Telomere Length Alterations Associated with Breast, Thyroid and Cervical Cancers
Telomeres are specialised structures of eukaryotic chromosomes that are present at each end of chromosomes. Telomeric length acts as a biological clock which helps to determine the life span of a cell and an organism. Telomeric shortening is also associated with various disease patterns including Dyskeratosis Congenita, Parkinson’s disease, Ulcerative Colitis and chronic hepatitis. Any anomality in the telomeric function initiates genomic instability which increases the risk of cancer. Individuals with short telomeres are at increased risk for cancer. This review paper aims to find out the studies pointing out the relation of telomeric length and different types of cancers including breast, thyroid and cervical cancer. A positive correlation has been found in between telomeric shortening and cancer occurrence. Further studies are suggested to strengthen the association of telomere length alterations with specific cancer type.
Telomeres are specialised structures of eukaryotic chromosomes that are present at each end of chromosomes. Telomeres are TTAGGG tandem repeats capping chromosomal ends1. The sequence of nucleotides is repeated approximately 1500 to 2000 times in human cells. Telomeres are essential for providing protection to genome from nucleolytic degradation and inter-chromosomal fusion. Telomeres also maintain the chromosomal and genomic stability2. Telomerase is the enzyme that maintains the telomeric length by the addition of guanine rich repetitive sequences. Telomeric length acts as a biological clock which helps to determine the life span of a cell and an organism. The shortening of telomere length can be attributed to various reasons. Stress is one of the main causes of shortening of telomeres3. At high stress levels, function of telomerase is impaired and shortening of telomeres gets accelerated3. Smoking is the second reason for reduction in telomeric length. Obesity has also been found in correlation with increased oxidative stress, DNA damage and telomere shortening. An unbalanced dietary habit also enhances the telomere shortening.
Telomeric shortening is also associated with various disease patterns including Dyskeratosis Congenita (DC)4,5, also known as Zinsser-Cole-Engman Syndrome, Parkinson’s disease, Ulcerative Colitis6 and chronic hepatitis7. Chronic Obstructive Pulmonary Disease (COPD)8,9 and Type 2 diabetes10–12 have also been found related with telomeric shortening. Leukocyte Telomere Length (LTL) is a biological marker of aging and shorter LTL is associated with adverse cardiovascular outcomes13–17. Telomere shortening was shown to parallel Alzheimer’s Disease (AD) associated dementia18. Various other studies also reported the association of telomere shortening and AD18–22.
Telomeres as Biomarkers
Telomere alteration and telomerase activity have been observed in most human cancers and are known to be a feature of malignancy23. Individuals with short telomeres are at an increased risk for cancer, since short telomeres lead to genomic instability24. Hence, telomeres may act as biomarkers for the prediction and progression of a cancer type. The studies reporting the telomere length being associated in different cancer types are summarized below.
Breast cancer risk is affected by Telomere Length (TL). Telomere dysfunction plays a significant role in the initiation of genomic instability during carcinogenesis in human breast cancer25. Working schedule may impact risk of breast cancer as TL is affected by intensive night work schedule. Working continuously for six consecutive nights for more than 5 years was found to decrease TL (-3.18, 95% CI: -6.46 TO -0.58, P = 0.016). There was a lower risk of breast cancer in nurses having longer TL, who worked more than four (OR: 0.37, 95% CI: 0.16 – 0.79, P = 0.014) or five (OR: 0.31, 95% CI: 0.10 – 0.83, P = 0.029) simultaneous night shifts for 5 years or more26. In another study by Kammori et al.27, a total of 44 breast cancer cases including 17 scirrhous, 15 papillotubular and 12 solid tubular carcinomas were investigated. Mean TL was found to be short in patients with large tumours, lymph node metastasis, vascular invasion and with third stage of tumour node metastasis. This data suggested the association of TL of cancer cells with the degree of cancer progression.
Genetic Polymorphisms in Breast Cancer
Several studies have reported an increase in breast cancer risk when patients are carriers of the CYP19 TTA polymorphism with > / = 10 repeats. In a study, a total of 180 postmenopausal healthy and 70 BC-diagnosed women were checked to understand the relationship between CYP19 TTA repetition polymorphism and telomere length. Patients with a BC diagnosis showed > 10 repetitions more frequently, compared with that of healthy women (50% vs. 23%, chi = 11.44, p = 0.0007)28. IGFBP7 promoter methylation status was evaluated by methylation-specific PCR and its expression levels were determined by western blotting. A comparison was done between breast cancer tissues and adjacent normal tissues among Turkish women. GFBP7 methylation was observed in 90% of tumour tissues and 59% of controls (P = 0.0002)29. Telomere dysfunction is known to activate ATM (Ataxia Telangiectasia Mutated)-mediated DNA damage response signalling pathways30. ATM participates in the signalling of telomere erosion, and inherited mutations in ATM have been associated with increased risk of cancer, particularly breast cancer. Renault et al.31 measured mean TL and genotyped seven Single-nucleotide Polymorphisms (SNPs) recurrently associated with TL in large population-based studies. ATM mutation carriers (HetAT) individuals were found to be at increased risk of cancer (OR = 2.9, 95% CI = 1.2 – 4.4, P = 0.01), and particularly of breast cancer for women (OR = 2.9, 95% CI = 1.2 – 7.1, P = 0.02), in comparison to their non- HetAT relatives. Similarly, knockdown of HMBOX1 was found associated with increased apoptosis rate and reduced expression of ATM32. The non-histone chromatin binding protein High Mobility Group AT-hook protein 2 (HMGA2) plays important roles in the repair and protection of genomic DNA in embryonic stem cells and cancer cells. In a study, HMGA2 was found to prevent ATM-dependent pTRF2T188 phosphorylation and attenuate signalling via the telomere specific ATM-CHK2-CDC25C DNA damage signalling axis33. High Mobility Group Box 1 (HMGB1) in tumour cells include replenishing telomeric DNA and maintaining cell immortality. Downregulation of HMGB1 modulated telomere homeostasis by changing the level of telomere-binding proteins, such as TPP1 (PTOP), TRF1 and TRF2. This downregulation also inhibited the ATM signalling pathways34. In another study, the role of ATM-mediated DNA damage response signalling in Androgen Receptor (AR)-inactivated prostate cancer cells was investigated. The induction of telomere dysfunction in cells treated with AR-antagonists (Casodex or MDV3100) or AR-siRNA was associated with a dramatic increase in phosphorylation of ATM. ATM inhibitor induces apoptosis in AR-inactivated cells by blocking the repair of damaged DNA at telomeres30.
Some studies have also been found reporting the association of TL and thyroid cancer35–37. Human epidermal growth factor receptor 2 (HER2) proto-oncogene plays an important role in the development and progression of breast and gastric cancers. Amplification of HER 2 gene in differentiated thyroid cancer was found to be in correlation with telomere shortening23. 69 cases of differentiated thyroid cancers were investigated. The telomeres of thyroid cancers, especially follicular carcinomas, were found to be significantly shorter than those of adjacent normal tissues23. Similarly, the frequency of HER2 amplification, genetic variations in sporadic Papillary Thyroid Cancer (sPTC) and familial Papillary Thyroid Cancer (fPTC) and association with relative telomere length and BRAF mutational status were investigated. RTL was found to be shorter in fPTCs than sPTCs (p < 0.001) and HER2 amplification in fPTCs was found to be invariably associated with BRAF (V600E) mutation38.
Only a few studies reported the association of cervical cancer with telomere shortening. Various compounds may be involved in shortening of TL as Merghoub et al.39 reported that tomentosin triggered telomere shortening and apoptosis in cervical cancer HeLa and SiHa cells. Similarly, Merghoub et al.40 reported that the extracts from Inula viscosa L. target telomeres, induce apoptosis and overcome drug resistance in tumour cells. It was also found that extracts raised telomere shortening by suppressing the telomerase activity. Another study reported the association among HMBOX1, telomere length and radiosensitivity in cervical cancer cells. Knock-down of HMBOX1 was found to be associated with increased apoptosis rate and decreased expression of ATM, ATR, p-ATM, p-ATR and BRCA141.
|S. No.||Author||Year||Type of cancer||Inference||Reference no.|
|Samulin et al.||2017||Breast cancer||Telomere shortening is associated with breast cancer risk in workers with long periods of consecutive night shifts.||42|
|Kammori et al.||2015||Breast cancer||Mean telomere length was found less in patients with TNM third stage; showed positive correlation with degree of cancer progression.||43|
|Cassar et al.||2017||Breast cancer||BMP7 induces breast cancer cell ageing by a mechanism involving BMPRII receptor-and Smad3- mediated repression of the hTERT gene.||44|
|Finot et al.||2017||Breast cancer||Genotoxic effect of ethyl paraben in the presence of S9 is associated with telomere shortening.||25|
|Sugishita et al.||2013||Thyroid cancer||Amplification of the human epidermal growth factor receptor 2 gene in differentiated thyroid cancer correlates with telomere shortening.||23|
|Merghoub et al.||2017||Cervical cancer||Tomentosin induced telomere shortening in cervical cancer cells in foetal fibroblast Wi38 and JW10 cells.||39|
|Merghoub et al.||2016||Cervical cancer||IV-HE and IV-DF extracts from Inula Viscosa L. induces telomere shortening and apoptosis in cervical cancer cells.||40|
|Zhou et al.||2017||Cervical cancer||Knockdown of HMBOX1 increases the radiosensitivity of cervical cancer cells through telomere shortening||41|
Telomeric length determines the life span of a cell and an organism. Any change in telomeric function can result in genomic instability which in-turn increases the risk of cancer. Telomeric shortening is also associated with various disease patterns including Parkinson’s disease, ulcerative colitis and chronic hepatitis. Individuals with short telomeres are at increased risk for cancer. This paper reviewed the studies pointing out the relation of telomeric length and different types of cancers including breast, thyroid and cervical cancer. A positive correlation has been found in between telomeric shortening and cancer occurrence. Mean telomere lengths were found lesser in patients with cancer and showed a positive correlation with degree of cancer progression. Further correlative studies are recommended to strengthen the association of telomere length alterations with specific cancer type.
Conflict of Interest
- Telomere shortening in Alzheimer’s disease patients. Ann Clin Lab Sci. 2016;46:260-265. 46/3/260 [pii]
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