Telomerase activity and alterations in telomere length in human brain tumors.
Telomerase activity was examined in 170 human brain tumor tissues, and terminal restriction fragment (TRF) length was examined in 152 of the 170. Telomerase activity was detected in 61.7% (66 of 107) of the neuroepithelial tumors. However, the detection rates of telomerase activity were widely different for different histopathological entities. In the case of astrocytic tumors, the detection rate was 20.0% (3 of 15) for grade II astrocytomas, 40.0% (6 of 15) for anaplastic astrocytomas, and 72.3% (34 of 47) for glioblastomas. The mean TRF length of the tumors with telomerase activity was significantly shorter than that of the tumors with undetectable telomerase activity for each tumor entity. In grade II and anaplastic astrocytomas, telomerase activity was an indicator of early histological progression and reduced survival of the patients, although there was no difference in MIB-1 staining indices between the tumors with and without telomerase activity at onset. In three astrocytic tumors, concurrence of telomere shortening and telomerase reactivation was observed at recurrence; in these cases, tumors progressed to a higher grade. Ten glioblastomas that progressed from lower-grade tumors exhibited telomerase activity, and their TRF lengths were reduced in 80% (8 of 10). In contrast, telomerase activity was detected in only 63.3% (19 of 30; P < 0.05) and the TRF length remained compatible with normal values in 56.7% (17 of 30; P < 0.01) of de novo glioblastomas. Thus, telomerase activity strongly correlated with potential tumor progression in the short term as well as with progression itself of the astrocytic tumors, whereas telomeres may still have been in the process of shortening in some of the de novo glioblastomas. High telomerase activity was exhibited in all primitive neuroectodermal tumors, anaplastic oligoastrocytomas, neuroblastomas, and oligodendrogliomas. TRF length was reduced in the majority (14 of 15) of three previously high-grade tumors, whereas it was compatible with that of normal brain tissues in the oligodendrogliomas, suggesting that telomerase activity with shortened telomeres correlates with the aggressive growth of high-grade neuroepithelial tumors. Tumor cell lines could be established from 17.2% (5 of 29) of neuroepithelial tumors with telomerase activity but not from tumors without this activity (P < 0.05), suggesting that telomerase reactivation is an essential event in the neuroepithelial cell immortalization in vitro. In nonneuroepithelial tumors, telomerase activity was detected in malignant tumors, such as germ cell tumors, lymphomas, metastatic adenocarcinomas, hemangiopericytomas, and an anaplastic meningioma. In contrast, such activity was not detected in benign tumors, including meningiomas, pituitary adenomas, hemangioblastomas and schwannomas, except for one hemangioblastoma that recurred four times and displayed malignant features at the fourth recurrence. These findings suggest that telomerase activity can be an index of malignant potential or malignancy itself in nonneuroepithelial brain tumors.
Hiraga
S
S
Department of Neurosurgery, Osaka University Medical School, Suita, Japan. shiraga@nsurg.med.osaka-u.ac.jp
Ohnishi
T
T
Izumoto
S
S
Miyahara
E
E
Kanemura
Y
Y
Matsumura
H
H
Arita
N
N
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001254:Astrocytoma / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D001932:Brain Neoplasms / Q000201:enzymology* / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D002648:Child; D002675:Child, Preschool; D005909:Glioblastoma / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D006801:Humans; D007223:Infant; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000378:metabolism*; D018241:Neuroectodermal Tumors, Primitive, Peripheral / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D016019:Survival Analysis; D019098:Telomerase / Q000378:metabolism*; D016615:Telomere / Q000235:genetics*; D014407:Tumor Cells, Cultured
D009363:Neoplasm Proteins; D019098:Telomerase