The Role of Telomeres in Stem Cells and Cancer

Güneş, Çagatay; Rudolph, K. Lenhard

doi:10.1016/j.cell.2013.01.010

Cited by 199 publications

(173 citation statements)

References 21 publications

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“…Multiple tumour suppressor genes and oncogenes have been described in invasive urothelial carcinoma, but often it is difficult to determine whether these are required for cancer development [110,111]. Recurrent mutations occur in genes such as TP53, FGFR3, PIK3CA, RB1 and HRAS, with TP53 and FGFR3 being the most common, together with promoter mutations of TERT [112][113][114]. Although TERT mutations are present in up to 79% of bladder neoplasms, they have no association with clinical outcome; however, its presence can be of great diagnostic utility, given the relative rarity of this mutation in other tumours that may have overlapping histology.…”

Section: Genomics Of Urothelial Carcinomamentioning

confidence: 99%

The 2016 WHO Classification of Tumours of the Urinary System and Male Genital Organs—Part B: Prostate and Bladder Tumours

et al. 2016

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It has been 12 yr since the publication of the last World Health Organization (WHO) classification of tumours of the prostate and bladder. During this time, significant new knowledge has been generated about the pathology and genetics of these tumours. Intraductal carcinoma of the prostate is a newly recognized entity in the 2016 WHO classification. In most cases, it represents intraductal spread of aggressive prostatic carcinoma and should be separated from high-grade prostatic intraepithelial neoplasia. New acinar adenocarcinoma variants are microcystic adenocarcinoma and pleomorphic giant cell adenocarcinoma. Modifications to the Gleason grading system are incorporated into the 2016 WHO section on grading of prostate cancer, and it is recommended that the percentage of pattern 4 should be reported for Gleason score 7. The new WHO classification further recommends the recently developed prostate cancer grade grouping with five grade groups. For bladder cancer, the 2016 WHO classification continues to recommend the 1997 International Society of Urological Pathology grading classification. Newly described or better defined noninvasive urothelial lesions include urothelial dysplasia and urothelial proliferation of uncertain malignant potential, which is frequently identified in patients with a prior history of urothelial carcinoma. Invasive urothelial carcinoma with divergent differentiation refers to tumours with some percentage of "usual type" urothelial carcinoma combined with other morphologies. Pathologists should mention the percentage of divergent histologies in the pathology report. PATIENT SUMMARY Intraductal carcinoma of the prostate is a newly recognized entity in the 2016 World Health Organization classification. Better defined noninvasive urothelial lesions include urothelial dysplasia and urothelial proliferation of uncertain malignant potential. v a i l a b l e a t w w w . s c i e n c e d i r e c t . c o m j AbstractIt has been 12 yr since the publication of the last World Health Organization (WHO) classification of tumours of the prostate and bladder. During this time, significant new knowledge has been generated about the pathology and genetics of these tumours.

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Section: Genomics Of Urothelial Carcinomamentioning

confidence: 99%

The 2016 WHO Classification of Tumours of the Urinary System and Male Genital Organs—Part B: Prostate and Bladder Tumours

et al. 2016

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“…2 Telomere length must be maintained for the immortalization of malignant cells. Two main telomeremaintenance mechanisms have been proposed: telomerase activation and the alternative lengthening of telomeres.…”

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“…Two main telomeremaintenance mechanisms have been proposed: telomerase activation and the alternative lengthening of telomeres. 2 Approximately 10-15% of cancers, notably gliomas and sarcomas, utilize alternative lengthening of telomeres as the telomeremaintenance mechanism. The alternative lengthening of telomeres-positive cells are characterized by marked telomere length heterogeneity and the presence of alternative lengthening of telomeresassociated promyelocytic leukemia bodies.…”

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Comprehensive screening of alternative lengthening of telomeres phenotype and loss of ATRX expression in sarcomas

et al. 2015

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According to cytogenetic aberrations, sarcomas can be categorized as complex or simple karyotype tumors. Alternative lengthening of telomeres is a telomere-maintenance mechanism common in sarcomas. Recently, this mechanism was found to be associated with loss of either α-thalassemia/mental retardation syndrome X-linked (ATRX) or death domain-associated (DAXX) protein. We previously reported that alternative lengthening of telomeres and loss of ATRX expression were common in leiomyosarcoma, angiosarcoma, pleomorphic liposarcoma, and dedifferentiated liposarcoma. In the present study, we screened an additional 245 sarcomas of other types to determine the prevalence of alternative lengthening of telomeres, loss of ATRX/DAXX expression, and their relationship. Undifferentiated pleomorphic sarcomas were frequently alternative lengthening of telomeres positive (65%) and loss of ATRX was seen in approximately half of the alternative lengthening of telomeres-positive tumors. Nineteen of 25 myxofibrosarcomas were alternative lengthening of telomerespositive, but only one was ATRX deficient. Three of 15 radiation-associated sarcomas were alternative lengthening of telomeres positive, but none of them was ATRX deficient. Alternative lengthening of telomeres and/or loss of ATRX were uncommon in malignant peripheral nerve sheath tumors, gastrointestinal stromal tumors, and embryonal rhabdomyosarcomas. By contrast, none of the 71 gene fusion-associated sarcomas was ATRX deficient or alternative lengthening of telomeres positive. All tumors exhibited preserved DAXX expression. Combining our previous studies and this study, a total of 384 sarcomas with complex karyotypes were examined, 83 of which were ATRX deficient (22%). By telomere-specific fluorescence in situ hybridization, 45% (138/308) were alternative lengthening of telomeres positive, 55% (76/138) of which were ATRX deficient. Loss of ATRX was highly associated with alternative lengthening of telomeres (Po 0.001). We conclude that alternative lengthening of telomeres is a frequent telomere-maintenance mechanism in cytogenetically complex sarcomas. Loss of ATRX is highly associated with this feature.

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“…Telomerase is a ribonucleoprotein and can add TTAGGG hexamers to the ends of chromosomes. 13 Telomerase activity is generally higher in cancer cells than normal cells and is required to maintain tumor growth. 13 Telomerase reverse transcriptase (TERT) is a catalytic subunit of telomerase, 14 and increased activity of TERT is present in most cancers, including ovarian cancer.…”

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confidence: 99%

“…13 Telomerase activity is generally higher in cancer cells than normal cells and is required to maintain tumor growth. 13 Telomerase reverse transcriptase (TERT) is a catalytic subunit of telomerase, 14 and increased activity of TERT is present in most cancers, including ovarian cancer. 14,15 Mutations of TERT promoter contribute to a mechanism that allows for increased telomerase activity and is found in melanomas, 16,17 thyroid carcinomas, 18,19 myxoid liposarcomas, hepatocellular carcinomas, urothelial carcinomas, squamous cell carcinomas of the tongue, medulloblastomas, and gliomas.…”

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confidence: 99%

Molecular alterations in endometrial and ovarian clear cell carcinomas: clinical impacts of telomerase reverse transcriptase promoter mutation

et al. 2015

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Recently, mutations of telomerase reverse transcriptase (TERT) promoter were found in several types of cancer. A few reports demonstrate TERT promoter mutations in ovarian clear cell carcinomas but endometrial clear cell carcinoma has not been studied. The aims of this study were to compare differences of molecular alterations and clinical factors, and identify their prognostic impact in endometrial and ovarian clear cell carcinomas. We evaluated mutations of the TERT promoter and PIK3CA, expression of ARID1A, and other clinicopathological factors in 56 ovarian and 14 endometrial clear cell carcinomas. We found that TERT promoter mutations were present in 21% (3/14) of endometrial clear cell carcinomas and 16% (9/56) of ovarian clear cell carcinomas. Compared with ovarian clear cell carcinomas, endometrial clear cell carcinomas showed older mean patient age (Po0.001), preserved ARID1A immunoreactivity (P ¼ 0.017) and infrequent PIK3CA mutation (P ¼ 0.025). In ovarian clear cell carcinomas, TERT promoter mutations were correlated with patient age 445 (P ¼ 0.045) and preserved ARID1A expression (P ¼ 0.003). In cases of endometrial clear cell carcinoma, TERT promoter mutations were not statistically associated with any other clinicopathological factors. In ovarian clear cell carcinoma patients with early FIGO stage (stages I and II), TERT promoter mutation was an independent prognostic factor and correlated with a shorter disease-free survival and overall survival (P ¼ 0.015 and 0.009, respectively). In recurrent ovarian clear cell carcinoma patients with early FIGO stage, TERT promoter mutations were associated with early relapse within 6 months (P ¼ 0.018). We concluded that TERT promoter mutations were present in endometrial and ovarian clear cell carcinomas. Distinct molecular alteration patterns in endometrial and ovarian clear cell carcinomas implied different processes of tumorigenesis in these morphologically similar tumors. In ovarian clear cell carcinoma of early FIGO stage, patients with TERT promoter mutation require close follow-up during the initial 6 months following chemotherapy. Modern Pathology (2015) 28, 303-311; doi:10.1038/modpathol.2014 published online 1 August 2014 Ovarian clear cell carcinoma represents 5-25% of all epithelial ovarian carcinomas with geographic variation. 1 Compared with high-grade serous adenocarcinomas, ovarian clear cell carcinomas are characterized by a higher incidence among Asians, younger patient age and early tumor staging at presentation, association with endometriosis, higher frequencies of AT-rich interactive domain 1 A (ARID1A) mutation and phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA) mutation, and higher resistance to first-line platinum and taxane-based chemotherapy.

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The Role of Telomeres in Stem Cells and Cancer

Cited by 199 publications

References 21 publications

The 2016 WHO Classification of Tumours of the Urinary System and Male Genital Organs—Part B: Prostate and Bladder Tumours

The 2016 WHO Classification of Tumours of the Urinary System and Male Genital Organs—Part B: Prostate and Bladder Tumours

Comprehensive screening of alternative lengthening of telomeres phenotype and loss of ATRX expression in sarcomas

Molecular alterations in endometrial and ovarian clear cell carcinomas: clinical impacts of telomerase reverse transcriptase promoter mutation

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