Telomeres and diseases (3)
Telomere shortening and cancer
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There is a lot of evidence that telomere shortening is associated with the development of cancer and may be a causal factor in the development of a number of oncological diseases. Patients with congenital dyskeratosis have a 1000–fold increased risk of developing tongue cancer and about 200-fold increased risk of developing acute myeloid leukemia [12]. In aplastic anemia, patients with the shortest telomeres (in the absence of mutations) have a 4-5-fold increased risk of malignant transformation of the disease into myelodispasia or leukemia [13]. Telomere-free end sections of chromosomes and aneuploidy are detected in bone marrow cell cultures of patients years before the onset of clinical symptoms. Moreover, in acute myeloid leukemia, diagnosed without previous bone marrow insufficiency, congenital mutations of TERT and TERC are detected in some patients [14].
Short leukocyte telomeres are a prognostic factor for the development of cancer in Beretta syndrome (manifestations are peptic ulcers, mucosal metaplasia and esophageal strictures) and ulcerative colitis, which is associated with the loss, appearance of excess and rearrangement of chromosomes in cancer cells [15,16], however, the mechanisms of this phenomenon are unclear. Are the short telomeres of leukocytes a reflection of the length of the telomeres of the affected organ or are they a biomarker of the effects of reactive oxygen species in chronic inflammatory processes? Free radicals can damage telomeres, therefore, cells cultured in room air are characterized by excessive shortening of telomeres compared to cells cultured under conditions of reduced oxygen pressure.
In general, during numerous genome-wide analyses for many types of cancer, single nucleotide polymorphisms of the TERT gene were identified as risk factors [17]. In a recent publication, the authors claim that short telomeres are associated with an increased risk of developing all types of cancer and associated mortality in a large population that has been monitored for more than 10 years [18]. Telomere shortening is an indirect concomitant symptom of aging, which in itself is an important risk factor for cancer (Fig. 2).
Figure 2. Telomere erosion and cancer risk
With congenital dyskeratosis (DKC), which is characterized by a high probability of phenotypic manifestations of the mutation, the risk of developing cancer, especially squamous cell carcinoma of the head and neck, as well as acute myeloid leukemia (AML), is increased. Patients with aplastic anemia are also at risk for the development of clonal malignant diseases, although to a lesser extent. Similarly, it seems that short telomeres are a prognostic factor for the progression of chronic inflammatory conditions from the gastrointestinal tract into malignant diseases: aplastic anemia (AA) progresses into myelodysplastic syndrome (MDS) or acute myeloid leukemia, inflammatory bowel disease (IBD) - into colon cancer, and Beret syndrome - into adenocarcinoma. The results of many genome-wide associative studies have shown that the TERT locus is a significant locus of predisposition to various types of cancer, but with relatively low probability levels.
Secondary iatrogenic (resulting from medical intervention) malignant hematological diseases develop after chemotherapy and radiotherapy, presumably having a stressful effect on bone marrow cells and causing shortening of their telomeres. More visual data were obtained when working with "knocked out" mouse models: animals of lines characterized by reduced activity of telomerase and tumor suppressor protein p53 develop various malignant tumors of epidermal origin, uncharacteristic for rodents, but often found in humans.
In most malignant diseases, activation of the telomerase gene or an alternative mechanism for maintaining telomere length (see above) is considered a prerequisite for ensuring cell immortality. Telomerase activity is too often elevated in malignant cells and cell lines to be considered an adequate therapeutic target. In general, short telomeres and the chromosomal theory of cancer etiology do not contradict these data.
Most of the cells whose telomeres reach a critically short length die or enter the phase of physiological aging. In the few surviving cells (possibly due to insufficient activity of the p53 protein and associated reactions to DNA damage), the telomere repair process is presumably subjected to strong selective pressure. Telomere shortening is a kind of equivalent of the "mutator gene phenotype", which increases the frequency of spontaneous chromosomal aberrations, ranging from quantitative changes to structural anomalies (translocations, insertions, deletions and telomere-associated terminal mergers of chromosomes), and, accordingly, increases the number of defective cells exposed to selection.
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