44 research outputs found
Prognosis in human glioblastoma based on expression of ligand growth hormone-releasing hormone, pituitary-type growth hormone-releasing hormone receptor, its splicing variant receptors, EGF receptor and PTEN genes
Purpose G lioblastoma (GB) is the most frequent brain
tumor. Despite recent improvement in therapeutic strategies,
the prognosis of GB remains poor. Growth hormone-releasing
hormone (GHRH) may act as a growth factor; antagonists
of GHRH have been successfully applied for experimental
treatment of different types of tumors. The expression profile
of GHRH receptor, its main splice variant SV1 and GHRH
have not been investigated in human GB tissue samples.
Methods We examined the expression of GHRH, fulllength
pituitary-type GHRH receptor (pGHRHR), its functional
splice variant SV1 and non-functional SV2 by RTPCR
in 23 human GB specimens. Epidermal growth factor
receptor (EGFR) and phosphatase and tensin homolog gene
(PTEN) expression levels were also evaluated by quantitative
RT-PCR. Correlations between clinico-pathological
parameters and gene expressions were analyzed.
Results E xpression of GHRH was found to be positive
in 61.9 % of samples. pGHRH receptor was not expressed
in our sample set, while SV1 could be detected in 17.4 %
and SV2 in 8.6 % of the GB tissues. In 65.2 and 78.3 %
of samples, significant EGFR over-expression or PTEN
under-representation could be detected, respectively. In
47.8 % of cases, EGFR up-regulation and PTEN down-regulation
occurred together. Survival was significantly poorer
in tumors lacking GHRH expression. This worse prognosis
in GHRH negative group remained significant even if SV1
was also expressed.
Conclusion Our study shows that GHRH and SV1 genes
expressed in human GB samples and their expression patterns
are associated with poorer prognosis
Subgroup-Specific Prognostic Implications of TP53 Mutation in Medulloblastoma
Purpose
Reports detailing the prognostic impact of TP53 mutations in medulloblastoma offer conflicting
conclusions. We resolve this issue through the inclusion of molecular subgroup profiles.
Patients and Methods
We determined subgroup affiliation, TP53 mutation status, and clinical outcome in a discovery
cohort of 397 medulloblastomas. We subsequently validated our results on an independent cohort
of 156 medulloblastomas.
Results
TP53 mutations are enriched in wingless (WNT; 16%) and sonic hedgehog (SHH; 21%)
medulloblastomas and are virtually absent in subgroups 3 and 4 tumors (P < .001). Patients with
SHH/TP53 mutant tumors are almost exclusively between ages 5 and 18 years, dramatically
different from the general SHH distribution (P < .001). Children with SHH/TP53 mutant tumors
harbor 56% germline TP53 mutations, which are not observed in children with WNT/TP53 mutant
tumors. Five-year overall survival (OS; +- SE) was 41% +- 9% and 81% +- 5% for patients with SHH
medulloblastomas with and without TP53 mutations, respectively (P < .001). Furthermore, TP53
mutations accounted for 72% of deaths in children older than 5 years with SHH medulloblastomas.
In contrast, 5-year OS rates were 90% +- 9% and 97% +- 3% for patients with WNT tumors
with and without TP53 mutations (P = .21). Multivariate analysis revealed that TP53 status was
the most important risk factor for SHH medulloblastoma. Survival rates in the validation cohort
mimicked the discovery results, revealing that poor survival of TP53 mutations is restricted to
patients with SHH medulloblastomas (P = .012) and not WNT tumors.
Conclusion
Subgroup-specific analysis reconciles prior conflicting publications and confirms that TP53
mutations are enriched among SHH medulloblastomas, in which they portend poor outcome and
account for a large proportion of treatment failures in these patients
Genetic aberrations leading to MAPK pathway activation mediate oncogene-induced senescence in sporadic pilocytic astrocytomas
PURPOSE
Oncogenic BRAF/Ras or NF1 loss can potentially trigger oncogene-induced senescence (OIS) through activation of the mitogen-activated protein kinase (MAPK) pathway. Somatic genetic abnormalities affecting this pathway occur in the majority of pilocytic astrocytomas (PA), the most prevalent brain neoplasm in children. We investigated whether OIS is induced in PA.
EXPERIMENTAL DESIGN
We tested expression of established senescence markers in three independent cohorts of sporadic PA. We also assessed for OIS in vitro, using forced expression of wild-type and V600E-mutant BRAF in two astrocytic cell lines: human telomerase reverse transcriptase (hTERT)-immortalized astrocytes and fetal astrocytes.
RESULTS
Our results indicate that PAs are senescent as evidenced by marked senescence-associated acidic β-galactosidase activity, low KI-67 index, and induction of p16(INK4a) but not p53 in the majority of 52 PA samples (46 of 52; 88.5%). Overexpression of a number of senescence-associated genes [CDKN2A (p16), CDKN1A (p21), CEBPB, GADD45A, and IGFBP7] was shown at the mRNA level in two independent PA tumor series. In vitro, sustained activation of wild-type or mutant BRAF induced OIS in both astrocytic cell lines. Loss of p16(INK4a) in immortalized astrocytes abrogated OIS, indicative of the role of this pathway in mediating this phenomenon in astrocytes. OIS is a mechanism of tumor suppression that restricts the progression of benign tumors. We show that it is triggered in PAs through p16(INK4a) pathway induction following aberrant MAPK activation.
CONCLUSIONS
OIS may account for the slow growth pattern in PA, the lack of progression to higher-grade astrocytomas, and the high overall survival of affected patients