Gene Summary

Gene:POT1; protection of telomeres 1
Aliases: CMM10, HPOT1
Summary:This gene is a member of the telombin family and encodes a nuclear protein involved in telomere maintenance. Specifically, this protein functions as a member of a multi-protein complex that binds to the TTAGGG repeats of telomeres, regulating telomere length and protecting chromosome ends from illegitimate recombination, catastrophic chromosome instability, and abnormal chromosome segregation. Increased transcriptional expression of this gene is associated with stomach carcinogenesis and its progression. Alternatively spliced transcript variants have been described. [provided by RefSeq, Jul 2008]
Databases:OMIM, VEGA, HGNC, Ensembl, GeneCard, Gene
Protein:protection of telomeres protein 1
Source:NCBIAccessed: 27 February, 2015


What does this gene/protein do?
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Cancer Overview

Research Indicators

Publications Per Year (1990-2015)
Graph generated 28 February 2015 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

Tag cloud generated 27 February, 2015 using data from PubMed, MeSH and CancerIndex

Specific Cancers (6)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Entity Topic PubMed Papers
Breast CancerPOT1 and Breast Cancer View Publications8
Stomach CancerPOT1 and Stomach Cancer View Publications5
Chronic Lymphocytic LeukemiaPOT1 and Chronic Lymphocytic Leukemia View Publications6
Melanoma, FamilialPOT1 and Predisposition to Familial Melanoma
Large genome-wide sequencing studies have identified missense mutations in POT1 as a risk factor for hereditary melanoma families and not present in unaffected controls (Robles-Espinoza CD et al, 2014 and Shi J et al 2014). Theses POT1 mutations included families without CDKN2A or CDK4 mutations, suggesting it may be a frequently mutated gene in hereditary melanoma.
View Publications4
Thyroid CancerPOT1 and Thyroid Cancer View Publications2
Parathyroid CancerPOT1 and Parathyroid Cancer View Publications2

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: POT1 (cancer-related)

Aoude LG, Pritchard AL, Robles-Espinoza CD, et al.
Nonsense mutations in the shelterin complex genes ACD and TERF2IP in familial melanoma.
J Natl Cancer Inst. 2015; 107(2) [PubMed] Related Publications
BACKGROUND: The shelterin complex protects chromosomal ends by regulating how the telomerase complex interacts with telomeres. Following the recent finding in familial melanoma of inactivating germline mutations in POT1, encoding a member of the shelterin complex, we searched for mutations in the other five components of the shelterin complex in melanoma families.
METHODS: Next-generation sequencing techniques were used to screen 510 melanoma families (with unknown genetic etiology) and control cohorts for mutations in shelterin complex encoding genes: ACD, TERF2IP, TERF1, TERF2, and TINF 2. Maximum likelihood and LOD [logarithm (base 10) of odds] analyses were used. Mutation clustering was assessed with χ(2) and Fisher's exact tests. P values under .05 were considered statistically significant (one-tailed with Yates' correction).
RESULTS: Six families had mutations in ACD and four families carried TERF2IP variants, which included nonsense mutations in both genes (p.Q320X and p.R364X, respectively) and point mutations that cosegregated with melanoma. Of five distinct mutations in ACD, four clustered in the POT1 binding domain, including p.Q320X. This clustering of novel mutations in the POT1 binding domain of ACD was statistically higher (P = .005) in melanoma probands compared with population control individuals (n = 6785), as were all novel and rare variants in both ACD (P = .040) and TERF2IP (P = .022). Families carrying ACD and TERF2IP mutations were also enriched with other cancer types, suggesting that these variants also predispose to a broader spectrum of cancers than just melanoma. Novel mutations were also observed in TERF1, TERF2, and TINF2, but these were not convincingly associated with melanoma.
CONCLUSIONS: Our findings add to the growing support for telomere dysregulation as a key process associated with melanoma susceptibility.

Bainbridge MN, Armstrong GN, Gramatges MM, et al.
Germline mutations in shelterin complex genes are associated with familial glioma.
J Natl Cancer Inst. 2015; 107(1):384 [PubMed] Article available free on PMC after 01/01/2016 Related Publications
Gliomas are the most common brain tumor, with several histological subtypes of various malignancy grade. The genetic contribution to familial glioma is not well understood. Using whole exome sequencing of 90 individuals from 55 families, we identified two families with mutations in POT1 (p.G95C, p.E450X), a member of the telomere shelterin complex, shared by both affected individuals in each family and predicted to impact DNA binding and TPP1 binding, respectively. Validation in a separate cohort of 264 individuals from 246 families identified an additional mutation in POT1 (p.D617Efs), also predicted to disrupt TPP1 binding. All families with POT1 mutations had affected members with oligodendroglioma, a specific subtype of glioma more sensitive to irradiation. These findings are important for understanding the origin of glioma and could have importance for the future diagnostics and treatment of glioma.

Motevalli A, Yasaei H, Virmouni SA, et al.
The effect of chemotherapeutic agents on telomere length maintenance in breast cancer cell lines.
Breast Cancer Res Treat. 2014; 145(3):581-91 [PubMed] Article available free on PMC after 01/01/2016 Related Publications
Mammalian telomeric DNA consists of tandem repeats of the sequence TTAGGG associated with a specialized set of proteins, known collectively as Shelterin. These telosomal proteins protect the ends of chromosomes against end-to-end fusion and degradation. Short telomeres in breast cancer cells confer telomere dysfunction and this can be related to Shelterin proteins and their level of expression in breast cancer cell lines. This study investigates whether expression of Shelterin and Shelterin-associated proteins are altered, and influence the protection and maintenance of telomeres, in breast cancer cells. 5-aza-2'-deoxycytidine (5-aza-CdR) and trichostatin A (TSA) were used in an attempt to reactivate the expression of silenced genes. Our studies have shown that Shelterin and Shelterin-associated genes were down-regulated in breast cancer cell lines; this may be due to epigenetic modification of DNA as the promoter region of POT1 was found to be partially methylated. Shelterin genes expression was up-regulated upon treatment of 21NT breast cancer cells with 5-aza-CdR and TSA. The telomere length of treated 21NT cells was measured by q-PCR showed an increase in telomere length at different time points. Our studies have shown that down-regulation of Shelterin genes is partially due to methylation in some epithelial breast cancer cell lines. Removal of epigenetic silencing results in up-regulation of Shelterin and Shelterin-associated genes which can then lead to telomere length elongation and stability.

Hoxha M, Fabris S, Agnelli L, et al.
Relevance of telomere/telomerase system impairment in early stage chronic lymphocytic leukemia.
Genes Chromosomes Cancer. 2014; 53(7):612-21 [PubMed] Related Publications
Several studies have proposed telomere length and telomerase activity as prognostic factors in chronic lymphocytic leukemia (CLL), whereas information addressing the role of telomere-associated genes is limited. We measured relative telomere length (RTL) and TERT expression levels in purified peripheral CD19(+) B-cells from seven healthy donors and 77 untreated CLLs in early stage disease (Binet A). Data were correlated with the major biological and cytogenetic markers, global DNA methylation (Alu and LINE-1), and clinical outcome. The expression profiles of telomere-associated genes were also investigated. RTL was decreased in CLLs as compared with controls (P < 0.001); within CLL, a progressive and significant RTL shortening was observed in patients from 13q- through +12, 11q-, and 17p- alterations; short telomeres were significantly associated with unmutated IGHV configuration and global DNA hypomethylation. Decreased RTL was associated with a shorter time to first treatment. A significant upregulation of POT1, TRF1, RAP1, MRE11A, RAD50, and RPA1 transcript levels was observed in CLLs compared with controls. Our study suggests that impairment of telomere/telomerase system represents an early event in CLL pathogenesis. Moreover, the correlation between telomere shortening and global DNA hypomethylation supports the involvement of DNA hypomethylation to increase chromosome instability. © 2014 Wiley Periodicals, Inc.

Robles-Espinoza CD, Harland M, Ramsay AJ, et al.
POT1 loss-of-function variants predispose to familial melanoma.
Nat Genet. 2014; 46(5):478-81 [PubMed] Article available free on PMC after 01/01/2016 Related Publications
Deleterious germline variants in CDKN2A account for around 40% of familial melanoma cases, and rare variants in CDK4, BRCA2, BAP1 and the promoter of TERT have also been linked to the disease. Here we set out to identify new high-penetrance susceptibility genes by sequencing 184 melanoma cases from 105 pedigrees recruited in the UK, The Netherlands and Australia that were negative for variants in known predisposition genes. We identified families where melanoma cosegregates with loss-of-function variants in the protection of telomeres 1 gene (POT1), with a proportion of family members presenting with an early age of onset and multiple primary tumors. We show that these variants either affect POT1 mRNA splicing or alter key residues in the highly conserved oligonucleotide/oligosaccharide-binding (OB) domains of POT1, disrupting protein-telomere binding and leading to increased telomere length. These findings suggest that POT1 variants predispose to melanoma formation via a direct effect on telomeres.

Shi J, Yang XR, Ballew B, et al.
Rare missense variants in POT1 predispose to familial cutaneous malignant melanoma.
Nat Genet. 2014; 46(5):482-6 [PubMed] Article available free on PMC after 01/01/2016 Related Publications
Although CDKN2A is the most frequent high-risk melanoma susceptibility gene, the underlying genetic factors for most melanoma-prone families remain unknown. Using whole-exome sequencing, we identified a rare variant that arose as a founder mutation in the telomere shelterin gene POT1 (chromosome 7, g.124493086C>T; p.Ser270Asn) in five unrelated melanoma-prone families from Romagna, Italy. Carriers of this variant had increased telomere lengths and numbers of fragile telomeres, suggesting that this variant perturbs telomere maintenance. Two additional rare POT1 variants were identified in all cases sequenced in two separate Italian families, one variant per family, yielding a frequency for POT1 variants comparable to that for CDKN2A mutations in this population. These variants were not found in public databases or in 2,038 genotyped Italian controls. We also identified two rare recurrent POT1 variants in US and French familial melanoma cases. Our findings suggest that POT1 is a major susceptibility gene for familial melanoma in several populations.

Zhang J, Jima D, Moffitt AB, et al.
The genomic landscape of mantle cell lymphoma is related to the epigenetically determined chromatin state of normal B cells.
Blood. 2014; 123(19):2988-96 [PubMed] Article available free on PMC after 08/05/2015 Related Publications
In this study, we define the genetic landscape of mantle cell lymphoma (MCL) through exome sequencing of 56 cases of MCL. We identified recurrent mutations in ATM, CCND1, MLL2, and TP53. We further identified a number of novel genes recurrently mutated in patients with MCL including RB1, WHSC1, POT1, and SMARCA4. We noted that MCLs have a distinct mutational profile compared with lymphomas from other B-cell stages. The ENCODE project has defined the chromatin structure of many cell types. However, a similar characterization of primary human mature B cells has been lacking. We defined, for the first time, the chromatin structure of primary human naïve, germinal center, and memory B cells through chromatin immunoprecipitation and sequencing for H3K4me1, H3K4me3, H3Ac, H3K36me3, H3K27me3, and PolII. We found that somatic mutations that occur more frequently in either MCLs or Burkitt lymphomas were associated with open chromatin in their respective B cells of origin, naïve B cells, and germinal center B cells. Our work thus elucidates the landscape of gene-coding mutations in MCL and the critical interplay between epigenetic alterations associated with B-cell differentiation and the acquisition of somatic mutations in cancer.

Qiang W, Wu Q, Zhou F, et al.
Suppression of telomere-binding protein TPP1 resulted in telomere dysfunction and enhanced radiation sensitivity in telomerase-negative osteosarcoma cell line.
Biochem Biophys Res Commun. 2014; 445(2):363-8 [PubMed] Related Publications
Mammalian telomeres are protected by the shelterin complex that contains the six core proteins POT1, TPP1, TIN2, TRF1, TRF2 and RAP1. TPP1, formerly known as TINT1, PTOP, and PIP1, is a key factor that regulates telomerase recruitment and activity. In addition to this, TPP1 is required to mediate the shelterin assembly and stabilize telomere. Previous work has found that TPP1 expression was elevated in radioresistant cells and that overexpression of TPP1 led to radioresistance and telomere lengthening in telomerase-positive cells. However, the exact effects and mechanism of TPP1 on radiosensitivity are yet to be precisely defined in the ALT cells. Here we report on the phenotypes of the conditional deletion of TPP1 from the human osteosarcoma U2OS cells using ALT pathway to extend the telomeres.TPP1 deletion resulted in telomere shortening, increased apoptosis and radiation sensitivity enhancement. Together, our findings show that TPP1 plays a vital role in telomere maintenance and protection and establish an intimate relationship between TPP1, telomere and cellular response to ionizing radiation, but likely has the specific mechanism yet to be defined.

Panero J, Stanganelli C, Arbelbide J, et al.
Expression profile of shelterin components in plasma cell disorders. Clinical significance of POT1 overexpression.
Blood Cells Mol Dis. 2014 Feb-Mar; 52(2-3):134-9 [PubMed] Related Publications
The core complex of telomere-associated proteins, named the shelterin complex, plays a critical role in telomere protection and telomere length (TL) homeostasis. In this study, we have explored changes in the expression of telomere-associated genes POT1, TIN2, RAP1 and TPP1, in patients with monoclonal gammopathy of undetermined significance (MGUS) and multiple myeloma (MM). A total of 154 patients: 70 with MGUS and 84 with MM were studied. Real-time quantitative PCR was used to quantify gene expression. TL was evaluated by Terminal Restriction Fragments. Our data showed increased expression of POT1, TPP1, TIN2 and RAP1 in MM with respect to MGUS patients, with significant differences for POT1 gene (p=0.002). In MM, the correlation of gene expression profiles with clinical characteristics highlighted POT1 for its significant association with advanced clinical stages, high calcium and β2-microglobulin levels (p=0.02) and bone lesions (p=0.009). In multivariate analysis, POT1 expression (p=0.04) was a significant independent prognostic factor for overall survival as well as the staging system (ISS) (p<0.02). Our findings suggest for the first time the participation of POT1 in the transformation process from MGUS to MM, and provide evidence of this gene as a useful prognostic factor in MM as well as a possible molecular target to design new therapeutic strategies.

Costa-Guda J, Arnold A
Genetic and epigenetic changes in sporadic endocrine tumors: parathyroid tumors.
Mol Cell Endocrinol. 2014; 386(1-2):46-54 [PubMed] Article available free on PMC after 05/04/2015 Related Publications
Parathyroid neoplasia is most commonly due to benign parathyroid adenoma but rarely can be caused by malignant parathyroid carcinoma. Evidence suggests that parathyroid carcinomas rarely, if ever, evolve through an identifiable benign intermediate, with the notable exception of carcinomas associated with the familial hyperparathyroidism-jaw tumor syndrome. Several genes have been directly implicated in the pathogenesis of typical sporadic parathyroid adenoma; somatic mutations in the MEN1 tumor suppressor gene are the most frequent finding, and alterations in the cyclin D1/PRAD1 oncogene are also firmly established molecular drivers of sporadic adenomas. In addition, good evidence supports mutation in the CDKN1B/p27 cyclin-dependent kinase inhibitor (CDKI) gene, and in other CDKI genes as contributing to disease pathogenesis in this context. Somatic defects in additional genes, including β-catenin, POT1 and EZH2 may contribute to parathyroid adenoma formation but, for most, their ability to drive parathyroid tumorigenesis remains to be demonstrated experimentally. Further, genetic predisposition to sporadic presentations of parathyroid adenoma appears be conferred by rare, and probably low-penetrance, germline variants in CDKI genes and, perhaps, in other genes such as CASR and AIP. The HRPT2 tumor suppressor gene is commonly mutated in parathyroid carcinoma.

El Idrissi M, Hervieu V, Merle P, et al.
Cause-specific telomere factors deregulation in hepatocellular carcinoma.
J Exp Clin Cancer Res. 2013; 32:64 [PubMed] Article available free on PMC after 05/04/2015 Related Publications
BACKGROUND: Among the numerous genetic defects associated with hepatocarcinogenesis, telomere abnormalities appear to play a role both in tumor promotion and maintenance. Telomeres, the chromosome extremities, are protected by specific proteins, the shelterin complex and by additional factors. Besides telomerase dysregulation, expression changes of these telomere factors have been observed in cancers.
METHODS: Here, we tested the hypothesis that such dysregulation might occur in hepatocellular carcinoma (HCC) with specific patterns depending on the cause of HCC. We compared telomere length, telomerase activity (TA), hTERT and telomere genes expression using PCR and Western-blot analyses between non-cirrhotic liver, peritumoral cirrhotic tissue (40 samples) and cancerous tissue (40 samples) derived from 40 patients with HBV-, HCV-, or alcohol-related HCC.
RESULTS: Alterations in TA, hTERT expression and telomere length between non-cirrhotic, cirrhotic, and tumor samples were not significantly influenced by the cause of HCC. In contrast, the expression pattern of hTR, shelterin, and non-shelterin telomere protective factors clearly distinguished the 3 causes of cirrhosis and HCC. For patients with HBV diseased liver, when compared with non-cirrhotic liver, the cirrhotic tissue underexpressed all shelterin and all but HMRE11A and RAD50 non-shelterin telomere factors. For HCV the expression level of POT1, RAP1, Ku80, and RAD50 was higher in cirrhotic than in non-cirrhotic liver samples without evidence for significant transcriptional change for the remaining genes. For alcohol-related liver diseases, the expression level of POT1, RAP1, TIN2, hMRE11A, hMRE11B, Ku70, Ku80, RAD50, TANK1, and PINX1 was higher in cirrhotic than in non-cirrhotic liver samples. For the 3 causes of HCC, there was no significant change in shelterin and non-shelterin gene expression between cirrhosis and HCC samples.
CONCLUSIONS: These results validate our hypotheses and demonstrate that cirrhosis and HCC add-up numerous telomere dysfunctions including numerous cause-specific changes that appear to occur early during the course of the disease.

Jung SW, Park NH, Shin JW, et al.
Prognostic impact of telomere maintenance gene polymorphisms on hepatocellular carcinoma patients with chronic hepatitis B.
Hepatology. 2014; 59(5):1912-20 [PubMed] Related Publications
UNLABELLED: Our goal was to determine whether single-nucleotide polymorphisms (SNPs) of telomere maintenance genes influence the development and clinical outcomes of patients with hepatitis B virus (HBV)-associated hepatocellular carcinoma (HCC). We evaluated 20 SNPs of five telomere maintenance genes in 702 patients with HCC and 351 hepatitis B virus surface antigen-positive controls without HCC. Significant SNPs were then validated in an independent cohort of 857 HCC patients and 429 controls. We assessed the association of each SNP with the development of HCC and overall survival through a multivariate Cox proportional analysis. A significantly increased risk of HCC development was identified for the telomerase-associated protein 1 (TEP1) rs1713449 SNP in both the discovery and replication phases (combined odds ratio = 1.42, P = 9.378 × 10(-5) ). In addition, the TEP1 rs1713449, TEP1 rs872072, protection of telomeres 1 homolog rs7784168, telomerase reverse transcriptase rs13167280, and telomeric repeat binding factor 1 rs2306494 SNPs had a significant effect on the overall survival, and a similar survival effect was validated in the replication cohort. Moreover, there was a significant dose-dependent association between the number of putatively high-risk genotypes of the five aforementioned SNPs and overall survival. The median survival time was significantly prolonged for patients with HCC with two or fewer putatively high-risk genotypes versus those with three or more high-risk genotypes (85 versus 44 months, log-rank P = 4.483 × 10(-5) ), and this was demonstrated in the replication cohort (52 versus 37 months, log-rank P = 0.026).
CONCLUSION: These observations suggest that the SNPs of telomere maintenance genes play a potential role in the development of HCC and the survival of HCC patients with chronic HBV infections.

Micco M, Collie GW, Dale AG, et al.
Structure-based design and evaluation of naphthalene diimide G-quadruplex ligands as telomere targeting agents in pancreatic cancer cells.
J Med Chem. 2013; 56(7):2959-74 [PubMed] Related Publications
Tetra-substituted naphthalene diimide (ND) derivatives with positively charged termini are potent stabilizers of human telomeric and gene promoter DNA quadruplexes and inhibit the growth of human cancer cells in vitro and in vivo. The present study reports the enhancement of the pharmacological properties of earlier ND compounds using structure-based design. Crystal structures of three complexes with human telomeric intramolecular quadruplexes demonstrate that two of the four strongly basic N-methyl-piperazine groups can be replaced by less basic morpholine groups with no loss of intermolecular interactions in the grooves of the quadruplex. The new compounds retain high affinity to human telomeric quadruplex DNA but are 10-fold more potent against the MIA PaCa-2 pancreatic cancer cell line, with IC50 values of ~10 nM. The lead compound induces cellular senescence but does not inhibit telomerase activity at the nanomolar dosage levels required for inhibition of cellular proliferation. Gene array qPCR analysis of MIA PaCa-2 cells treated with the lead compound revealed significant dose-dependent modulation of a distinct subset of genes, including strong induction of DNA damage responsive genes CDKN1A, DDIT3, GADD45A/G, and PPM1D, and repression of genes involved in telomere maintenance, including hPOT1 and PARP1.

Ramsay AJ, Quesada V, Foronda M, et al.
POT1 mutations cause telomere dysfunction in chronic lymphocytic leukemia.
Nat Genet. 2013; 45(5):526-30 [PubMed] Related Publications
Chronic lymphocytic leukemia (CLL) is the most frequent leukemia in adults. We have analyzed exome sequencing data from 127 individuals with CLL and Sanger sequencing data from 214 additional affected individuals, identifying recurrent somatic mutations in POT1 (encoding protection of telomeres 1) in 3.5% of the cases, with the frequency reaching 9% when only individuals without IGHV@ mutations were considered. POT1 encodes a component of the shelterin complex and is the first member of this telomeric structure found to be mutated in human cancer. Somatic mutation of POT1 primarily occurs in gene regions encoding the two oligonucleotide-/oligosaccharide-binding (OB) folds and affects key residues required to bind telomeric DNA. POT1-mutated CLL cells have numerous telomeric and chromosomal abnormalities that suggest that POT1 mutations favor the acquisition of the malignant features of CLL cells. The identification of POT1 as a new frequently mutated gene in CLL may facilitate novel approaches for the clinical management of this disease.

Butler KS, Hines WC, Heaphy CM, Griffith JK
Coordinate regulation between expression levels of telomere-binding proteins and telomere length in breast carcinomas.
Cancer Med. 2012; 1(2):165-75 [PubMed] Article available free on PMC after 05/04/2015 Related Publications
Telomere dysregulation occurs in both the in situ and invasive stages of many carcinomas, including breast. Knockout experiments have identified several telomere-associated proteins required for proper telomere function and maintenance, including telomere repeat-binding factor 1 and 2 (TRF1 and TRF2), protection of telomeres (POT1), and TRF1-interacting nuclear factor 2 (TIN2). Using telomere content assays and quantitative reverse transcription-polymerase chain reaction (RT-PCR), we examined the relationship between telomere length and the mRNA levels of telomere-associated proteins in breast tumors. The levels of TRF2, TRF1, TIN2, and POT1 mRNA, but not telomerase reverse transcriptase (TERT) RNA, are inversely correlated with telomere content in breast tumors. Significant associations were identified between the mRNA levels of TRF1, TIN2, and POT1; however, there were no significant associations with the mRNA levels of TRF2 or TERT. These associations suggest that a complex transcriptional program coordinately regulates the expression of these mRNAs. We examined the promoter regions of the telomere-associated proteins to identify transcription factors consistent with the observed patterns of presumed coordinate expression. We demonstrated in human breast cancer cell lines that expressions of TRF1, TIN2, and POT1 are upregulated by dexamethasone, suggesting activation of the glucocorticoid receptor, whereas TERT, TRF2, TRF1, TIN2, and POT1 are upregulated by tumor necrosis factor-α (TNF-α), suggesting activation of the nuclear factor kappa B transcription factor. These findings link telomere content in breast tumors to the coordinate expression of several telomere-associated proteins previously shown to be negative regulators of telomere length in cell lines. The results further suggest a possible link between the expressions of the telomere-associated proteins and mediators of stress and inflammation.Telomere content assays and quantitative RT-PCR demonstrate that the levels of TRF2, TRF1, TIN2, and POT1 mRNA, but not telomerase reverse transcriptase (TERT) RNA, are inversely correlated with telomere content in breast tumors. Within human breast cancer cell lines, expressions of TRF1, TIN2, and POT1 are upregulated by dexamethasone, suggesting activation of the glucocorticoid receptor, whereas TERT, TRF2, TRF1, TIN2, and POT1 are upregulated by TNF-α, suggesting activation of the NFκB transcription factor. These findings link telomere content in breast tumors to the expression of several telomere-associated proteins previously shown to be negative regulators of telomere length in cell lines and suggest a link between the expressions of the telomere-associated proteins and mediators of stress and inflammation.

Liu F, Pu XY, Huang SG, et al.
Expression of hPOT1 in HeLa cells and the probability of gene variation of hpot1 Exon14 in endometrial cancer are much higher than in other cancers.
Asian Pac J Cancer Prev. 2012; 13(11):5659-63 [PubMed] Related Publications
To investigate the expression of hPOT1 in the HeLa cell line and screen point mutations of hpot1 in different tumor tissues a two step osmotic method was used to extract nuclear proteins. EMSA was performed to determine the expression of hPOT1 in the HeLa cell line. PCR was also employed to amplify the exon14 sequence of the hpot1 gene in various of cancer tissues. A SV gel and PCR clean-up system was performed to enrich PCR products. DNAStar was used to analyse the exon14 sequence of the hpot1 gene. hPOT1 was expressed in the HeLa cell line and the signal was gradually enhanced as the amount of extracted nuclear proteins increased. The DNA fragment of exon14 of hpot1 was successfully amplified in the HeLa cell line and all cancer tissues, point mutations being observed in 2 out of 3 cases of endometrial cancer (66.7%) despite the hpot1 sequence being highly conserved. However, the sequence of hpot1 exon14 do not demonstrate point mutations in most cancer tissues. Since hPOT1 was expressed in HeLa cell and the probability of gene point variants was obviously higher in endometrial cancer than other cancers, it may be involved in the pathogenesis of gynecological cancers, especially in cervix and endometrium.

Kato M, Nakayama M, Agata M, Yoshida K
Gene expression levels of human shelterin complex and shelterin-associated factors regulated by the topoisomerase II inhibitors doxorubicin and etoposide in human cultured cells.
Tumour Biol. 2013; 34(2):723-33 [PubMed] Related Publications
Human telomerase reverse transcriptase (hTERT) is responsible for telomere elongation, and its activity is strongly related to the expression level of the hTERT gene; however, the transcriptional regulation of telomeric genes, which play a central role in telomere maintenance and protection by facilitating replication and regulating telomerase access, is poorly understood. In this study, we aimed to reveal the changes in the mRNA expression of six components of the shelterin complex and three shelterin complex-associated factors in topoisomerase II inhibitor-treated human cultured cells. Using a quantitative gene expression analysis, we found that a reduction in telomeric repeat-binding factor 1 (TRF1), protection of telomeres (POT1), and TRF1-interacting ankyrin-related ADP-ribose polymerase 1 (TNKS1) mRNAs was observed in etoposide- and doxorubicin-treated HeLa and U-2 OS cells, while an increased TRF2-interacting telomeric protein (RAP1) mRNA level was observed in U-2 OS cells. Furthermore, doxorubicin suppressed TRF1 and POT1 mRNAs in both Saos-2 and WI-38 cells and increased RAP1 mRNA in WI-38 cells. In agreement with the results obtained in the quantitative gene expression analysis in U-2 OS cells, the topoisomerase II inhibitors negatively and positively regulated the POT1 and RAP1 gene promoters, respectively. Taken together, these results suggest the successful identification of unique topoisomerase II inhibitor-inducible telomeric genes and provide mechanistic insight into the regulation of telomeric gene expression by chemotherapeutic agents.

He M, Bian B, Gesuwan K, et al.
Telomere length is shorter in affected members of families with familial nonmedullary thyroid cancer.
Thyroid. 2013; 23(3):301-7 [PubMed] Article available free on PMC after 05/04/2015 Related Publications
BACKGROUND: The theory that short telomere length and genetic defects in maintaining telomere length are associated with familial nonmedullary thyroid cancer (FNMTC) is controversial. Thus, the aim of this study was to determine whether telomere length and genes involved in maintaining telomere length are altered in FNMTC.
METHODS: Blood samples were collected from 44 members (13 affected and 31 unaffected) of six families with FNMTC and from 60 controls. Quantitative polymerase chain reaction (Q-PCR) and reverse transcription PCR were performed to analyze relative telomere length (RTL), gene copy number, and mRNA expression of telomerase reverse transcriptase (hTERT), telomere repeat binding factor 1 (TRF1), telomere repeat binding factor 2 (TRF2), repressor activator protein 1 (RAP1), TRF1 interacting nuclear factor 2 (TIN2), tripeptidyl peptidase 1 (TPP1), and protection of telomere 1 (POT1).
RESULTS: Affected members had shorter RTL, as compared with unaffected members (0.98 vs. 1.23, p<0.01). There was no significant difference in hTERT, TRF1, TRF2, RAP1, TIN2, TPP1, and POT1 gene copy number or mRNA expression between affected and unaffected members.
CONCLUSIONS: RTL is shorter in affected members with FNMTC but is not associated with altered copy number or expression in hTERT, TRF1, TRF2, RAP1, TIN2, TPP1, and POT1. The small differences in RTL preclude the utility of RTL as a marker for FNMTC in at-risk individuals.

Shen J, Terry MB, Liao Y, et al.
Genetic variation in telomere maintenance genes, telomere length and breast cancer risk.
PLoS One. 2012; 7(9):e44308 [PubMed] Article available free on PMC after 05/04/2015 Related Publications
BACKGROUND: Telomeres at the ends of eukaryotic chromosomes play a critical role in maintaining the integrity and stability of the genome and participate in the initiation of DNA damage/repair responses.
METHODS: We performed a case-control study to evaluate the role of three SNPs (TERT-07, TERT-54 and POT1-03) in telomere maintenance genes previously found to be significantly associated with breast cancer risk. We used sister-sets obtained from the New York site of the Breast Cancer Family Registry (BCFR). Among the 313 sister-sets, there were 333 breast cancer cases and 409 unaffected sisters who were evaluated in the current study. We separately applied conditional logistic regression and generalized estimating equations (GEE) models to evaluate associations between the three SNPs and breast cancer risk within sister-sets. We examined the associations between genotype, covariates and telomere length among unaffected sisters using a GEE model.
RESULTS: We found no significant associations between the three SNPs in telomere maintenance genes and breast cancer risk by both conditional logistic regression and GEE models, nor were these SNPs significantly related to telomere length. Among unaffected sisters, shortened telomeres were statistically significantly correlated with never hormone replacement therapy (HRT) use. Increased duration of HRT use was significantly associated with reduced telomere length. The means of telomere length were 0.77 (SD = 0.35) for never HRT use, 0.67 (SD = 0.29) for HRT use < 5 yrs and 0.59 (SD = 0.24) for HRT use ≥ 5 yrs after adjusting for age of blood donation and race and ethnicity.
CONCLUSIONS: We found that exogenous hormonal exposure was inversely associated with telomere length. No significant associations between genetic variants and telomere length or breast cancer risk were observed. These findings provide initial evidence to understand hormonal exposure in the regulation of telomere length and breast cancer risk but need replication in prospective studies.

Newey PJ, Nesbit MA, Rimmer AJ, et al.
Whole-exome sequencing studies of nonhereditary (sporadic) parathyroid adenomas.
J Clin Endocrinol Metab. 2012; 97(10):E1995-2005 [PubMed] Related Publications
CONTEXT: Genetic abnormalities, such as those of multiple endocrine neoplasia type 1 (MEN1) and Cyclin D1 (CCND1) genes, occur in <50% of nonhereditary (sporadic) parathyroid adenomas.
OBJECTIVE: To identify genetic abnormalities in nonhereditary parathyroid adenomas by whole-exome sequence analysis.
DESIGN: Whole-exome sequence analysis was performed on parathyroid adenomas and leukocyte DNA samples from 16 postmenopausal women without a family history of parathyroid tumors or MEN1 and in whom primary hyperparathyroidism due to single-gland disease was cured by surgery. Somatic variants confirmed in this discovery set were assessed in 24 other parathyroid adenomas.
RESULTS: Over 90% of targeted exons were captured and represented by more than 10 base reads. Analysis identified 212 somatic variants (median eight per tumor; range, 2-110), with the majority being heterozygous nonsynonymous single-nucleotide variants that predicted missense amino acid substitutions. Somatic MEN1 mutations occurred in six of 16 (∼35%) parathyroid adenomas, in association with loss of heterozygosity on chromosome 11. However, no other gene was mutated in more than one tumor. Mutations in several genes that may represent low-frequency driver mutations were identified, including a protection of telomeres 1 (POT1) mutation that resulted in exon skipping and disruption to the single-stranded DNA-binding domain, which may contribute to increased genomic instability and the observed high mutation rate in one tumor.
CONCLUSIONS: Parathyroid adenomas typically harbor few somatic variants, consistent with their low proliferation rates. MEN1 mutation represents the major driver in sporadic parathyroid tumorigenesis although multiple low-frequency driver mutations likely account for tumors not harboring somatic MEN1 mutations.

Shen J, Gammon MD, Terry MB, et al.
Genetic polymorphisms in telomere pathway genes, telomere length, and breast cancer survival.
Breast Cancer Res Treat. 2012; 134(1):393-400 [PubMed] Article available free on PMC after 05/04/2015 Related Publications
The impact of genetic variants in telomere pathway genes on telomere length and breast cancer survival remains unclear. We hypothesized that telomere length and genetic variants of telomere pathway genes are associated with survival among breast cancer patients. A population-based cohort study of 1,026 women diagnosed with a first primary breast cancer was conducted to examine telomere length and 52 genetic variants of 9 telomere pathway genes. Adjusted Cox regression analysis was employed to examine associations between telomere length, genetic variants and all-cause and breast cancer-specific mortality. Longer telomere length was significantly correlated with all-cause mortality in the subgroup with HER-2/neu negative tumors (HR=1.90, 95% CI: 1.12-3.22). Carrying the PINX1-33 (rs2277130) G-allele was significantly associated with increased all-cause mortality (HR=1.45, 95% CI: 1.06-1.98). Three SNPs (TERF2-03 rs35439397, TERT-14 rs2853677, and TERT-67 rs2853669) were significantly associated with reduced all-cause mortality. A similar reduced trend for breast cancer-specific mortality was observed for carrying the TERT-14 (rs2853677) T-allele (HR=0.57, 95% CI: 0.39-0.84), while carrying the POT1-18 (rs1034794) T-allele significantly increased breast cancer-specific mortality (HR=1.48, 95% CI: 1.00-2.19). However, none of the associations remained significant after correction for multiple tests. A significant dose-response effect was observed with increased number of unfavorable alleles/genotypes (PINX1-33 G-allele, POT1-18 T-allele, TERF2-03 GG, TERT-14 CC, and TERT-67 TT genotypes) and decreased survival. These data suggest that unfavorable genetic variants in telomere pathway genes may help to predict breast cancer survival.

Cantara S, Capuano S, Capezzone M, et al.
Lack of mutations of the telomerase RNA component in familial papillary thyroid cancer with short telomeres.
Thyroid. 2012; 22(4):363-8 [PubMed] Related Publications
BACKGROUND: The occurrence of familial papillary thyroid cancer (FPTC) is well established but no susceptibility genes for this disease have been discovered. Our group has recently demonstrated that patients with FPTC have shorter telomeres, not associated with mutations in telomerase reverse transcriptase, gene than patients with sporadic papillary thyroid cancer (SPTC), healthy subjects (HS), and unaffected family members (UFMs). Several diseases, however, have short telomeres associated with mutations in the telomerase RNA component (TERC) gene or in the shelterin complex (POT1, RAP1, TIN2, TPP1, TRF1, and TRF2) genes. The objective of the present study was to verify whether short telomeres observed in FPTC patients were related to mutations in TERC or shelterin genes.
METHODS: Sixty-six patients with FPTC, 46 UFMs, 111 patients with SPTC, and 153 HS were analyzed by polymerase chain reaction followed by denaturing high performance liquid chromatography analysis and direct sequencing for the presence of TERC or shelterin gene mutations. When present, single-nucleotide polymorphisms were tested by χ(2) analysis at the genotypic, allelic, and haplotypic levels.
RESULTS: The entire sequence of the TERC gene was analyzed with particular attention to known mutations known to be associated with short telomeres. All samples appeared to be homozygous wild type for A-771G, C-99G, G305A, G322A, C323T, C408G, G450A, T467C, G508A, A514G, G623A, and C727G substitutions and for the 378Δ→3' deletion in the TERC gene. In addition, upon analysis of all samples for shelterin proteins, we observed a significant decrease in POT1 and RAP1 protein expression in the blood of FPTC patients compared with SPTC subjects. However, no mutations or polymorphisms were found when in the coding sequences of both genes.
CONCLUSIONS: To our knowledge this is the first study of TERC mutations or alterations in the shelterin complex in relation to FPTC. Shorter telomeres observed in FPTC are not linked to mutations or polymorphisms in TERC, POT1, or RAP1 genes.

Wan SM, Tie J, Zhang YF, et al.
Silencing of the hPOT1 gene by RNA inference promotes apoptosis and inhibits proliferation and aggressive phenotype of gastric cancer cells, likely through up-regulating PinX1 expression.
J Clin Pathol. 2011; 64(12):1051-7 [PubMed] Related Publications
BACKGROUND: The human protection of telomeres 1 (hPOT1) protein, a single-strand telomeric DNA binding protein, plays an important role in telomere protection and telomere length regulation. However, its effect on invasion of gastric cancer remains unclear.
AIMS: To explore the role of hPOT1 in the proliferation and invasion of gastric cancer cells.
METHODS: The gastric expression of hPOT1 was examined in normal gastric mucosa (n=25), intestinal metaplasia (n=20), gastric dysplasia (n=20) and gastric cancer (n=150) by immunohistochemistry. The mean optical density (MOD) of the immunostaining was determined by semi-quantitative image analysis. The role of hPOT1 in the cell proliferation, apoptosis and invasion of gastric cancer 7901 cells was determined by means of the RNA interference (RNAi) of hPOT1 mRNA. The effects of hPOT1 RNAi on the expression of hPinX1 and hTERT were detected with western blotting.
RESULTS: The hPOT1 MOD was progressively increased from the normal mucosa to intestinal metaplasia, dysplasia, and gastric cancer. An increased hPOT1 expression significantly correlated with tumour serosal invasion, node metastasis and advanced stage. Transfection of hPOT1 siRNA into SGC-7901 cells led to a decrease in cell proliferation, colony formation and invasion, and also an increase of apoptosis. An up-regulation of hPinX1 and down-regulation of hTERT were found in gastric cancer cells with hPOT1 siRNA.
CONCLUSIONS: Increased hPOT1 expression is associated with an advanced tumour stage. hPOT1 RNAi inhibits proliferation and invasion, and induces apoptosis of gastric cancer cells. The effects of hPOT1 RNAi seem to be functionally linked to up-regulation of PinX1 and down-regulation of hTERT.

Chi JT, Thrall DE, Jiang C, et al.
Comparison of genomics and functional imaging from canine sarcomas treated with thermoradiotherapy predicts therapeutic response and identifies combination therapeutics.
Clin Cancer Res. 2011; 17(8):2549-60 [PubMed] Article available free on PMC after 05/04/2015 Related Publications
PURPOSE: While hyperthermia is an effective adjuvant treatment to radiotherapy, we do not completely understand the nature of the response heterogeneity.
EXPERIMENTAL DESIGN: We performed gene expression analysis of 22 spontaneous canine sarcomas before and after the first hyperthermia treatment administered as an adjuvant to radiotherapy. In parallel, diffusion-weighted MRI (DWI) was done prior to the treatment course and at the end of therapy.
RESULTS: From the integrative analysis of gene expression and DWI, we identified significant correlation between tumor responses with genes involved in VEGF signaling, telomerase, DNA repair, and inflammation. The treatment-induced changes in gene expression identified 2 distinct tumor subtypes with significant differences in their gene expression and treatment response, as defined by changes in DWI. The 2 tumor subtypes could also be readily identified by pretreatment gene expression. The tumor subtypes, with stronger expression response and DWI increase, had higher levels of HSP70, POT1, and centrosomal proteins, and lower levels of CD31, vWF, and transferrin. Such differential gene expression between the 2 subtypes was used to interrogate connectivity map and identify linkages to an HSP90 inhibitor, geldanamycin. We further validated the ability of geldanamycin to enhance cell killing of human tumor cells with hyperthermia and radiotherapy in clonogenic assays.
CONCLUSIONS: To our knowledge, this is one of the first successful attempts to link changes in gene expression and functional imaging to understand the response heterogeneity and identify compounds enhancing thermoradiotherapy. This study also demonstrates the value of canine tumors to provide information generalizable to human tumors.

Nan H, Qureshi AA, Prescott J, et al.
Genetic variants in telomere-maintaining genes and skin cancer risk.
Hum Genet. 2011; 129(3):247-53 [PubMed] Article available free on PMC after 05/04/2015 Related Publications
Telomere-related genes play an important role in maintaining the integrity of the telomeric structure that protects chromosome ends, and telomere dysfunction may lead to tumorigenesis. We evaluated the associations between 39 SNPs, including 38 tag-SNPs in telomere-related genes (TERT, TRF1, TRF2, TNKS2, and POT1) and one SNP (rs401681) in the TERT-CLPTM1L locus which has been identified as a susceptibility locus to skin cancer in the previous GWAS, and the risk of skin cancer in a case-control study of Caucasians nested within the Nurses' Health Study (NHS) among 218 melanoma cases, 285 squamous cell carcinoma (SCC) cases, 300 basal cell carcinoma (BCC) cases, and 870 controls. Of the 39 SNPs evaluated, ten showed a nominal significant association with the risk of at least one type of skin cancer. After correction for multiple testing within each gene, two SNPs in the TERT gene (rs2853676 and rs2242652) and one SNP in the TRF1 gene (rs2981096) showed significant associations with the risk of melanoma. Also, the SNP rs401681 in the TERT-CLPTM1L locus was replicated for the association with melanoma risk. The additive odds ratio (OR) [95% confidence interval (95% CI)] of these four SNPs (rs2853676[T], rs2242652[A], rs2981096[G], and rs401681[C]) for the risk of melanoma was 1.43 (1.14-1.81), 1.50 (1.14-1.98), 1.87 (1.19-2.91), and 0.73 (0.59-0.91), respectively. Moreover, we found that the rs401681[C] was associated with shorter relative telomere length (P for trend, 0.05). We did not observe significant associations for SCC or BCC risk. Our study provides evidence for the contribution of genetic variants in the telomere-maintaining genes to melanoma susceptibility.

Kojima K, Hiyama E, Otani K, et al.
Telomerase activation without shortening of telomeric 3'-overhang is a poor prognostic factor in human colorectal cancer.
Cancer Sci. 2011; 102(2):330-5 [PubMed] Related Publications
Our previous report demonstrated a good correlation between high telomerase activity of cancer tissues and a poor prognosis of patients with colorectal cancers, except for several cases. To elucidate the additional factors that contribute to patient prognosis, the correlation among the expression levels of telomere binding proteins (TBP), the lengths of telomeres, the lengths of telomere 3'-overhang (3'-OH) and telomerase activity in 106 paired colorectal cancer and corresponding noncancerous mucosa (NCM) specimens were examined. The expression levels of eight TBP genes (TRF1, TRF2, TIN2, TANK1, TANK2, POT1, RAP1 and TPP1) were analyzed. Among the 106 cases, 35 cases had shortened telomeres (<7 kb), 15 had shortened 3'-OH (3'-OH length ratio of cancer/NCM <0.5) and 88 were classified as telomerase-activated cancers (activity ratio of cancer/NCM >2). Comparison between NCM and cancer in each case showed that all TBP except for POT1 were downregulated in cancers. A survival analysis using a Cox proportional hazard model showed that the survival rate of the telomerase-activated cases with shortened 3'-OH and that of telomerase-inactivated cases were significantly better than that of telomerase-activated cases without 3'-OH shortening, that is, restored or maintained 3'-OH (P = 0.018). In the telomerase-activated cancers, the length of 3'-OH was significantly correlated with the expression levels of POT1. Elongation of telomeric overhang by telomerase, which might be regulated by POT1, may contribute to the increase of malignant potential in colorectal cancers.

Prescott J, McGrath M, Lee IM, et al.
Telomere length and genetic analyses in population-based studies of endometrial cancer risk.
Cancer. 2010; 116(18):4275-82 [PubMed] Article available free on PMC after 05/04/2015 Related Publications
BACKGROUND: Telomeres are protective structures at the ends of linear chromosomes, regulated by a host of associated proteins. When telomeres become dysfunctional, genomic instability ensues. The vast majority of cells undergo apoptosis, although a rare cell may survive and become tumorigenic.
METHODS: The authors used conditional logistic regression to examine relative telomere length in peripheral blood leukocytes, genetic variants at telomere maintenance gene loci (TERT, TNKS2, POT1, TERF1, TERF2), and endometrial cancer risk in case-control studies nested within the Nurses' Health Study and the Women's Health Study.
RESULTS: Relative telomere length was significantly inversely correlated with body mass index and weight gain since age 18 years. The authors did not observe a relationship between relative telomere length and endometrial cancer risk. Women in the shortest quartile had a multivariate-adjusted odds ratio (OR) of 1.20 (95% confidence interval [95% CI], 0.73-1.96; P for trend = .37) compared with women in the longest quartile. The authors found an elevation in endometrial cancer risk among women carrying at least 1 minor allele of RS2736122 (TERT; OR, 1.18; 95% CI, 1.01-1.38) or RS12412538 (TNKS2; OR, 1.16; 95% CI, 1.00-1.34).
CONCLUSIONS: Relative telomere length was not associated with endometrial cancer risk. Other aspects of telomere maintenance remain to be explored.

Ning X, Yang S, Wang R, et al.
POT1 deficiency alters telomere length and telomere-associated gene expression in human gastric cancer cells.
Eur J Cancer Prev. 2010; 19(5):345-51 [PubMed] Related Publications
Telomeres are the end structures of linear chromosomes in eukaryotic cells. The integrity of a telomere is essential for the overall stability of the chromosome. The human protection of telomeres 1 (hPOT1) protein, a single-stranded telomeric DNA binding protein, plays an important role in telomere protection and telomere length regulation. Here, we show that the loss of hPOT1 by RNA interference in BGC823 (poorly differentiated human gastric adenocarcinoma) cells leads to an increase in multinucleated giant cells, a decrease in cell proliferation and colony formation, induction of senescence and apoptosis, shortened telomere length, upregulation of the TRF1 gene and downregulation of the TRF2, tankyrase1 and hTERT genes. These results suggest that the loss of hPOT1 results in a decrease in the viability of BGC823 cells; hPOT1 regulates telomere length positively and has an influence on the expression of other telomere-associated genes in the cells.

Shen J, Gammon MD, Wu HC, et al.
Multiple genetic variants in telomere pathway genes and breast cancer risk.
Cancer Epidemiol Biomarkers Prev. 2010; 19(1):219-28 [PubMed] Article available free on PMC after 05/04/2015 Related Publications
PURPOSE: To explore the etiologic role of genetic variants in telomere pathway genes and breast cancer risk.
METHODS: A population-based case-control study, the Long Island Breast Cancer Study Project, was conducted, and 1,067 cases and 1,110 controls were included in the present study. Fifty-two genetic variants of nine telomere-related genes were genotyped.
RESULTS: Seven single nucleotide polymorphisms (SNP) showed significant case-control differences at the level of P < 0.05. The top three statistically significant SNPs under a dominant model were TERT-07 (rs2736109), TERT-54 (rs3816659), and POT1-03 (rs33964002). The odds ratios (OR) were 1.56 [95% confidence interval (95% CI), 1.22-1.99] for the TERT-07 G-allele, 1.27 (95% CI, 1.05-1.52) for the TERT-54 T-allele, and 0.79 (95% CI, 0.67-0.95) for the POT1-03 A-allele. TERT-67 (rs2853669) was statistically significant under a recessive model; the OR of the CC genotype was 0.69 (95% CI, 0.69-0.93) compared with the T-allele. However, none of the SNPs retained significance after Bonferroni adjustment for multiple testing at the level of P < 0.001 (0.05/52) except for TERT-07. When restricted to Caucasians (94% of the study subjects), a stronger association for the TERT-07 G-allele was observed with an OR of 1.60 (95% CI, 1.24-2.05; P = 0.0002). No effect modifications were found for variant alleles and menopausal status, telomere length, cigarette smoking, body mass index status, and family history of breast cancer risk.
CONCLUSIONS: Four SNPs in the TERT and POT1 genes were significantly related with overall breast cancer risk. This initial analysis provides valuable clues for further exploration of the biological role of telomere pathway genes in breast cancer.

Choi JE, Kang HG, Jang JS, et al.
Polymorphisms in telomere maintenance genes and risk of lung cancer.
Cancer Epidemiol Biomarkers Prev. 2009; 18(10):2773-81 [PubMed] Related Publications
This study was conducted to comprehensively evaluate the associations between polymorphisms in telomere maintenance genes (TERT, TRF1, TNKS1, TRF2, RAP1, and POT1) and lung cancer risk. We captured 35 polymorphisms in the genes and determined their frequencies in 27 healthy Koreans. Ten haplotype-tagging polymorphisms were examined in a case-control study that consisted of 720 lung cancer patients and 720 healthy controls. The TERT rs2735940 g.C > T and rs2736098 g.G > A, and TNKS1 rs6985140 g.A > G were significantly associated with the risk of lung cancer. In the haplotype analysis, the TERT rs2735940T/rs2736098A haplotype (ht4) was associated with a significantly increased risk of lung cancer compared with the rs2735940C/rs2736098G haplotype (adjusted odds ratio, 1.26; 95% confidence interval, 1.07-1.50; P = 0.008). When the TERT ht4 and TNKS1 rs6985140G as risk alleles, the risk of lung cancer increased in a dose-dependent manner as the number of risk alleles increased (P(trend) < 0.001). Subjects with two to four risk alleles were at a significantly increased risk of lung cancer (adjusted odds ratio, 1.67; 95% confidence interval, 1.23-2.27; P = 0.001) compared with subjects with zero risk allele. These findings suggest that genetic variants in the TERT and TNKS1 genes contribute to genetic susceptibility to lung cancer.

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