mutations and their putative effects on telomere length is shown in Figure 1B.

Although the role of germline telomerase and shelterin mutations in familial cancer may at first appear limited to small subsets of cancer patients, there is epidemiologic evidence supporting long telomere length itself as being associated with cancer risk. This has been shown for melanoma and lung adenocarcinoma as well as other cancers ( 74 – 76 ). Larger genome-wide association studies (GWAS) further assert these associations ( 77 ). GWAS are designed to identify common variants that play a role in disease risk ( 78 ), and while the associated single nucleotide polymorphisms (SNPs) may not in themselves be pathogenic, they may be in cis with genes that are. GWAS for melanoma, glioma, and CLL risk have all identified SNPs near telomere maintenance genes, including TERT, RTEL1, NAF1, and POT1 ( 79 – 82 ). In a meta-analysis of 372 GWAS data sets, SNPs near TERT were one of the most common recurrent findings in cancer studies ( 83 ). One important pattern emerges from examining these cancer GWAS. They show that the cancer-associated risk alleles are also the long-telomere alleles identified in telomere-length GWAS. A Danish study of more than 95,000 individuals found that long telomere–associated SNPs identified in GWAS were also associated with increased risk of cancers, especially melanoma and glioma ( 84 ). These data linking genetic variants with long telomere length, along with the data showing that long telomere length itself is cancer-associated, establish that genetically determined long telomere length is a risk factor for a subset of human cancers.

Another set of analyses illustrates how differential effects of common alleles affect disease risk. An initial review of the data may show that hits from GWAS for leukocyte telomere length, IPF, and lung cancer converge on hits near telomere-related genes (Figure 2A). To better illustrate this, we will focus on SNPs near TERT, RTEL1, and NAF1, which were identified in studies on telomere length, IPF, and lung adenocarcinoma. For the TERT SNP rs2736100, which is likely the most commonly recurrent hit in cancer GWAS ( 83 , 85 ), the A short telomere allele, which has a frequency of 0.5, is associated with IPF risk ( 77 , 86 ), consistent with the known link between short telomeres and IPF risk ( 41 ). By contrast, the C allele, which is associated with long telomere length, is a recurrent hit in lung adenocarcinoma ( 77 , 85 , 87 ). SNPs near RTEL1 and NAF1 (rs755017 and rs7675998, respectively) follow similar differential effects, with the short telomere allele associated with IPF and the long telomere allele with lung adenocarcinoma (refs. 86 , 87 , and Figure 2B).

Shared SNPs identified in GWAS near telomere genes are associated with both telomere length and disease risk, but the directionality of the effect is allele-dependent. (A) intersection of shared SNPs across GWAS for leukocyte telomere length, lung adenocarcinoma and idiopathic pulmonary fibrosis. The shared SNPs fall near telomere maintenance genes. The alleles for each SNP have differential effects on telomere length with the effect size shown on base pairs. rs2736100 is in intron 2 of TERT. rs755017 is 140 kb downstream of the RTEL1 transcription start site in exon 2. rs7675998 falls 40 kb upstream of the NAF1 transcription start site. (B) Schematic forest plot shows the odds ratio of disease risk with short and long telomere SNPs such as those shown in the table in A. Data in B are adapted with permission from JAMA Oncology ( 88 ).

A recent meta-analysis further illustrates the importance of telomere length extremes in disease risk. The study pooled 83 GWAS and collectively included data from 400,000 cases and 1 million controls ( 88 ). Among these various phenotypes, the disease that had the strongest association with short telomere SNPs was IPF. The additive effect of these common short telomere SNPs translated to an odds ratio of 10. This finding also underscores the existing literature linking a major subset of IPF risk to short telomere length ( 14 , 15 , 41 , 89 , 90 ). In contrast, long telomere SNPs were associated with cancers that we have considered here and elsewhere to be part of the long telomere syndrome spectrum, including melanoma and glioma (ref. 88 and Figure 2B).

The evidence that long telomere length is cancer-predisposing has been well documented in vertebrate animal models. When the tumorigenic potential of oncogenes, such as overexpressed Myc or Kras G12D , was compared in short- and long-telomere mice, long-telomere mice invariably had a worse outcome, developing more aggressive tumors and showing decreased survival (refs. 91 , 92 , and Figure 3A). These adverse outcomes were seen in both telomerase–wild-type and -null long-telomere mice (Figure 3A). Similar patterns have also been seen in cancer-prone models in which cancers are inducible by loss of a tumor suppressor such as Apc Min or Ink4a ( 93 , 94 ). These models contrast with the exception of Tp53 +/– mice, which developed more tumors on the short telomere background ( 95 ). Since most humans are germline TP53-intact, and in light of the emerging observations that humans with short telomere syndrome have a relatively low risk of cancer, we believe the current models that are informed primarily on the basis of in vitro data may be overestimating the impact of short telomeres as a driver of genome instability and cancer in humans.

Long telomeres promote cancer-related mortality in mice and proposed mechanism for long-telomere melanomagenesis. (A) Survival curve summarizing data from mouse models examining the role of telomerase and telomere length in cancer-related survival. It shows a survival advantage for short-telomere mice in a model of Myc-induced lymphoma, according to Feldser et al. (adapted with permission from Cancer Cell ref. 91 ). (B) Schematic model for how long-telomere melanoma cells prone to environmentally induced DNA damage may have an advantage in cancer progression.

The tight association between melanoma risk and long telomere length raises the question of whether there may be some tissue specificity in melanocytes. Melanocytes are highly vulnerable to ultraviolet-induced genotoxic damage. In this context, short telomeres may limit the proliferative potential of mutation-bearing melanocytes, while longer telomere length may be permissive for increased replicative potential. This in turn would allow the acquisition of additional genetic or epigenetic changes that would allow melanomagenesis. This model is clinically supported by the recent observations showing a high penetrance of cutaneous nevi in some POT1 mutation carriers ( 69 ). It would also explain the absence of any melanoma cases in patients with short telomere syndrome phenotypes.

Initial paradigms of the role of telomeres in cancer benefitted from foundational studies in simple organisms and cell-based models. Now, with the advent of new human genetic observations, there is an opportunity to integrate new data to refine the current understanding of the role of telomeres in cancer. Our synthesis of the recent body of work indicates that the risk of cancer susceptibility associated with long telomeres is greater than that associated with genetically determined short telomere length in humans. This observation is also supported by a large body of existing animal model data. The collective overview thus raises the question as to whether current models may be overestimating the role of short telomeres as a driver of human carcinogenesis. The opportunity to study the role of telomere length in human cancer is a prime example of how cancer biology is enriched and challenged by clinical observations. One final note regarding the role of long telomere length in cancer susceptibility relates to the commercial advertising of products that claim to lengthen telomeres for purposes of reversing or preventing aging. This discourse has limitations and does not have a rigorous scientific basis ( 96 ). The human genetic observations we reviewed here support the idea that excessively long telomeres do not equate with youth but rather with a capacity for cancer cells to grow unchecked with fewer brakes.

We are grateful to Carol Greider, Alexandra Pike, Dustin Gable, and other members of the Armanios laboratory for helpful comments and discussions. Work in the Armanios group is supported by NIH grants CA225027 and HL119476, the Maryland Cigarette Restitution Fund, the Commonwealth Foundation, the Gary Williams Foundation, and an S&R Foundation Kuno Award (to MA). We also acknowledge a gift in the name of P. Godrej. PJL received support from NIH T32CA009071.

Conflict of interest: EJM is currently employed by and has stock options in SQZ Biotech, a cell therapy company.


Section Summary

The ends of the chromosomes pose a problem during DNA replication as polymerase is unable to extend them without a primer. Telomerase, an enzyme with a built-in RNA template, extends the ends by copying the RNA template and extending one end of the chromosome. DNA polymerase can then extend the DNA using the primer. In this way, the ends of the chromosomes are protected. This is important as evidence indicates telomere length may play a role in regulating cell division and the process of aging.