OS3.3  Radiological characteristics and natural history of adult IDH wild type astrocytomas with TERT promoter mutations

Abstract BACKGROUND Adult IDH-wildtype astrocytomas with TERT promoter mutations (TERTp) are associated with a poor prognosis. OBJECTIVE To analyze the radiological presentation and natural history of adult IDH-wildtype astrocytomas with TERTp. METHODS We retrospectively reviewed the characteristics of 40 IDH-wildtype TERTp-mutant astrocytomas (grade II n = 19, grade III n = 21) and compared them to those of 114 IDH-mutant lower grade gliomas (LGG), of 92 IDH-wildtype TERTp-mutant glioblastomas, and of 15 IDH-wildtype TERTp-wildtype astrocytomas. RESULTS Most cases of IDH-wildtype TERTp-mutant astrocytomas occurred in patients aged >50 yr (88%) and presented as infiltrative lesions without contrast enhancement (73%) that were localized in the temporal and/or insular lobes (37.5%) or corresponded to a gliomatosis cerebri (43%). Thalamic involvement (33%) and extension to the brainstem (27%) were frequently observed, as was gyriform infiltration (33%). This radiological presentation was different from that of IDH-mutant LGG, IDH-wildtype TERTp-mutant glioblastomas, and IDH-wildtype TERTp-wildtype astrocytomas. Tumor evolution before treatment initiation was assessable in 17 cases. Ten cases demonstrated a rapid growth characterized by the apparition of a ring-like contrast enhancement and/or a median velocity of diametric expansion (VDE) ≥8 mm/yr but 7 cases displayed a slow growth (VDE <8 mm/yr) that could last several years before anaplastic transformation. Median overall survival of IDH-wildtype TERTp-mutant astrocytomas was 27 mo. CONCLUSION IDH-wildtype TERTp-mutant astrocytomas typically present as nonenhancing temporo-insular infiltrative lesions or as gliomatosis cerebri in patients aged >50 yr. In the absence of treatment, although rapid tumor growth is frequent, an initial falsely reassuring, slow growth can be observed.

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TERT promoter mutations in progressive treatment-resistant meningiomas.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.2047 ◽

2017 ◽

Vol 35 (15_suppl) ◽

pp. 2047-2047 ◽

Cited By ~ 2

Author(s):

Tareq A. Juratli ◽

Christian Thiede ◽

Dietmar Krex ◽

Priscilla Kaliopi Brastianos ◽

Hiroaki Wakimoto ◽

...

Keyword(s):

Initial Diagnosis ◽

Lower Grade ◽

Treatment Resistant ◽

Mutation Status ◽

Tert Promoter ◽

Tert Promoter Mutations ◽

Promoter Gene ◽

History Of ◽

Promoter Mutations

2047 Background: Recurrent meningiomas often undergo a grade-progression to become atypical or malignant upon recurrence. Detailed study of progressive meningioma has been hampered by the lack of available paired specimens. Here, we sequenced the TERT promoter ( TERTp) in a large series of patients with treatment-resistant meningiomas at initial diagnosis as well as their sequential recurrences. Methods: We scored 77 meningiomas from 36 patients for TERTp mutations. All patients in this study developed recurrences during the median follow-up of 13.3 years (range 6.4 - 25.5 years) and underwent three surgeries on average (range 2-8). Additionally, we screened geographically distinct sites of all TERTp-mutant meningiomas to interrogate intratumoral heterogeneity. Results: TERTp mutations were detected in 18 tumor samples (18/77 = 23.3%) from 12 patients, but not in any of the matched blood sample DNAs, excluding germline mutations. Notably, the TERTp mutations were absent in the initial lower-grade tumor and were present in the subsequent recurrent tumors. Moreover, we observe emergent spatial heterogeneity in the form of mixed populations of recurrent tumor cells containing different mutation status of the TERT promoter gene in three cases. Patients with emergence of TERTp -mutant meningiomas had a significantly shorter overall survival than their TERTp wild-type counterparts, when measured from the time of initial diagnosis (2.4 vs 11.1 years, 95% CI 0.25-4.54 vs 9.3- 16.8 years p = 0.007). Conclusions: Our data confirm the high frequency of TERTp mutations and the emergence of TERT promoter mutation in recurrent progressive meningiomas, strongly indicating the presence of ongoing evolution impacting the natural history of these tumors. TERTp mutations are mostly associated with poor outcome. Finally, our study provides important insight into the complexity of tumor heterogeneity and has important implications for targeted therapy in treatment-resistant meningiomas.

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151 TERT Promoter Mutations in Progressive Treatment-resistant Meningiomas

Neurosurgery ◽

10.1093/neuros/nyx417.151 ◽

2017 ◽

Vol 64 (CN_suppl_1) ◽

pp. 236-237

Author(s):

Tareq A Juratli ◽

Ganesh Shankar ◽

Mara Koerner ◽

Shilpa Tummala ◽

Hiroaki Wakimoto ◽

...

Keyword(s):

Initial Diagnosis ◽

Lower Grade ◽

Treatment Resistant ◽

Mutation Status ◽

Tert Promoter ◽

Tert Promoter Mutations ◽

Promoter Gene ◽

History Of ◽

Promoter Mutations

Abstract INTRODUCTION Recurrent meningiomas often undergo a grade-progression to become atypical or malignant upon recurrence. Detailed study of progressive meningioma has been hampered by the lack of available paired specimens. Here, we sequenced the TERT promoter (TERTp) in a large series of patients with treatment-resistant meningiomas at initial diagnosis as well as their sequential recurrences. METHODS We scored 77 meningiomas from 36 patients for TERTp mutations. All patients in this study developed recurrences during the median follow-up of 13.3 years (range 6.4-25.5 years) and underwent three surgeries on average (range 2–8). Additionally, we screened geographically distinct sites of all TERTp-mutant meningiomas to interrogate intratumoral heterogeneity. RESULTS >TERTp mutations were detected in 18 tumor samples (18/77 = 23.3%) from 12 patients, but not in any of the matched blood sample DNAs, excluding germline mutations. Notably, the TERTp mutations were absent in the initial lower-grade tumor and were present in the subsequent recurrent tumors. Moreover, we observe emergent spatial heterogeneity in the form of mixed populations of recurrent tumor cells containing different mutation status of the TERT promoter gene in three cases. Patients with emergence of TERTp-mutant meningiomas had a significantly shorter overall survival than their TERTp wild-type counterparts, when measured from the time of initial diagnosis (2.4 vs 11.1 years, 95% CI 0.25-4.54 vs 9.3- 16.8 years P = 0.007). CONCLUSION Our data confirm the high frequency of TERTp mutations and the emergence of TERT promoter mutation in recurrent progressive meningiomas, strongly indicating the presence of ongoing evolution impacting the natural history of these tumors. TERTp mutations are mostly associated with poor outcome. Finally, our study provides important insight into the complexity of tumor heterogeneity and has important implications for targeted therapy in treatment-resistant meningiomas.

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Frequent Somatic TERT Promoter Mutations in Thyroid Cancer: Higher Prevalence in Advanced Forms of the Disease

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2013-2383 ◽

2013 ◽

Vol 98 (9) ◽

pp. E1562-E1566 ◽

Cited By ~ 247

Author(s):

Iñigo Landa ◽

Ian Ganly ◽

Timothy A. Chan ◽

Norisato Mitsutake ◽

Michiko Matsuse ◽

...

Keyword(s):

Thyroid Cancer ◽

Cell Lines ◽

Transcriptional Response ◽

Telomerase Activity ◽

Wild Type ◽

Thyroid Cancers ◽

Ras Mutations ◽

Tert Promoter ◽

Tert Promoter Mutations ◽

Promoter Mutations

Background: TERT encodes the reverse transcriptase component of telomerase, which adds telomere repeats to chromosome ends, thus enabling cell replication. Telomerase activity is required for cell immortalization. Somatic TERT promoter mutations modifying key transcriptional response elements were recently reported in several cancers, such as melanomas and gliomas. Objectives: The objectives of the study were: 1) to determine the prevalence of TERT promoter mutations C228T and C250T in different thyroid cancer histological types and cell lines; and 2) to establish the possible association of TERT mutations with mutations of BRAF, RAS, or RET/PTC. Methods: TERT promoter was PCR-amplified and sequenced in 42 thyroid cancer cell lines and 183 tumors: 80 papillary thyroid cancers (PTCs), 58 poorly differentiated thyroid cancers (PDTCs), 20 anaplastic thyroid cancers (ATCs), and 25 Hurthle cell cancers (HCCs). Results: TERT promoter mutations were found in 98 of 225 (44%) specimens. TERT promoters C228T and C250T were mutually exclusive. Mutations were present in 18 of 80 PTCs (22.5%), in 40 of 78 (51%) advanced thyroid cancers (ATC + PDTC) (P = 3 × 10−4 vs PTC), and in widely invasive HCCs (4 of 17), but not in minimally invasive HCCs (0 of 8). TERT promoter mutations were seen more frequently in advanced cancers with BRAF/RAS mutations compared to those that were BRAF/RAS wild-type (ATC + PDTC, 67.3 vs 24.1%; P < 10−4), whereas BRAF-mutant PTCs were less likely to have TERT promoter mutations than BRAF wild-type tumors (11.8 vs 50.0%; P = .04). Conclusions: TERT promoter mutations are highly prevalent in advanced thyroid cancers, particularly those harboring BRAF or RAS mutations, whereas PTCs with BRAF or RAS mutations are most often TERT promoter wild type. Acquisition of a TERT promoter mutation could extend survival of BRAF- or RAS-driven clones and enable accumulation of additional genetic defects leading to disease progression.

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