Telomeres and Telomerase in Adrenocortical Carcinoma

  • Tobias Else
  • Peter J. Hornsby


Telomeres are the outer ends of chromosomes and consist of noncoding hexameric repeats of DNA (TTAGGG). There are two main challenges inherently connected to these structures. First, they need to be protected by special mechanisms to prevent their recognition as DNA breaks by DNA surveillance mechanisms and potential processing by the DNA repair machinery. Second, due to the semiconservative mechanism of DNA replication using RNA primers, small stretches of telomeric sequences are lost with each cell division. This is referred to as the “end-replication problem”. The first challenge is met by a specialized structure of the telomere and its association with protein factors that prevent its recognition as damaged DNA and regulate the access of the DNA repair machinery. In the absence of mechanisms to overcome the end-replication problem, the ongoing loss of telomere sequences in somatic cells ultimately leads to critically short and dysfunctional telomeres that will lead to signaling events, resulting in the removal of these cells from the pool of proliferating cells by mechanisms such as senescence, crisis, or potentially apoptosis. These mechanisms prevent the accumulation of telomere dysfunction-induced genomic aberrations.


Idiopathic Pulmonary Fibrosis Adrenocortical Carcinoma Telomere Repeat Amplification Protocol Telomere Repeat Amplification Protocol Dyskeratosis Congenita 
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Telomeres are the outer ends of chromosomes and consist of noncoding hexameric repeats of DNA (TTAGGG). There are two main challenges inherently connected to these structures. First, they need to be protected by special mechanisms to prevent their recognition as DNA breaks by DNA surveillance mechanisms and potential processing by the DNA repair machinery. Second, due to the semiconservative mechanism of DNA replication using RNA primers, small stretches of telomeric sequences are lost with each cell division. This is referred to as the “end-replication problem”. The first challenge is met by a specialized structure of the telomere and its association with protein factors that prevent its recognition as damaged DNA and regulate the access of the DNA repair machinery. In the absence of mechanisms to overcome the end-replication problem, the ongoing loss of telomere sequences in somatic cells ultimately leads to critically short and dysfunctional telomeres that will lead to signaling events, resulting in the removal of these cells from the pool of proliferating cells by mechanisms such as senescence, crisis, or potentially apoptosis. These mechanisms prevent the accumulation of telomere dysfunction-induced genomic aberrations. Telomere shortening can be overcome, e.g., in stem cell compartments and malignant cells, by telomere maintenance mechanisms (TMMs). TMMs either involve the action of telomerase, a ribonucleoprotein that adds telomeric repeats to the telomere or involve alternative TMMs (ALT), the molecular bases of which need yet to be determined. There is experimental and observational evidence that telomeres and telomerase play a role in carcinogenesis in general and in the adrenal cortex in particular. When there is inactivation of checkpoint mechanisms, which normally would induce apoptosis or senescence, critically short or dysfunctional telomeres can set off processes of genome shuffling, such as breakage-fusion-bridge cycles (BFBs), leading to the loss or amplification of genomic material. BFBs and their morphological correlate, anaphase bridges, are important hallmarks of the stage of crisis. Crisis, like senescence, is a terminal state in which cells will persist and eventually die by presumably unspecific mechanisms. Only very rarely, clones may emerge and bypass crisis and acquire TMMs. TMMs can have a dual role with regards to tumorigenesis. Depending on the timing of activation of these mechanisms, before or after the acquisition of genomic alterations (meaning before or after crisis), they can either act as an antitumorigenic mechanism by preventing the occurrence of critically short telomeres or help maintaining a malignant phenotype by stabilizing the genome at later stages of tumorigenesis, thereby providing the basis of immortality.

This chapter will focus on the basic principles of telomere and telomerase in cellular physiology and will then detail the knowledge of this field pertinent to adrenocortical carcinoma (ACC). Telomere pathophysiology involves the action of p53, a main gatekeeper of the DNA surveillance and repair machinery, as well as other factors in this pathway. Therefore, telomere biology is closely connected to the pathophysiology of inherited cancer syndromes like Li-Fraumeni syndrome (LFS).

13.1 The End-Replication Problem and Telomerase

Telomeres are composed of hexameric telomeric repeats. With every round of DNA replication, telomeres shorten by roughly 40–100 bp [1]. The reason for this is depicted in Fig. 13.1. While leading strand synthesis by DNA polymerases is carried out to completion, lagging strand synthesis depends on small randomly priming RNA fragments. This on average leads to a loss of telomeric sequences of the emerging chromosome copy. Over consecutive rounds of chromosome replication, this leads to telomere shortening [2]. Cells that experience critical telomere shortening progress to an irreversible cell cycle arrest termed senescence or initiate programmed cell death, termed apoptosis [3, 4, 5]. Both mechanisms are commonly induced by p53-sensitive signaling pathways [6, 7]. In human fibroblast cultures, this state is mirrored by a gradual slowing of cell proliferation until the entire population enters senescence. It occurs after a number of population doublings characteristic for the cell type, often in the range of 50 as for human skin fibroblasts. It is also known as the Hayflick limit [8, 9]. The process of telomere shortening is often referred to as a main mechanism of cellular aging. However, this is mainly a theoretical consideration with only little direct evidence that telomere shortening can result in senescence in vivo [10].
Fig. 13.1

Model of telomere shortening and telomerase activity. (a) Telomere shortening. A 3’-overhang is created by the lagging strand synthesis after excision of the RNA primer resulting in a shortened telomere. 3’-synthesis of the leading strand can be carried to completion by the DNA polymerase. A 3’-overhang is created by a yet unidentified mechanism, most likely a 5’-exonuclease. After a certain number of cell divisions, telomeres become critically short and induce cellular senescence or apoptosis. (b) Telomere maintenance. Telomerase, consisting of the protein (TERT) and RNA (TERC) subunit, extends telomeres by adding telomeric repeats (TTAGGG) in the 3’-direction. The DNA polymerase can then synthesize the lagging strand. This process can maintain telomere length or lead to telomere lengthening (Figure modified from Else [45])

In stem cell compartments, such as the hematopoietic system, the basal layer of the skin and germ cell epithelia, as well as in embryonic stem cells, the activity of the specialized ribonucleoprotein telomerase overcomes the issue of excessive telomere shortening [11, 12, 13]. Telomerase consists of an RNA component, which harbors a telomeric repeat template, and a protein subunit with reverse transcriptase activity [14, 15]. This enzyme acts by adding telomeric repeats to the chromosome ends in a 5’ to 3’ direction. The lagging strand is then synthesized in the usual way by the DNA polymerase using RNA primers. This mechanism prevents shortening of telomeres and the progression to a length based dysfunctional state and ensures a life time replenishment of tissues. Telomerase activity distinguishes somatic cell types from stem cells such as embryonic stem cells [16]. On the basis of sequence similarities, evolutionary evidence, and an overlap in functional characteristics, it is hypothesized that the telomerase reverse transcriptase shares a common ancestry with the reverse transcriptase of retrotransposons [17].

It is estimated that >90% of malignant human tumors have TMMs. The vast majority of malignant tumors (90%) exploit telomerase as a mechanism of telomere length maintenance, rendering them resistant to telomere-based crisis induced by excessive telomere shortening [18]. The remaining tumors use ALT, which maintains telomere length and integrity in a telomerase-independent manner [19]. The underlying molecular mechanisms of this process are less well understood. These seem to depend on the action of DNA helicases (e.g., WRN and BLM) and most likely employ an exchange of telomere sequences between chromosomes and possibly extrachromosomal telomeric DNA [20, 21].

As pointed out earlier, telomerase activity can theoretically also serve as an anti-cancer mechanism. While this seems to be a paradox, it can be explained by the different timing of acquisition of telomerase activity. When telomerase is expressed at early stages of carcinogenesis, i.e., premalignant stages, it may prevent the occurrence of dysfunctional telomeres induced by telomere shortening, ensuring genomic and telomere integrity and protecting the cell from acquisition of oncogenic mutations through BFBs.

13.2 Telomeres

Telomeres play a key role in the maintenance of genome stability and therefore need to meet one main challenge. They need to avoid being recognized as a DNA break by the DNA surveillance and repair machinery. This task is ensured by two mechanisms. Telomere DNA forms a specialized structure, the so-called T-loop, where the 3’ single-stranded overhang loops back and intercalates (“hides”) into an opening of the double-stranded telomeric DNA, called the D-loop [22]. The 3’ single-stranded overhang results from lagging strand synthesis as described above (Fig. 13.2, Table 13.1). The 3’ single-stranded overhang of the leading strand is produced by a putative exonuclease, which to date has not been definitively identified. Furthermore, telomeres are bound by a complex of six main proteins [23]. This complex, also termed shelterin, forms the telomere cap, which further prevents the recognition of telomeric DNA as a DNA double-strand break and regulates telomerase access. The shelterin complex consists of six different core proteins, which either bind to telomeric DNA or serve as interconnectors between DNA-bound shelterin complex proteins (Table 13.1). TRF1 and TRF2 bind directly to double-stranded telomeric repeats [24, 25]. POT1 binds to the single-stranded 3’-overhang [26]. The remaining three components of this complex bind to DNA-bound factors and form several different configurations, which are proposed to serve different functions [27]. RAP1 binds to TRF2, TIN2 binds to TRF1 and TRF2, and TPP1/ACD serves as an interconnector between TIN2 and POT1 [28, 29, 30, 31, 32, 33]. The importance of these factors is underscored by the fact that deficiency of most of the shelterin components renders telomeres dysfunctional and induces signaling events leading to the induction of senescence or apoptosis [6, 34, 35, 36]. Dysfunctional telomeres can therefore either arise from critical decrease in number of telomeric repeats or from shelterin component deficiency [3, 4, 6]. Whether apoptosis or senescence is induced by telomere dysfunction seems to be dependent on cell type and degree of telomere dysfunction [37, 38]. In human cells in the presence of functional checkpoints, telomere dysfunction leads to signaling events inducing senescence as the main non-replicative state [5]. Experimental data, at least in the murine organism and in cell culture experiments with overwhelming sudden telomere dysfunction (e.g., induced by transduction with a dominant negative isoform of TRF2) also suggests the possibility of apoptosis induction [6, 37, 39, 40]. However, it remains unclear, whether telomere dysfunction-induced apoptosis plays a significant role in in vivo tumor prevention. The lack of detection may also be due to the usual transient character of apoptosis in tissues. Cells in final static states such as crisis and senescence accumulate, and can rather easily be detected, while apoptotic cells may escape analysis as cell remains are readily eliminated, e.g. by macrophages. In the adrenal cortex senescence seems to be the major mechanism. Dysfunctional telomeres can be detected as TIFs in tissue sections, where telomere hybridization signals co-localize with factors of the DNA surveillance machinery, such as γH2AX or 53BP1 [36]. Dysfunctional telomeres activate ATM and ATR phosphorylation followed by a subsequent signaling cascade that activates p53 to stall the cell cycle and induce apoptosis or senescence [6, 7]. A hallmark of senescence induction is the activation of p21, which lies downstream of p53 signaling, but is also characterized by the activation of p16, which plays, at least in human cells, an adjunct role in response to dysfunctional telomeres [41, 42]. The non-replicative state of senescence is also referred to as M1 (mortality stage 1) [43].
Fig. 13.2

The telomere cap complex (shelterin complex). Multiple shelterin complexes can be found at the telomere DNA T-loop and exist in different compositions to serve the multiple functions of the telomere, protect it from recognition, and processing by the DNA surveillance machinery. On the right a “magnified” model of the telomere cap complex (shelterin complex) bound to the end of the telomere is shown. (POT1, protection of telomeres 1; ACD, adrenocortical dysplasia homolog (TPP1/ACD); TERT, telomerase reverse transcriptase; TERF2IP, TERF2-interacting protein (RAP1); TERF2, telomeric repeat-binding factor 2 (TRF2); TERF1, telomeric repeat-binding factor 1 (TRF1); TINF2, TRF1-interacting nuclear factor 2 (TIN2)) (Figure modified from Else [45])

Table 13.1

Telomere-associated proteins (chromosomal location, function, associated hereditary diseases)


Chromosomal location


Associated diseases



Shelterin component

None reported



Shelterin component

None reported



Shelterin component

None reported



Shelterin component

None reported



Shelterin component

None reported



Shelterin component

Sporadic DC, autosomal dominant DC, Hoyeraal Hreidarsson



Telomerase RNA component

Sporadic and hereditary IPF, sporadic and hereditary aplastic anemia, hereditary liver cirrhosis, autosomal dominant DC



Telomerase protein subunit, catalytic subunit

Sporadic and hereditary IPF, sporadic and hereditary aplastic anemia, hereditary liver cirrhosis, autosomal dominant DC




X-linked DC, Hoyeraal Hreidarsson




Autosomal recessive DC




Autosomal recessive DC

In the absence of sufficient checkpoints that would act to detect dysfunctional telomeres, cells bypass the stage of senescence and enter a state called crisis [43]. Crisis is characterized by chromosomal end-to-end fusions, leading to aneuploidy, and by mitotic catastrophe, leading to an arrest in mitosis [44]. Therefore, crisis represents a second terminal state, which is also referred to as M2 (mortality stage 2) [43]. Only extremely rarely clones will manage to escape this stage and give rise to a fully malignant tumor. These clones must acquire: (1) alterations leading to malignant transformation (e.g., via transient BFBs, see below) and (2) TMMs for genomic stabilization to acquire immortality (e.g., telomerase activity).

In summary, telomeres may play two different roles in carcinogenesis depending on the presence or absence of sufficient checkpoints of telomere and DNA integrity. In the presence of these checkpoints, telomere dysfunction induces removal of cells from the pool of proliferating cells and serves as an anti-cancer mechanism. On the other hand, in the absence of these checkpoints dysfunctional fusogenic telomeres may serve as a starting point for BFBs and lead to the acquisition of a pro-cancer genome. However, it is important to mention that BFBs leading to genomic rearrangements, which provide the cell with TMMs, are very likely rare events and therefore crisis still acts as a tumor suppressor mechanism.

13.3 Telomere-Based Model of Carcinogenesis

There are two main steps in order to acquire a full malignant phenotype in the telomere-based model of carcinogenesis. The first event leads to the acquisition of a pro-cancer genome while the second event stabilizes telomeres and prevents crisis-based growth arrest [45, 46, 47].

As described above, dysfunctional telomeres usually signal to induce preferentially senescence and possibly apoptosis. This is of course only true in cells with proficient DNA surveillance machinery and intact checkpoint mechanisms. Therefore, most of our knowledge of dysfunctional telomere-induced carcinogenesis stems from animal models and human syndromes deficient in main DNA surveillance signaling factors, such as p53 or ATM, as well as proteins necessary for telomere maintenance and integrity. The two main mouse models are homozygous Terc –/– mice, which acquire telomere dysfunction in late generations due to excessive telomere shortening, and adrenocortical dysplasia (acd) mice, which are deficient in the shelterin component Tpp1/Acd [48, 49, 50, 51, 52]. Terc –/– mice tend to develop cancers at late generations and old age [53]. Additional p53 deficiency of Terc –/– mice leads to an acceleration of tumor incidence compared to Terc +/+ /p53 –/– mice [49, 51]. On the contrary, acd mice exhibit signs of telomere dysfunction already within the first generation and do not develop tumors unless they are challenged with a second event such as p53 deficiency [48, 54, 55]. p53 –/– /acd mice develop cancer at a significantly earlier age than p53 –/– mice, which carry the wt Tpp1/Acd allele, and which have intact telomeres. In both animal models it has been shown that tissues display a higher degree of telomere dysfunction as evidenced by the occurrence of telomere dysfunction-induced foci (TIFs). Tissues and tumors from these mice show an increase in anaphase bridges. These are morphological correlates of telomere fusions, which can serve as a starting point for BFBs. BFBs are thought to be the main mechanism leading to genomic alterations in the setting of telomere dysfunction (Fig. 13.3). In case of checkpoint deficiency, e.g., absence of p53, cells with dysfunctional telomeres, either as a result of critical shortening (e.g., Terc –/– ) or due to deficiency of a shelterin component (acd mice), fail to undergo apoptosis or senescence [3, 4, 37]. The uncapped telomeres are recognized by the DNA repair machinery and are fused by cellular ligases (e.g., as part of non-homologous end-joining processes (NHEJ)) resulting in dicentric chromosomes. These chromosomal alterations can be observed in metaphase spreads of mouse embryonic fibroblasts from several shelterin-deficient animals [35, 54, 56, 57, 58]. During mitosis those dicentric chromosomes may be pulled to the opposite poles of the emerging daughter cells, and in anaphase these chromatin strings can be observed as anaphase bridges. Eventually, these dicentric chromosomes break at a location that is not necessarily the former fusion point. As a result, the genome of one of the daughter cells will have genomic gains and the other one losses. The new DNA breaks can serve again as starting points for BFBs, leading to further amplification or losses of genetic loci [59, 60]. The genomic alterations can be either visualized by spectral karyotyping or analyzed by comparative genomic hybridization [48, 49, 61]. Both available mouse models of telomere dysfunction have been subjected to these analyses and show typical translocations and genomic copy number changes, which are in accordance with presumed BFBs.
Fig. 13.3

Model of genomic shuffling by breakage fusion bridge (BFB) cycles. Dysfunctional telomeres (absent red circles) fuse and form dicentric chromosomes. During cell division, the fused chromosomes are pulled to the two different poles of the emerging daughter cells. During anaphase these can be observed as anaphase bridges, chromosomal material spanning from one daughter cell to the other. Eventually, a break occurs and creates another open (unprotected) end, which can serve as a new starting point for a subsequent BFB. Ultimately, this process leads to genomic amplifications and deletions (Figure modified from Else [45])

There is growing evidence from the analysis of human pathologies that telomere dysfunction and the subsequent development of genomic aberrations take place in early malignant or premalignant lesions [62]. Recent studies have focused on breast cancer and colon cancer [63, 64, 65, 66]. Both tumors have well-defined histological stages of carcinoma progression from premalignant stages. During the development of breast cancer genomic instability occurs at a very early stage, during the progression from usual ductal hyperplasia to ductal carcinoma in situ [63]. In human colon cancer as well as in the Apc min mouse model, telomere-based genomic instability has been detected at the stage of high-grade dysplasia and carcinoma in situ but not in adenomas [64, 67].

In the second step of the telomerase-based model of tumorigenesis, malignant cells acquire telomerase activity or an alternative TMM [47, 63, 68]. Genomic alterations resulting from end-to-end fusions in most incidences will lead to crisis and mitotic arrest [43]. Only very rarely clones will escape and bypass the stage of crisis and acquire telomerase activity or ALT [69]. These TMMs lead to a stabilization of telomeres and provide the emerging clone with an indefinite potential to proliferate without undergoing telomere dysfunction-based crisis. Indeed, roughly 90% of human cancers are positive for telomerase activity [18]. In breast cancer, telomerase activity can first be detected during the progression from usual ductal hyperplasia to ductal carcinoma in situ, presumably shortly after the acquisition of genomic alterations necessary for progression to a malignant phenotype [63].

In summary, in order to give rise to an immortal malignant cell clone, this clone will need to bypass senescence through some kind of checkpoint deficiency and acquire a malignant phenotype, possibly through further genomic alterations generated by BFBs. This genomic instability due to dysfunctional telomeres seems to parallel early stages of progression from pre-malignant to malignant lesions. Of note, sufficient telomerase activity as a preventive mechanism is absent during this phase, underscoring the potential importance of telomerase activity as an anti-cancer mechanism. While these genomic aberrations lead to a malignant phenotype, immortality is acquired by later activation of telomerase activity (or ALT).

13.4 Telomerase in Experimental Adrenocortical Carcinoma

TERT-expressing vectors have been employed in several tissue-engineering experiments involving xenografts in immunodeficient mice. Human or bovine adrenocortical cells transduced with a TERT expression vector, when transplanted under the renal capsule, produce sufficient hormones to prevent death of adrenalectomized mice [70] (Fig. 13.5). It is noteworthy that these cells do not form tumors. Therefore, the simple introduction of telomerase activity into a normal telomerase-negative cell does not induce a malignant phenotype. When this xenotransplant model was applied to test different oncogene requirements for malignant transformation, an important observation was made. In the past, experiments with human fibroblasts and other human cell types had shown that the minimal requirement for a full malignant tumor-forming phenotype was the inactivation of the retinoblastoma (pRB) and p53 tumor-suppressor pathways (for example, by the action of viral proteins such as SV40 LT), acquisition of a constitutive mitogenic signal provided by oncogenic Ras, and perturbation of protein phosphatase 2A by SV40 ST as well as introduction of telomerase activity [71, 72, 73]. In all these experiments cells were transplanted or injected into the subcutaneous tissue of immunodeficient nude mice. However, when adrenocortical cells (or fibroblasts) of human or bovine origin were transplanted under the kidney capsule, transduction with SV40 LT and oncogenic Ras were sufficient to induce a fully malignant phenotype – there was no necessity for telomerase activity [74, 75]. A thorough analysis of these tumor cells did not show acquisition of any telomere maintenance mechanism, neither telomerase activity nor alternative telomere lengthening. These experiments challenged the paradigm that telomerase activity or other telomere maintenance mechanisms are needed for a malignant transformation, and clearly showed that telomere maintenance mechanisms are not necessary for a malignant phenotype of adrenocortical cells. Two other roles of telomerase were identified in subsequent experiments. First, telomerase is sufficient to induce immortality, and second, it was hypothesized that telomerase may play a role in malignant transformation different from its role in telomere maintenance. Transduction with SV40 LT and oncogenic Ras were sufficient to induce a malignant phenotype, but these cell clones lacked immortality [75]. When tumors of these cells were harvested, diluted, and serially transplanted, tumor growth ceased and transplanted cells entered a stage of crisis after a definite number of serial transplantations. An immortal phenotype with an “indefinite” number of serial transplantation could be induced when telomerase activity was conferred by transducing TERT additionally into these cells, consistent with the concept that TMMs are necessary for immortality (Fig. 13.4). However, this does not explain why TERT is needed for a malignant phenotype of fibroblasts when transplanted subcutaneously. A possible explanation is that TERT serves different functions aside from its role at the telomere. There is accumulating evidence that there is an alternative TERT function in stem cell physiology, independent of telomeres. It has been shown in several experiments that ectopic TERT alters overall gene expression patterns of different cell types, which cannot simply be explained by its role at the telomere [76, 77, 78, 79].
Fig. 13.4

Telomere-focused model of tumorigenesis. Dysfunctional telomeres, either as a consequence of telomere decapping or resulting from telomere shortening, will be recognized by the DNA surveillance machinery and induce senescence (M1) or apoptosis (telomeres are shown as red circles). In the setting of checkpoint deficiency, such as p53 deficiency, chromosomes may fuse and start BFBs, leading to a shuffling of the genome and genomic amplifications and deletions. These cells usually enter the state of crisis (M2), a terminal non-proliferative state. Only very rarely a clone will gain a mechanism of telomere maintenance (TMM, either telomerase-dependent or independent). TMMs stabilize the genome and the emerging cancer cells acquire independence of telomere shortening-induced senescence or apoptosis (Figure modified from Else [45])

Fig. 13.5

Experimental restoration of tumorigenicity by hTERT. Representative experiments are shown in which cells isolated from telomerase-negative tumors, formed from Ras G12V /SV40TAg-transduced human and bovine adrenocortical cells, were transduced with TERT and retransplanted into immunodeficient mice. After establishment of the 1° tumor, 2° and subsequent tumors were formed by subcutaneous implantation of tumor fragments. The retroviruses used are indicated. The times shown are the number of days after transplantation before the tumor reached a diameter of 0.5 cm (Figure from Sun et al. [75])

In summary, telomerase activity or TMMs are not necessary to induce a malignant phenotype in the setting of xenotransplantation under the kidney capsule, but they are necessary to induce immortality and “indefinite” tumor growth/cell proliferation. They are therefore important for the maintenance of a malignant tumor phenotype. Moreover, telomerase may present an interesting therapeutic target. Though inhibition of telomerase or TMMs is unlikely to lead to tumor shrinkage, it still may stall tumor growth, stop tumor progression, and may induce a crisis state of tumor cells. Additional non-telomere functions of telomerase need to be further investigated.

13.5 Human Syndromes with Defects in Telomere Physiology

To date, only dyskeratosis congenita (DC) and various variations of this syndrome can clearly be attributed to defects in telomere physiology; however, there are several other syndromes that impact telomere physiology as well as other cellular DNA surveillance, repair and replication mechanisms [80, 81]. None of these syndromes, with the exception of LFS, have been reported to be associated with ACC. This may be due to the fact that these patients usually succumb to other kinds of malignancies, and ACC may be as rare in these patients as in the general population.

The main syndromes are DC and related disorders (e.g., aplastic anemia, idiopathic pulmonary fibrosis), which are caused by mutations in the telomerase subunits TERC or TERT (autosomal dominant), a telomerase-associated protein, DKC (X-linked recessive), the shelterin complex component TIN2 (autosomal dominant), or other genes encoding parts of the telomerase holoenzyme (e.g., NOP10) [80, 82, 83, 84, 85, 86]. All of these gene products serve functions at the telomere. DC is mainly inherited in an autosomal-dominant, an autosomal-recessive, or an X-chromosomal recessive fashion. Depending on the gene mutated and on the gene mutation, there is a great variation of severity and of organs affected, ranging from isolated aplastic anemia or idiopathic pulmonary fibrosis to the severe Hoyeraal-Hreidarsson syndrome [87]. TERT and TERC mutations vary in their penetrance and human pedigrees. These mutations seem to be subjected to genetic anticipation, which means that the severity of the phenotype increases and the age of onset decreases over generations [87]. The main clinical features of DC are refractory anemia and bone marrow failure, presumably due to exhaustion of stem cell compartments, and early onset of tumors [88]. The spectrum of malignancies is mainly dominated by squamous cell cancer of the head and neck and skin, but other neoplasias such as gastrointestinal neoplasms and lymphoma have also been described [89].

ACC is one of the disease-defining neoplasms in LFS [90, 91]. Most interestingly, it has recently been shown that the age of first tumor manifestation is correlated with telomere length, meaning the shorter the telomere, the earlier a patient within the same LFS pedigree will manifest disease [92]. Though this study did not focus on LFS patients with ACC in particular, it nevertheless links LFS to telomere pathophysiology and telomere shortening, which can be interpreted as a pro-oncogenic mechanism in these patients.

13.6 Telomerase and Adrenocortical Carcinoma

Shortly after the discovery of telomerase activity, it became clear that this mechanism is heavily exploited by malignant tumors. Roughly 90% of all human tumor samples are telomerase positive [18]. Later, several tumor entities were described that did not display telomerase activity, yet maintained telomere integrity and length [19]. Most of these samples had very long telomeres, by far exceeding the usual length of human telomeres of ∼5 kb, and also showed a distribution over a wide range of lengths. This mechanism was termed ALT. Classical examples of tumor entities that use ALT are liposarcoma, glioblastoma, and osteosarcoma [93, 94, 95]. While the mechanisms underlying telomere length maintenance by telomerase activity are mostly understood, the mechanisms underlying ALT are still enigmatic [20, 21]. Interestingly, one of the first reports describing surrogate parameters of ALT, i.e., long telomeres and the immunohistochemical co-localization of a bright telomere signal with PML bodies, included several adrenal tumors [19]. Unfortunately, these adrenal tumors were not further specified with regard to their histology and clinical behavior. Several studies have surveyed TMMs in benign and malignant adrenocortical tumors [96, 97, 98, 99, 100, 101, 102]. All but one study focused on telomerase activity alone [97]. Most studies find telomerase activity in the majority of malignant lesions and not in benign neoplasms or normal adrenal tissue. The study by Mannelli et al. also finds telomerase activity in 9 of 11 benign lesions, but states that telomerase activity was significantly lower when compared to ACC [100]. Bamberger et al. also found low levels of telomerase activity in all samples, including normal adrenal control tissue [96]. This study employed an ELISA-based method; with this method it is difficult to determine a threshold cut-off for telomerase activity. This is usually very easy using the traditional radioactive telomere repeat amplification protocol (TRAP) assay, which gives a clearly negative or positive result. On average, they detected higher levels of telomerase activity in ACC vs. normal tissue, and telomerase activity was higher in 6 of 7 ACCs when compared to benign adenomas. Though results from these different studies are difficult to compare for several reasons, such as differences in material preparation, differences in clinical descriptions and differences in methods measuring telomerase activity, it seems to be clear that most malignant lesions are positive for telomerase activity while most benign lesions are not (Table 13.2). ALT seems to play a minor role in ACCs, but is present in a subset of ACCs either together with telomerase activity or as the only TMM [97]. This further supports a role for TMMs in maintaining immortality in ACC. This assumption also makes TMMs an interesting potential therapeutic target. Several telomerase inhibitors have shown anti-tumor activity in in vitro and in vivo experiments and the first compounds are progressing to phase I clinical trials [103, 104].
Table 13.2

Studies of telomere maintenance mechanisms in ACC



Sample sizea





Kinoshita et al. [111]






Positive sample had some malignant features

Hirano et al. [98]







Teng et al. [102]






Weak activity in the positive ACA

Bamberger et al. [96]






Higher level in ACC vs. ACA and NL, quantitative PCR-based assayb

Mannelli et al. [100]






Higher levels in ACCs vs. ACA

Else et al. [97]






1 ACC positive for ALT, 2 ACC indeterminate







aTotal sample size includes other tumors tested in these studies (e.g., pheochromocytoma, lymphoma)

bThe employed method does not distinguish positive vs. negative activity as well as the traditional radioactive TRAP method

13.7 Telomeres and Adrenocortical Carcinoma

There is growing evidence that telomere dysfunction may play a role in adrenocortical tumorigenesis as well [45, 48]. Unfortunately, the small sample sizes available for adrenocortical tumors have so far precluded a thorough analysis as has been done for other tumors, such as breast cancer. Another problem is that the molecular events leading to malignant lesions in other tissues have been very well described; the adenoma to carcinoma progression of colon cancer is a classical example. Interestingly, despite the high incidence of benign adrenocortical tumors, there is no convincing evidence that these tumors may present precursor lesions for ACC. The frequency of progression of adrenocortical adenomas to ACC is basically unknown, if it exists at all. Despite these limitations and differences from other tumor entities, there are currently several lines of evidence arguing for a possible role of telomere dysfunction in adrenocortical tumorigenesis. In general, ACCs show a high degree of aneuploidy and genomic diversity, which can be explained by some event furthering genomic instability; telomere-induced genomic instability is one possible explanation (see  Chapter 9). Observational studies using gene expression arrays show significant differences in expression of genes encoding shelterin complex components between benign lesions and ACC [45, 105]. While this may reflect general alterations in telomere physiology, it may also suggest a direct role of disproportional expression of these factors in inducing telomere dysfunction and subsequently genomic instability. Several studies of other malignancies, such as T-cell leukemia, B-CLL, gastric cancer, non-small cell lung cancer, and breast cancer have shown alterations in expression levels of shelterin component-coding genes [106, 107, 108, 109, 110]. Probably, the most direct evidence comes from the acd mouse, which develops telomere dysfunction-induced genomic alterations. In p53-proficient acd mice, dysfunctional telomeres lead to the induction of senescence in adrenococortical cells. About 5% of p53 heterozygous acd mice develop bona fide ACC as evidenced by Sf1 expression [48]. Though ACCs occur only in a small proportion of these animals, it is still noteworthy in light of the lack of the extreme rarity of this cancer in any other mouse model. Furthermore, it provides evidence that dysfunctional telomeres are sufficient to induce ACCs. However, it does not answer the question of whether telomere dysfunction is involved in human adrenocortical tumorigenesis.


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Copyright information

© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  1. 1.Department of Internal Medicine – Division of Metabolism, Endocrinology & DiabetesUniversity of Michigan Health System, University of MichiganAnn ArborUSA
  2. 2.Department of Physiology and Barshop Institute for Longevity and Aging StudiesUniversity of Texas Health Science CenterSan AntonioUSA

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