Research IndicatorsGraph generated 11 March 2017 using data from PubMed using criteria.
Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic. Tag cloud generated 11 March, 2017 using data from PubMed, MeSH and CancerIndex
Specific Cancers (3)
Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.
Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).
OMIM, Johns Hopkin University
Referenced article focusing on the relationship between phenotype and genotype.
International Cancer Genome Consortium.
Summary of gene and mutations by cancer type from ICGC
Cancer Genome Anatomy Project, NCI
COSMIC, Sanger Institute
Somatic mutation information and related details
GEO Profiles, NCBI
Search the gene expression profiles from curated DataSets in the Gene Expression Omnibus (GEO) repository.
Latest Publications: TEP1 (cancer-related)
Sriprapun M, Chuaypen N, Khlaiphuengsin A, et al.Association of PINX1 but not TEP1 Polymorphisms with Progression to Hepatocellular Carcinoma in Thai Patients with Chronic Hepatitis B Virus Infection.
Asian Pac J Cancer Prev. 2016; 17(4):2019-25 [PubMed
] Related Publications
Hepatocellular carcinoma (HCC) is major health problem with high mortality rates, especially in patients with hepatitis B virus (HBV) infection. Telomerase function is one of common mechanisms affecting genome stability and cancer development. Recent studies demonstrated that genetic polymorphisms of telomerase associated genes such as telomerase associated protein 1 (TEP1) rs1713449 and PIN2/TERF1-interacting telomerase inhibitor 1 (PINX1) rs1469557 may be associated with risk of HCC and other cancers. In this study, 325 patients with HCC and 539 non-HCC groups [193 healthy controls, 80 patients with HBV-related liver cirrhosis (LC) and 266 patients with HBV-related chronic hepatitis (CH)] were enrolled to explore genetic polymorphisms of both SNPs using the allelic discrimination method based on MGB probe TaqMan real time PCR. We demonstrated that all genotypes of both genes were in Hardy-Wienberg equilibrium (>0.05). Moreover, there was no significant association between rs1713449 genotypes and HCC risk, HCC progression and overall survival (>0.05). Interestingly, we observed positive association of rs1469557 with risk of HCC when compared with the LC group under dominant (CC versus CT+TT, OR=1.89, 95% CI= 1.06-3.40, P=0.031) and allelic (C versus T alleles, OR=1.75, 95% CI=1.04-2.94, P=0.033) models, respectively. Moreover, overall survival of HCC patients with CC genotype of rs1469557 was significantly higher than non-CC genotype (Log-rank P=0.015). These findings suggest that PINX1 rs1469557 but not TEP1 rs1469557 might play a role in HCC progression in Thai patients with LC and be used as the prognosis marker to predict overall survival in HCC patients.
Lim B, Kim C, Kim JH, et al.Genetic alterations and their clinical implications in gastric cancer peritoneal carcinomatosis revealed by whole-exome sequencing of malignant ascites.
Oncotarget. 2016; 7(7):8055-66 [PubMed
] Free Access to Full Article Related Publications
Peritoneal carcinomatosis accompanied by malignant ascites is a major cause of death of advanced gastric cancer (GC). To comprehensively characterize the underlying genomic events involved in GC peritoneal carcinomatosis, we analyzed whole-exome sequences of normal gastric tissues, primary tumors, and malignant ascites from eight GC patients. We identified a unique mutational signature biased toward C-to-A substitutions in malignant ascites. In contrast, the patients who received treatment of adjuvant chemotherapy showed a high rate of C-to-T substitutions along with hypermutation in malignant ascites. Comparative analysis revealed several candidate mutations for GC peritoneal carcinomatosis: recurrent mutations in COL4A6, INTS2, and PTPN13; mutations in druggable genes including TEP1, PRKCD, BRAF, ERBB4, PIK3CA, HDAC9, FYN, FASN, BIRC2, FLT3, ROCK1, CD22, and PIK3C2B; and mutations in metastasis-associated genes including TNFSF12, L1CAM, DIAPH3, ROCK1, TGFBR1, MYO9B, NR4A1, and RHOA. Notably, gene ontology analysis revealed the significant enrichment of mutations in the Rho-ROCK signaling pathway-associated biological processes in malignant ascites. At least four of the eight patients acquired somatic mutations in the Rho-ROCK pathway components, suggesting the possible relevance of this pathway to GC peritoneal carcinomatosis. These results provide a genome-wide molecular understanding of GC peritoneal carcinomatosis and its clinical implications, thereby facilitating the development of effective therapeutics.
Gu C, Li Q, Zhu Y, et al.Genetic variants in the TEP1 gene are associated with prostate cancer risk and recurrence.
Prostate Cancer Prostatic Dis. 2015; 18(4):310-6 [PubMed
] Related Publications
BACKGROUND: Telomere-related genes play an important role in carcinogenesis and progression of prostate cancer (PCa). It is not fully understood whether genetic variations in telomere-related genes are associated with development and progression in PCa patients.
METHODS: Six potentially functional single-nucleotide polymorphisms (SNPs) of three key telomere-related genes were evaluated in 1015 PCa cases and 1052 cancer-free controls, to test their associations with risk of PCa. Among 426 PCa patients who underwent radical prostatectomy (RP), the prognostic significance of the studied SNPs on biochemical recurrence (BCR) was also assessed using the Kaplan-Meier analysis and Cox proportional hazards regression model. The relative telomere lengths (RTLs) were measured in peripheral blood leukocytes using real-time PCR in the RP patients.
RESULTS: TEP1 rs1760904 AG/AA genotypes were significantly associated with a decreased risk of PCa (odds ratio (OR): 0.77, 95% confidence interval (CI): 0.64-0.93, P=0.005) compared with the GG genotype. By using median RTL as a cutoff level, RP patients with TEP1 rs1760904 AG/AA genotypes tended to have a longer RTL than those with the GG genotype (OR: 1.55, 95% CI: 1.04-2.30, P=0.031). A significant interaction between TEP1 rs1713418 and age in modifying PCa risk was observed (P=0.005). After adjustment for clinicopathologic risk factors, the presence of heterozygotes or rare homozygotes of TEP1 rs1760904 and TNKS2 rs1539042 were associated with BCR in the RP cohorts (hazard ratio: 0.53, 95% CI: 0.36-0.79, P=0.002 and hazard ratio: 1.67, 95% CI: 1.07-2.48, P=0.017, respectively).
CONCLUSIONS: These data suggest that genetic variations in the TEP1 gene may be biomarkers for risk of PCa and BCR after RP.
We first aimed to generate transformed cell lines from a human induced pluripotent stem cell (hiPSC)-teratoma, and then examined the tumorigenic risks of the differentiated cells from hiPSC explant, because hiPSC-derivatives give rise to tumors in immune-deficient mice when transplanted. The colonies isolated from sparse cultures of hiPSC-teratoma cells expressed NANOG and OCT3/4 strongly, and telomerase reverse transcriptase (TERT) weakly. However, soft agar assay demonstrated that only one of them generated colonies in the gel, though hiPSCs, hTERT-transfected immortal cells, and its oncogene-transfected cells did not form any colonies. Furthermore, none of colonies isolated from the soft agar gel on primary culture (passage 0) of teratoma cells, expressed NANOG and OCT3/4 in the expanded cultures. The second soft agar assay on the colony-derived cells was unexpectedly negative. The cumulative growth curve, telomere shortening, and senescence-associated β-galactosidase (SA β-gal) staining confirmed the mortality of these cells, suggesting their reversible transformation. By using medium for embryonic stem cell (ESC medium) after MCDB 131 (MCDB) medium, the differentiated culture cells derived from hiPSC-teratoma converted into the cells expressing undifferentiated marker proteins, which lost afterwords even in ESC medium with feeder SNL76/7. The reversibility of transformation and de-differentiation suggest that tumorigenic risks of differentiated cells arise when they are exposed to suitable niches in vivo. Thus, removal of only the undifferentiated cells from iPSC-derivatives before transplantation does not solve the problem. Elucidation of mechanisms of reversibility and control of epigenetic changes is discussed as a safety bottleneck for hiPSC therapy.
Kamada M, Mitsui Y, Kumazaki T, et al.Tumorigenic risk of human induced pluripotent stem cell explants cultured on mouse SNL76/7 feeder cells.
Biochem Biophys Res Commun. 2014; 453(3):668-73 [PubMed
] Related Publications
The potential for tumor formation from transplanted human induced pluripotent stem cell (hiPSC) derivatives represents a high risk in their application to regenerative medicine. We examined the genetic origin and characteristics of tumors, that were formed when 13 hiPSC lines, established by ourselves, and 201B7 hiPSC from Kyoto University were transplanted into severe combined immune-deficient (SCID) mice. Though teratomas formed in 58% of mice, five angiosarcomas, one malignant solitary fibrous tumor and one undifferentiated pleomorphic sarcoma formed in the remaining mice. Three malignant cell lines were established from the tumors, which were derived from mitomycin C (MMC)-treated SNL76/7 (MMC-SNL) feeder cells, as tumor development from fusion cells between MMC-SNL and hiPSCs was negative by genetic analysis. While parent SNL76/7 cells produced malignant tumors, neither MMC-SNL nor MMC-treated mouse embryo fibroblast (MEF) produced malignant tumors. When MMC-SNL feeder cells were co-cultured with hiPSCs, growing cell lines were generated, that expressed genes similar to the parent SNL76/7 cells. Thus, hiPSCs grown on MMC-SNL feeder cells have a high risk of generating feeder-derived malignant tumors. The possible mechanism(s) of growth restoration and the formation of multiple tumor types are discussed with respect of the interactions between MMC-SNL and hiPSC.
The role of the mitochondria in the process of carcinogenesis, mainly oxidative phosphorylation, mostly concerns their participation in the production of free radicals and ATP and in the process of apoptosis. The purpose of this study was to detect potential changes in the genes encoding the subunits 6 and 8 of the ATP synthase and their impact on the enzyme's biochemical properties, structure and function in patients with breast tumors. The tested material was mitochondrial DNA (mtDNA) isolated from specimens of ductal carcinoma (carcinoma ductale) Tp1-2Np0-1Mp0, blood and non-cancerous tissue of mammary gland (control), sampled from 50 patients who had been operated for breast cancer. In the case of missense-type changes in the mtDNA, protein prediction software was used to assess their effect on the biochemical properties of the protein, its structure and function. We identified 8 changes in the ATP6 gene in 36/50 examined breast cancer cell samples and 5 changes in the ATP8 gene (10/50). Most of them were homoplasmic changes of missense type. Four of the changes (A8439C, G8858C, C9130G and T9119G) had not been described in the literature before. The identified mutations and polymorphisms, especially those of missense type, can affect mitochondrial functions, especially if the conservative domain of the protein is concerned. Replacement of 'wild-type' mtDNA by mutated mtDNA can be an important event in carcinogenesis.
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.
Szaflarski W, Sujka-Kordowska P, Pula B, et al.Expression profiles of vault components MVP, TEP1 and vPARP and their correlation to other multidrug resistance proteins in ovarian cancer.
Int J Oncol. 2013; 43(2):513-20 [PubMed
] Related Publications
Vaults are cytoplasmic ribonucleoprotein particles composed of three proteins (MVP, TEP1, vPARP) and vault‑associated RNAs (vRNAs). Although the cellular functions of vaults remain unclear, vaults are strongly linked to the development of multidrug resistance (MDR), the major obstacle to the efficient treatment of cancers. Available published data suggest that vaults and their components are frequently upregulated in broad variety of multidrug-resistant cancer cell lines and tumors of different histological origin. Here, we provide detailed analysis of vault protein expression in post-surgery ovarian cancer samples from patients that were not exposed to chemotherapy. Our analysis suggests that vault proteins are expressed in the ovaries of healthy individuals but their expression in cancer patients is changed. Specifically, MVP, TEP1 and vPARP mRNA levels are significantly decreased in cancer samples with tendency of lower expression in higher-grade tumors. The pattern of vault protein mRNA expression is strongly correlated with the expression of other MDR-associated proteins such as MDR1, MRP1 and BCRP. Surprisingly, the protein levels of MVP, TEP1 and vPARP are actually increased in the higher‑grade tumors suggesting existence of post-transcriptional regulation of vault component production.
Rubis B, Holysz H, Gladych M, et al.Telomerase downregulation induces proapoptotic genes expression and initializes breast cancer cells apoptosis followed by DNA fragmentation in a cell type dependent manner.
Mol Biol Rep. 2013; 40(8):4995-5004 [PubMed
] Free Access to Full Article Related Publications
The aim of the study was to analyze the consequence of silencing genes coding for the key subunits of the telomerase complex, i.e. TERT, TERC and TP1 in human breast cancer MCF7 and MDA-MB-231cells. The transfection was performed using Lipofectamine2000 and pooled siRNAs. The cytotoxic and/or antiproliferative effect of siRNA was measured by the SRB assay, the cell cycle was analysed by flow cytometry and DNA fragmentation by TUNEL analysis. Telomerase activity was assessed by TRAP, followed by PAGE and ELISA assays. Telomerase downregulation was also assessed using qPCR in order to estimate the changes in the expression profile of genes engaged in apoptosis. It was revealed that treatment of breast cancer cells with different siRNAs (100 nM) resulted in a cell type and time-dependent effects. The downregulation of telomerase subunits was followed by reduction of telomerase activity down to almost 60% compared to control cells. However, a significant effect was only observed when the TERT subunit was downregulated. Its silencing resulted in a significant (p<0.05) increase of apoptosis (over 10% in MCF7 and about 5% in MDA-MB-231 cells, corresponding to the Annexin V assay) and DNA fragmentation (almost 30% in MCF7 and over 25% in MDA-MB-231 cells). Interestingly, also several proapoptotic genes were induced after the downregulation of the key telomerase subunit, including Bax, Bik or caspase-1 and caspase-14, as well as NGFR and TNFSF10 which were upregulated twice and more.
Telomeres are involved in maintaining genomic stability. Previous studies have linked both telomere length (TL) and telomere-related genes with cancer. We evaluated associations between telomere-related genes, TL, and breast cancer risk in an admixed population of US non-Hispanic white (1,481 cases, 1,586 controls) and U.S. Hispanic and Mexican women (2,111 cases, 2,597 controls) from the Breast Cancer Health Disparities Study. TL was assessed in 1,500 women based on their genetic ancestry. TL-related genes assessed were MEN1, MRE11A, RECQL5, TEP1, TERC, TERF2, TERT, TNKS, and TNKS2. Longer TL was associated with increased breast cancer risk [odds ratio (OR) 1.87, 95% confidence interval (CI) 1.38, 2.55], with the highest risk (OR 3.11, 95% CI 1.74, 5.67 p interaction 0.02) among women with high Indigenous American ancestry. Several TL-related single nucleotide polymorphisms had modest association with breast cancer risk overall, including TEP1 rs93886 (OR 0.82, 95% CI 0.70,0.95); TERF2 rs3785074 (OR 1.13, 95% CI 1.03,1.24); TERT rs4246742 (OR 0.85, 95% CI 0.77,0.93); TERT rs10069690 (OR 1.13, 95% CI 1.03,1.24); TERT rs2242652 (OR 1.51, 95% CI 1.11,2.04); and TNKS rs6990300 (OR 0.89, 95% CI 0.81,0.97). Several differences in association were detected by hormone receptor status of tumors. Most notable were associations with TERT rs2736118 (ORadj 6.18, 95% CI 2.90, 13.19) with estrogen receptor negative/progesterone receptor positive (ER-/PR+) tumors and TERT rs2735940 (ORadj 0.73, 95% CI 0.59, 0.91) with ER-/PR- tumors. These data provide support for an association between TL and TL-related genes and risk of breast cancer. The association may be modified by hormone receptor status and genetic ancestry.
Telomeres are critical in maintaining genomic stability. Genetic variants in telomere pathway genes may affect telomere and telomerase function, and subsequently cancer risk. We evaluated 126 SNPs from 10 genes related to telomere regulation in relation to bladder cancer risk. Five SNPs, 4 from TEP1 gene and 1 from PINX1 gene, were found to be highly significant (P<0.01). Out of these, the most significant association was found in rs2228041 of TEP1 (OR 1.66, 95% CI 1.19-2.31) while rs1469557 of PINX1 had a protective effect (OR 0.75, 95% CI 0.61-0.93). Haplotype analysis showed that a TEP1 haplotype consisting of the variant alleles of 7 SNPs exhibited a 2.28 fold increased risk (95% CI 1.13-4.60). We then performed cumulative analysis of multiple risk variants, as well as Classification and Regression Tree (CART) to look for gene-gene interactions. In cumulative effect analysis, the group with 4-5 risk variants had an OR of 2.57 (95% CI = 1.62-4.09) versus the reference group with 0 risk variants. The CART analysis categorized individuals into five subgroups with different bladder cancer risk profiles based on their distinct genotype background. To our knowledge, this is one of the largest, most comprehensive studies on bladder cancer risk concerning telomere-regulating pathway gene SNPs and our results support that genetic variations of telomere maintenance modulate bladder cancer risk individually and jointly.
Schrappe M, Valsecchi MG, Bartram CR, et al.Late MRD response determines relapse risk overall and in subsets of childhood T-cell ALL: results of the AIEOP-BFM-ALL 2000 study.
Blood. 2011; 118(8):2077-84 [PubMed
] Related Publications
The prognostic value of MRD in large series of childhood T-ALL has not yet been established. Trial AIEOP-BFM-ALL 2000 introduced standardized quantitative assessment of MRD for stratification, based on immunoglobulin and TCR gene rearrangements as polymerase chain reaction targets: Patients were considered MRD standard risk (MRD-SR) if MRD was negative at day 33 (time point 1 [TP1]) and day 78 (TP2), analyzed by at least 2 sensitive markers; MRD intermediate risk (MRD-IR) if positive either at day 33 or 78 and < 10(-3) at day 78; and MRD high risk (MRD-HR) if ≥ 10(-3) at day 78. A total of 464 patients with T-ALL were stratified by MRD: 16% of them were MRD-SR, 63% MRD-IR, and 21% MRD-HR. Their 7-year event-free-survival (SE) was 91.1% (3.5%), 80.6% (2.3%), and 49.8% (5.1%) (P < .001), respectively. Negativity of MRD at TP1 was the most favorable prognostic factor. An excellent outcome was also obtained in 32% of patients turning MRD negative only at TP2, indicating that early (TP1) MRD levels were irrelevant if MRD at TP2 was negative (48% of all patients). MRD ≥ 10(-3) at TP2 constitutes the most important predictive factor for relapse in childhood T-ALL. The study is registered at http://www.clinicaltrials.gov; "Combination Chemotherapy Based on Risk of Relapse in Treating Young Patients With Acute Lymphoblastic Leukemia," protocol identification #NCT00430118 for BFM and #NCT00613457 for AIEOP.
Si SY, Song SJ, Zhang JZ, et al.Cloning of mouse telomerase reverse transcriptase gene promoter and identification of proximal core promoter sequences essential for the expression of transgenes in cancer cells.
Oncol Rep. 2011; 26(2):377-82 [PubMed
] Related Publications
Telomerase is a ribonucleoprotein complex, whose function is to add motif-specific nucleotides to the end of chromosomes. Telomerase consists of three major subunits, the telomerase RNA template (hTR), the telomerase-associated protein (TEP1) and telomerase reverse transcriptase (TERT). TERT is the most important component responsible for the catalytic activity of telomerase and a rate-limiting determinant of the activity. Telomerase activities were at high levels in approximately 90% of mouse cancers or tumor-derived cell lines through TERT transcriptional up-regulation. Unlike human telomerase, telomerase activity exists in colon, liver, ovary and testis but not in brain, heart, stomach and muscle in normal mouse tissues. In this study, we prepared 5' truncations of 1086 bp fragments upstream of the initiating ATG codon of the mTERT gene to construct luciferase reporter gene plasmids, and transfected these plasmids into a normal mouse cell line and several cancer lines to identify the core promoter region essential for transcriptional activation in cancer cells by a luciferase assay. We constructed a eukaryotic expression vector of membrane-expressing staphylococcal endotoxin A (SEA) gene driven by the core promoter region of the mTERT gene and observed if the core promoter region could express the SEA gene in these cancer cells, but not in normal cells following transfection with the construct. The results showed that the transcriptional activities of each fragment of the mTERT gene promoter in the cancer cell lines Hepa1-6, B16 and CT26 were higher than those in NIH3T3 cells, and the proximal 333-bp fragment was the core promoter of the mTERT gene in the cancer cells. The proximal 333-bp fragment was able to make the SEA express on the surface of the cancer cells, but not in NIH3T3 cells. It provides a foundation for cancer targeting gene therapy by using the mTERT gene promoter.
Gyenge EB, Hiestand S, Graefe S, et al.Cellular and molecular effects of the liposomal mTHPC derivative Foslipos in prostate carcinoma cells in vitro.
Photodiagnosis Photodyn Ther. 2011; 8(2):86-96 [PubMed
] Related Publications
BACKGROUND: Meso-tetra-hydroxyphenyl-chlorine (mTHPC) is among the most powerful photosensitizers available for photodynamic therapy (PDT). However, the mechanisms leading to cell death are poorly understood. We here focused on changes at DNA and RNA levels after treatment with the liposomal mTHPC derivative Foslipos in vitro.
METHODS: After determination of darktoxicity, laser conditions and uptake kinetics, PC-3 prostate carcinoma cells were subjected to PDT with Foslipos, followed by assessment of cell numbers directly (TP0) or 1h (TP1), 2h (TP2), 5h (TP5) and 24h (TP24) after illumination. Nucleic acids had been extracted for evaluation of RNA amounts and integrity as well as for estimation of abasic sites as a measure for DNA damage. Furthermore, expression changes of 84 genes related to oxidative stress were investigated by quantitative polymerase chain reaction.
RESULTS: Already at TP0, the number of dead cells was significantly higher after PDT versus controls and at TP24 more than 90% of cells had been destroyed. PDT resulted in a severe damage of both RNA and DNA. Gene expression analyses revealed an impact of PDT on pathways for oxidative and metabolic stress, heat shock, proliferation and carcinogenesis, growth arrest, inflammation, DNA repair and apoptosis signaling.
CONCLUSIONS: Mechanisms of Foslipos-mediated PDT comprise a combination of acute and delayed lethal effects in PC-3 cells. The latter may include death processes initiated by nucleic acid damage, activation of stress and growth arrest genes in combination with a reduced capability to adequately cope with oxidative toxicity. Our results will help to better understand molecular photodynamic effects.
Yamaji K, Okamoto T, Yokota S, et al.Minimal residual disease-based augmented therapy in childhood acute lymphoblastic leukemia: a report from the Japanese Childhood Cancer and Leukemia Study Group.
Pediatr Blood Cancer. 2010; 55(7):1287-95 [PubMed
] Related Publications
BACKGROUND: The majority of minimal residual disease (MRD)-positive patients with acute lymphoblastic leukemia (ALL) have poor outcomes. The ALL2000 study was performed to evaluate the efficacy of augmented chemotherapy based on MRD-restratification in childhood ALL.
PROCEDURE: Between 2000 and 2004, 305 eligible patients with precursor B or T-cell ALL were enrolled in the ALL2000 study. The ALL941-based therapy protocol utilized PCR MRD assays using Immunoglobulin and T-cell receptor gene rearrangements. They were initially stratified into three risk-groups according to leukocyte count and age, and MRD levels were measured at weeks 5 (TP1) and 12 (TP2) for a second stratification. From week 14, patients with MRD levels ≥ 10(-3) received an increase in therapy (one risk group higher), while the remainder continued to receive the initial risk-adapted therapy.
RESULTS: The overall 5-year event-free survival (EFS) rate for ALL2000 was 79.7 ± 2.4%. MRD stratification was feasible for 234 of 301 patients (77%) who achieved complete remission. The EFS rate of the MRD stratifiable (MRD) group was 82.5 ± 2.6%, considerably superior to the 74.7 ± 5.7% of MRD non-stratifiable (Non-MRD) group (P = 0.084) and the 74.4 ± 2.1% for ALL 941 (P = 0.012). MRD-positive patients at TP2 showed inferior outcomes as compared with MRD-negative cases, but the difference did not reach a statistically significant level in any risk groups or immunophenotypes.
CONCLUSIONS: These results suggest that augmented therapy for MRD-positive patients at TP2 contributed to better outcomes of the ALL2000 study.
Sadeq V, Isar N, Manoochehr TAssociation of sporadic breast cancer with PTEN/MMAC1/TEP1 promoter hypermethylation.
Med Oncol. 2011; 28(2):420-3 [PubMed
] Related Publications
PTEN/MMAC1/TEP1 encodes a tumor suppressor protein, which regulates cell cycle progression, translation, and apoptosis by blocking the activation of Akt/PKB. The loss of PTEN function increases cell survival and induces tumor invasion. In this study, PTEN promoter status and its correlation with genetic and pathologic parameters were analyzed in genomic DNA from Iranian patients with breast cancer. DNA methylation patterns in the CpG islands were determined by a methylation-specific PCR (MSP) assay. PTEN promoter methylation was found to be present in 37 of 53(70%) tumor tissues and none in 20 normal counterparts. Moreover, promoter methylation was found in patients with heterozygote mutation in the PTEN gene. The pathological history of cancerous tissue sections showed that PTEN gene could be inactivated at the stages III and IV in sporadic breast cancer. These findings suggested that promoter hypermethylation of PTEN might contribute to the progression of sporadic breast cancer in human.
Cui L, Li Z, Wu M, et al.Combined analysis of minimal residual disease at two time points and its value for risk stratification in childhood B-lineage acute lymphoblastic leukemia.
Leuk Res. 2010; 34(10):1314-9 [PubMed
] Related Publications
The study was aimed to explore the value of minimal residual disease (MRD) for risk stratification in childhood precursor-B-acute lymphoblastic leukemia. MRD was monitored at two time points (TP1, after induction and TP2, before consolidation therapy) by quantitative detection of monoclonal immunoglobulin heavy chain gene rearrangements. This study stratified 105 patients into three MRD risk groups: standard-risk, MRD<10(-4) at both TP1 and TP2; high-risk, TP1>or=10(-2) or TP2>or=10(-3); and others were classified as intermediate-risk. We incorporated this MRD risk information to refine risk stratification among these patients and developed a new classification system that predicted the treatment outcomes more successfully than did the traditional risk classification criteria.
Varadi V, Brendle A, Brandt A, et al.Polymorphisms in telomere-associated genes, breast cancer susceptibility and prognosis.
Eur J Cancer. 2009; 45(17):3008-16 [PubMed
] Related Publications
Telomeres are essential structures for maintaining chromosomal stability and their length has been reported to correlate with cancer risk and clinical outcome. Single nucleotide polymorphisms (SNPs) in genes encoding telomere-associated proteins could affect telomere length and chromosomal stability by influencing gene expression or protein configuration in the telomeres. Here, we report the results of the first association study on genetic variation in telomere-associated genes and their effect on telomere length, breast cancer (BC) susceptibility and prognosis. We genotyped 14 potentially functional and most informative SNPs in nine telomere-associated genes (TERT, TEP1, TERF1, TERF2, TERF2IP, ACD, POT1, TNKS and TNKS2) in 782 incident BC cases and 1559 matched controls. Relative telomere length (RTL) varied statistically significantly between the genotypes of the SNPs rs446977 (TEP1, p=0.04), rs938886 (TEP1, p=0.04) and rs6990097 (TNKS, p=0.04). However, none of them was associated with BC susceptibility and only rs6990097 correlated with regional lymph node metastasis (odds ratio (OR) 1.38, 95% confidence interval (CI) 1.08-1.77). The strongest association with BC susceptibility was observed for rs3785074 (TERF2, OR 0.51, 95% CI 0.31-0.83) and rs10509637 (TNKS2, OR 1.33, 95% CI 1.08-1.62). Haplotype and diplotype analysis confirmed the association of the TNKS2 gene with BC susceptibility. rs3785074 (TERF2) was additionally associated with histologic grade (OR 1.44, 95% CI 1.08-1.92) and negative oestrogen receptor status (OR 2.93, 95% CI 1.13-7.58). None of the SNPs showed a significant correlation with survival of the breast cancer patients. With these results, none of the SNPs represents any valuable prognostic marker for BC.
Bladder cancer is the fourth most common malignancy in men and the eighth most common in women in western countries. Single nucleotide polymorphisms (SNPs) in genes that regulate telomere maintenance, mitosis, inflammation, and apoptosis have not been assessed extensively for this disease. Using a population-based study with 832 bladder cancer cases and 1,191 controls, we assessed genetic variation in relation to cancer susceptibility or survival. Findings included an increased risk associated with variants in the methyl-metabolism gene, MTHFD2 (OR 1.7 95% CI 1.3-2.3), the telomerase TEP1 (OR 1.8 95% CI 1.2-2.6) and decreased risk associated with the inflammatory response gene variant IL8RB (OR 0.6 95% CI 0.5-0.9) compared to wild-type. Shorter survival was associated with apoptotic gene variants, including CASP9 (HR 1.8 95% CI 1.1-3.0). Variants in the detoxification gene EPHX1 experienced longer survival (HR 0.4 (95% CI 0.2-0.8). These genes can now be assessed in multiple study populations to identify and validate SNPs appropriate for clinical use.
Yang SM, Fang DC, Yang JL, et al.Antisense human telomerase reverse transcriptase could partially reverse malignant phenotypes of gastric carcinoma cell line in vitro.
Eur J Cancer Prev. 2008; 17(3):209-17 [PubMed
] Related Publications
Telomerase activity is detected in more than 90% of examined tumors but not in most normal somatic cells. Among three subunits of human telomerase, human telomerase reverse transcriptase (hTERT) is the rate-limiting component for telomerase activity. Therefore, targeting hTERT represents a promising approach for diminishing telomerase function that will probably not cause substantial side effects on telomerase negative somatic cells. To explore the effects of antisense hTERT (ahTERT) on the malignant phenotypes of human SGC-7901 gastric cancer cell line in vitro, an antisense eukaryotic expression vector of hTERT was constructed by gene recombinant technology. Telomerase activity by telomeric repeat amplification protocol-ELISA, mRNA of telomerase subunits, c-myc and bcl-2 by reverse transcript-PCR, terminal restriction fragment (TRF) by Southern blot, cell cycle distribution by flow cytometry and protein expression of hTERT, c-myc and bcl-2 by Western blot were analyzed in SGC-7901 cells before and after transfection. Cloning efficiency assay in soft agar and tumorigenesis in nude mice were also examined and evaluated in the above cells. The results demonstrated that after ahTERT transfection, the proliferation of SGC-7901 cells was significantly inhibited. Further study showed that telomerase activity, telomere length, the mRNA and protein expression of hTERT, bcl-2 and c-myc were decreased in ahTERT-transfected cells. There were, however, no obvious effects on transcription of human telomerase RNA (hTR) and human telomerase associated protein1 (TP1) in both transfected and untransfected cells. Flow cytometric analysis displayed an accumulation of G0/G1 phase and a decreasing proliferation index (PI) in ahTERT-transfected cells. Moreover, no tumorigenicity was found after subcutaneous injection of ahTERT-transfected cells in nude mice, whereas palpable tumors were observed in mice injected with control cells. Our study indicates that exogenous ahTERT can inhibit proliferation and partially reverse malignant phenotypes of SGC-7901 cells via the suppression of telomerase activity, hTERT, c-myc and bcl-2 expression. Antisense technology targeted hTERT strategy might be a potential approach for gastric cancer therapy.
Flohr T, Schrauder A, Cazzaniga G, et al.Minimal residual disease-directed risk stratification using real-time quantitative PCR analysis of immunoglobulin and T-cell receptor gene rearrangements in the international multicenter trial AIEOP-BFM ALL 2000 for childhood acute lymphoblastic leukemia.
Leukemia. 2008; 22(4):771-82 [PubMed
] Related Publications
Detection of minimal residual disease (MRD) is the most sensitive method to evaluate treatment response and one of the strongest predictors of outcome in childhood acute lymphoblastic leukemia (ALL). The 10-year update on the I-BFM-SG MRD study 91 demonstrates stable results (event-free survival), that is, standard risk group (MRD-SR) 93%, intermediate risk group (MRD-IR) 74%, and high risk group (MRD-HR) 16%. In multicenter trial AIEOP-BFM ALL 2000, patients were stratified by MRD detection using quantitative PCR after induction (TP1) and consolidation treatment (TP2). From 1 July 2000 to 31 October 2004, PCR target identification was performed in 3341 patients: 2365 (71%) patients had two or more sensitive targets (< or =10(-4)), 671 (20%) patients revealed only one sensitive target, 217 (6%) patients had targets with lower sensitivity, and 88 (3%) patients had no targets. MRD-based risk group assignment was feasible in 2594 (78%) patients: 40% were classified as MRD-SR (two sensitive targets, MRD negativity at both time points), 8% as MRD-HR (MRD > or =10(-3) at TP2), and 52% as MRD-IR. The remaining 823 patients were stratified according to clinical risk features: HR (n=108) and IR (n=715). In conclusion, MRD-PCR-based stratification using stringent criteria is feasible in almost 80% of patients in an international multicenter trial.
Marone R, Cmiljanovic V, Giese B, Wymann MPTargeting phosphoinositide 3-kinase: moving towards therapy.
Biochim Biophys Acta. 2008; 1784(1):159-85 [PubMed
] Related Publications
Phosphoinositide 3-kinases (PI3K) orchestrate cell responses including mitogenic signaling, cell survival and growth, metabolic control, vesicular trafficking, degranulation, cytoskeletal rearrangement and migration. Deregulation of the PI3K pathway occurs by activating mutations in growth factor receptors or the PIK3CA locus coding for PI3Kalpha, by loss of function of the lipid phosphatase and tensin homolog deleted in chromosome ten (PTEN/MMAC/TEP1), by the up-regulation of protein kinase B (PKB/Akt), or the impairment of the tuberous sclerosis complex (TSC1/2). All these events are linked to growth and proliferation, and have thus prompted a significant interest in the pharmaceutical targeting of the PI3K pathway in cancer. Genetic targeting of PI3Kgamma (p110gamma) and PI3Kdelta (p110delta) in mice has underlined a central role of these PI3K isoforms in inflammation and allergy, as they modulate chemotaxis of leukocytes and degranulation in mast cells. Proof-of-concept molecules selective for PI3Kgamma have already successfully alleviated disease progress in murine models of rheumatoid arthritis and lupus erythematosus. As targeting PI3K moves forward to therapy of chronic, non-fatal disease, safety concerns for PI3K inhibitors increase. Many of the present inhibitor series interfere with target of rapamycin (TOR), DNA-dependent protein kinase (DNA-PK(cs)) and activity of the ataxia telangiectasia mutated gene product (ATM). Here we review the current disease-relevant knowledge for isoform-specific PI3K function in the above mentioned diseases, and review the progress of >400 recent patents covering pharmaceutical targeting of PI3K. Currently, several drugs targeting the PI3K pathway have entered clinical trials (phase I) for solid tumors and suppression of tissue damage after myocardial infarction (phases I,II).
Telomeres, consisting of TTAGGG nucleotide repeats and a protein complex at chromosome ends, are critical for maintaining chromosomal stability. Genomic instability, following telomere crisis, may contribute to breast cancer pathogenesis. Many genes critical in telomere biology have limited nucleotide diversity, thus, single nucleotide polymorphisms (SNPs) in this pathway could contribute to breast cancer risk. In a population-based study of 1995 breast cancer cases and 2296 controls from Poland, 24 SNPs representing common variation in POT1, TEP1, TERF1, TERF2 and TERT were genotyped. We did not identify any significant associations between individual SNPs or haplotypes and breast cancer risk; however, data suggested that three correlated SNPs in TERT (-1381C>T, -244C>T, and Ex2-659G>A) may be associated with reduced risk of breast cancer among individuals with a family history of breast cancer (odds ratios 0.73, 0.66, and 0.57, 95% confidence intervals 0.53-1.00, 0.46-0.95 and 0.39-0.84, respectively). In conclusion, our data do not support substantial overall associations between SNPs in telomere pathway genes and breast cancer risk. Intriguing associations with variants in TERT among women with a family history of breast cancer warrant follow-up in independent studies.
Faucherre A, Taylor GS, Overvoorde J, et al.Zebrafish pten genes have overlapping and non-redundant functions in tumorigenesis and embryonic development.
Oncogene. 2008; 27(8):1079-86 [PubMed
] Related Publications
In human cancer, PTEN (Phosphatase and TENsin homolog on chromosome 10, also referred to as MMAC1 and TEP1) is a frequently mutated tumor suppressor gene. We have used the zebrafish as a model to investigate the role of Pten in embryonic development and tumorigenesis. The zebrafish genome encodes two pten genes, ptena and ptenb. Here, we report that both Pten gene products from zebrafish are functional. Target-selected inactivation of ptena and ptenb revealed that Ptena and Ptenb have redundant functions in embryonic development, in that ptena-/- and ptenb-/- mutants did not show embryonic phenotypes. Homozygous single mutants survived as adults and they were viable and fertile. Double homozygous ptena-/-ptenb-/- mutants died at 5 days post fertilization with pleiotropic defects. These defects were rescued by treatment with the phosphatidylinositol-3-kinase inhibitor, LY294002. Double homozygous embryos showed enhanced cellular proliferation. In addition, cell survival was dramatically enhanced in embryos that lack functional Pten upon gamma-irradiation. Surprisingly, adult ptenb-/- zebrafish developed ocular tumors later in life, despite the expression of ptena in adult eyes. We conclude that whereas Ptena and Ptenb have redundant functions in embryonic development, they apparently do not have completely overlapping functions later in life. These pten mutant zebrafish represent a unique model to screen for genetic and/or chemical suppressors of Pten loss-of-function.
Salhab M, Jiang WG, Newbold RF, Mokbel KThe expression of gene transcripts of telomere-associated genes in human breast cancer: correlation with clinico-pathological parameters and clinical outcome.
Breast Cancer Res Treat. 2008; 109(1):35-46 [PubMed
] Related Publications
BACKGROUND: Telomerase is a ribonucleoprotein enzyme that synthesises telomeres in human germ cells, embryogenesis and in cancer, maintaining chromosomal length, stability and cellular immortality. The hTERT gene is the rate-limiting determinant of telomerase reactivation during immortalization and malignant transformation. Telomeric DNA-binding proteins have been attracting increasing interest due to their essential role in the regulation of telomeric DNA length and in protecting against chromosomal end-to-end fusion. These proteins include hTR, TRF1, TRF2, TANK1, TANK2, POT1, TIN2, EST1, and TEP. This study represents the first comprehensive investigation of the mRNA expression of key telomere-related genes in human breast cancer.
METHODS: One hundred and twenty seven tumour tissues and 33 normal tissues were analyzed. Levels of transcription of hTERT, hTR, TRF1, TRF2, TANK1, TANK2, POT1, TIN2, EST1, and TEP1 were determined using real-time quantitative PCR. The mRNA expression of these genes was normalized against CK19 and was then analyzed against the pathological parameters and clinical outcome over a 10 year follow up period.
RESULTS: The mRNA expressions of hTERT, hTR, TANK1, EST1, and TEP1 were higher in tumour samples compared with normal breast tissue. This reached statistical significance for EST1 when comparing good prognosis tumours with normal breast tissue (means=11013 vs 1160, P=0.05). Both hTERT and TEP1 levels significantly predicted overall survival (P=0.012 and 0.005 respectively) and disease-free survival (P=0.0011 and 0.01 respectively). The mRNA levels of TANK2 and POT1 were lower in malignant tissues compared with non-malignant breast tissues and this difference reached statistical significance when comparing the levels in normal tissues with those in advanced tumours (P=0.0008 and P=0.038 respectively). Their levels fell further with increasing tumour's stage and were higher in tumours from patients who remained disease free compared with those who developed local recurrence or distant metastasis or died from breast cancer.TRF2 showed a trend similar to that of TANK2 and POT1. Furthermore, there was a highly significant correlation between TANK1 expression and that of hTERT, hTR, TRF1, TRF2 and EST1, (r=0.533, 0.586, 0.608, 0.644 and 0.551 respectively, P<0.001).
CONCLUSIONS: Genes encoding telomere-associated proteins display different patterns of mRNA expression in human breast cancer, and in normal breast tissue, suggesting different and sometimes opposing roles in mammary carcinogenesis. hTERT, hTR, TANK1, EST1 and TEP1 seem to be up-regulated, with hTERT and TEP1 correlating with clinical outcome. Conversely, TANK2 and POT1 transcription levels demonstrate a compelling trend to be lower in malignant tissues and lower still in those patients who develop recurrent disease suggesting that TANK2 and POT1 may act as tumour suppressor genes possibly by negatively regulating telomerase activity.
Shervington A, Patel R, Lu C, et al.Telomerase subunits expression variation between biopsy samples and cell lines derived from malignant glioma.
Brain Res. 2007; 1134(1):45-52 [PubMed
] Related Publications
Although scientific advances have recognised the prognostic power of telomerase activity in different cancers, as yet there has been no investigation regarding the expression variation of telomerase subunits in glioma tissues and cell lines. In this study, a recurrent anaplastic ependymoma and seven glioblastoma biopsy samples, four cell lines and four controls including two normal brain tissues were analysed for telomerase subunit expression profiles together with telomerase activity. Since telomerase activity is linked to tumourgenesis, the genes were analysed with respect to their expression variation. TEP1 was expressed in all glioma cell lines and 70% of glioblastoma tissues, in addition to the control brain tissues. Tankyrase was expressed in 85% of the glioblastoma tissues and was down-regulated in the recurrent anaplastic ependymoma tissue control cell lines. However, it was expressed in the control tissues. Dyskerin was expressed in all cell lines and tissues apart from U87-MG and NHA cells and the recurrent anaplastic ependymoma tissue. As expected, PARP1 and GAPDH showed constitutive expression throughout all cell lines and tissues since both are known to be housekeeping genes. hTERT was expressed in all glioma cell lines and tissues but was absent in the control cells and tissues. Telomerase activity was absent in IPDDC-A2 cells and 57% of the glioblastoma tissues. These results suggest that hTERT expression and not telomerase activity possibly represents a simple and reliable biological diagnostic tool.
Fèvre-Montange M, Champier J, Szathmari A, et al.Microarray analysis reveals differential gene expression patterns in tumors of the pineal region.
J Neuropathol Exp Neurol. 2006; 65(7):675-84 [PubMed
] Related Publications
Several types of tumors are known to originate from the pineal region, among them pineal parenchymal tumors (PPTs) and papillary tumors of the pineal region (PTPRs), probably derived from the subcommissural organ. As a result of their rarity, their histologic diagnosis remains difficult. To identify molecular markers, using CodeLink oligonucleotide arrays, gene expression was studied in 3 PPTs (2 pineocytomas and one pineoblastoma), 2 PTPRs, and one chordoid glioma, another rare tumor of the third ventricle. Because PTPR and chordoid glioma may present ependymal differentiation, gene expression was also analyzed in 4 ependymomas. The gene patterns of the 3 PPTs fell in the same cluster. The pineocytomas showed high expression of TPH, HIOMT, and genes related to phototransduction in the retina (OPN4, RGS16, and CRB3), whereas the pineoblastoma showed high expression of UBEC2, SOX4, TERT, TEP1, PRAME, CD24, POU4F2, and HOXD13. Using reverse transcriptase-polymerase chain reaction on 13 PPTs, we demonstrated that PRAME, CD24, POU4F2, and HOXD13 might be candidates for grading PPT with intermediate differentiation. PTPRs, classified with chordoid glioma and separately from ependymomas, showed high expression of SPEDF, KRT18, and genes encoding proteins reported to be expressed in the subcommissural organ, namely ZFH4, RFX3, TTR, and CGRP. Our results highlight the usefulness of gene expression profiling for classify tumors of the pineal region and identify genes with potential use as diagnostic markers.
Nowak T, Januszkiewicz D, Zawada M, et al.Amplification of hTERT and hTERC genes in leukemic cells with high expression and activity of telomerase.
Oncol Rep. 2006; 16(2):301-5 [PubMed
] Related Publications
Reactivation of telomerase plays an important role in carcinogenesis. Malignant cells almost always possess high activity and expression of telomerase. The aim of this study was to see whether there is any relationship between telomerase activity and expression and hTERT and hTERC gene amplification in acute lymphoblastic leukemia (ALL) and non-lymphoblastic leukemia (ANLL) cells. In addition telomere length was tested in leukemic cells at the time of diagnosis and during remission. Expression of the three components of telomerase (hTERT, hTERC and TP1) as well as telomerase activity was found both in ALL and ANLL cells. Telomerase activity was diminished in patients in remission. The leukemic cells showed considerable heterogeneity of terminal restriction fragments, that is telomere length. ALL cells showed a variable pattern of telomere length in contrast to ANLL cells which produced a predominantly short telomere pattern. Telomere length in the lymphocytes of leukemia patients was shorter in remission as compared to the time of diagnosis. FISH analysis revealed amplification of hTERT and hTERC genes in ALL and ANLL cells. Quantitative analysis showed that leukemic cells possess higher number of hTERT and hTERC copies than the normal PBL. Our results suggest that the activation of telomerase in leukemic cells is connected with amplification of hTERT and hTERC genes. The high expression and activity of telomerase found in leukemic cells may be partially explained by amplified hTERT and hTERC genes. Amplification of the telomerase genes seems to be a common event in carcinogenesis and may play a role in telomerase reactivation leading to cell immortalization.
Scheper MA, Nikitakis NG, Sarlani E, et al.Cowden syndrome: report of a case with immunohistochemical analysis and review of the literature.
Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2006; 101(5):625-31 [PubMed
] Related Publications
Cowden syndrome is a rare condition defined by multiple hamartomatous growths and a guarded prognosis owing to the high risk of cancer development. The syndrome is inherited as an autosomal dominant trait with incomplete penetrance and variable expressivity. The PTEN/MMAC1/TEP1 tumor suppressor gene on chromosome 10q23.3, has proven to contain a germline mutation predisposing for uncontrolled cell growth and survival via the PI3K/AKT pathway. Presented here is a case of Cowden syndrome in a patient with multiple hamartomas of the nose, midfacial skin and oral mucosa, and fissured tongue; plus a history of bipolar disease, iron deficiency anemia, basal cell carcinoma, fibroids of the uterus, and arthritis. The family history was significant for a daughter diagnosed with lung cancer. A final diagnosis of Cowden syndrome was made on the basis of established criteria and confirmed using immunohistochemistry directed against PTEN and phosphorylated-AKT.
Campbell LJ, Fidler C, Eagleton H, et al.hTERT, the catalytic component of telomerase, is downregulated in the haematopoietic stem cells of patients with chronic myeloid leukaemia.
Leukemia. 2006; 20(4):671-9 [PubMed
] Related Publications
Telomere shortening is associated with disease progression in chronic myeloid leukaemia (CML). To investigate the biology and regulation of telomerase in CML, we evaluated expression of the telomerase components, its regulators and several telomeric-associated proteins. Quantitative real-time-polymerase chain reaction (PCR) was used to compare gene expression in the CD34+/leukaemic blast cells of 22 CML patient samples to the CD34+ cell population of healthy individuals. hTERT, the catalytic component of telomerase, was downregulated in eight of 12 chronic phase (CP) patients (P = 0.0387). Furthermore, hTERT was significantly downregulated in two of three patients in accelerated phase (AP) and seven of seven patients in blast crisis (BC), P = 0.0017. Expression of hTR and telomeric-associated proteins TEP1, TRF1, TRF2, tankyrase and PinX1 was high in the majority of CP and AP patients. With the exceptions of TEP1 and hTR, expression of these factors was highest in CP and decreased during disease progression. Expression of c-Myc, a positive regulator of hTERT transcription, correlated with hTERT expression and decreased with disease progression, falling below control levels in BC. hTERT levels were increased in CP patients following successful treatment with imatinib, relative to untreated CP patients. We suggest that reduced hTERT expression directly causes the shortened telomeres observed in CML.