The RNA component of telomerase as a marker of biologic potential and clinical outcome in childhood neuroblastic tumors.
BACKGROUND
Telomerase is a ribonucleoprotein enzyme associated with cellular immortality that may be useful in determining the biologic potential of a tumor. Neuroblastoma (NB), ganglioneuroblastoma (GNB), and ganglioneuroma (GN) are neuroblastic tumors (NTs) that exhibit a spectrum of histologic features and are often associated with unpredictable behavior and clinical outcome.


METHODS
The authors investigated the expression of the RNA component of human telomerase (hTR) by in situ hybridization in 32 cases of NTs (including 24 NBs, 4 GNBs, and 4 GNs), using [35S]-UTP labeled single stranded sense and antisense RNA probes. Eight NBs were early stage, 12 NBs were advanced stage, and 4 NBs were Stage IVS, a widely metastatic variant associated with an excellent clinical prognosis. Four NBs had N-myc amplification. In addition, the authors compared a proliferation marker, MIB-1, with hTR expression in a subset of tumors.


RESULTS
Thirty of 32 NTs expressed hTR, with expression varying from weak (1+) to intense (4+). Most advanced stage NBs (9 of 12) and only 2 of 8 early stage NBs had moderate to intense (2 to 4-) expression of hTR. The remaining early stage tumors (6 of 8) and 3 of 12 advanced stage NBs had absent or weak expression of hTR (0 to 1+). There was no disease progression in any of the patients with absent or weak expression of hTR. In contrast, 8 tumors (from 7 patients) with moderate to intense expression of hTR in the tumor sections had adverse clinical outcomes, including recurrence, persistent disease, or death. hTR expression in all the Stage IVS tumors was weak, despite the fact that the patients had widely metastatic disease at presentation. The mean hTR score of 3.1 for NBs associated with an adverse outcome (n = 8) was significantly different from the mean hTR score of 1.3 for NBs associated with a favorable outcome (n = 16), P < 0.001. hTR expression in the GNB/GNs was limited to the ganglion cells only; Schwann cells were negative for hTR expression. Stage IVS tumors, which are associated with an excellent outcome, had high MIB-1 but weak hTR expression, indicating that the latter may be a better discriminator of true biologic potential and that hTR levels do not always correlate with cell proliferation.


CONCLUSIONS
Increased hTR expression may reflect the potential for aggressive behavior within the spectrum of NTs; conversely, down-regulation of hTR may be useful in identifying subsets with limited capacity for progression and a favorable prognosis.
Maitra
A
A
Department of Pathology, University of Texas Southwestern Medical Center, Dallas 75235-8593, USA.
Yashima
K
K
Rathi
A
A
Timmons
C F
CF
Rogers
B B
BB
Shay
J W
JW
Gazdar
A F
AF
D000293:Adolescent; D034961:Antigens, Nuclear; D014408:Biomarkers, Tumor / Q000032:analysis*; D002648:Child; D002675:Child, Preschool; D018305:Ganglioneuroblastoma / Q000737:chemistry* / Q000473:pathology; D005729:Ganglioneuroma / Q000737:chemistry* / Q000473:pathology; D006801:Humans; D017403:In Situ Hybridization; D007223:Infant; D019394:Ki-67 Antigen; D009447:Neuroblastoma / Q000737:chemistry* / Q000473:pathology; D009687:Nuclear Proteins / Q000032:analysis; D011379:Prognosis; D012313:RNA / Q000032:analysis*; D019098:Telomerase / Q000032:analysis* / Q000235:genetics
D034961:Antigens, Nuclear; D014408:Biomarkers, Tumor; D019394:Ki-67 Antigen; D009687:Nuclear Proteins; D012313:RNA; D019098:Telomerase