<i>TP53</i> alterations and clinical outcome in low grade astrocytomas

Kraus, Jürgen; Bolln, Carsten; Wolf, Helmut K.; Neumann, Jürgen; Kindermann, D; Fimmers, Rolf; Förster, Frank; Baumann, Axel; Schlegel, Uwe

doi:10.1002/gcc.2870100211

Cited by 57 publications

(31 citation statements)

References 14 publications

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“…A trend to poor outcome had been previously observed in patients with p53 immunopositive astrocytic tumors without reaching statistical signi®cance (al Sarraj and Bridges, 1995; Chozick et al, 1994; Iuzzolino et al, 1994;Kyritsis et al, 1995), and others have found no dierence (Kraus et al, 1994). These studies are limited by the inaccuracy of immunohistochemistry in the determination of p53 status (Hall and Lane, 1994).…”

Section: Relationship Between Tp53 Status and Outcomementioning

confidence: 89%

Cells with TP53 mutations in low grade astrocytic tumors evolve clonally to malignancy and are an unfavorable prognostic factor

Ishii¹,

Tada²,

Hamou³

et al. 1999

Oncogene

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It is important to understand how low grade tumors recur and progress to malignant lesions since this dramatically shortens patient survival. Here, we evaluated the concept that malignant progression and poor prognosis of low grade astrocytic tumors are TP53 dependent through clonal expansion of mutated cells. TP53 status was established in primary and recurrent tumors from 36 patients with WHO grade II astrocytic tumors and two tumor types were found. Tumors from 14 patients (39%; type 1) had TP53 mutated cells, and 92% of these recurred with 57% progressing to malignancy. The evolution of TP53 mutated cells before and after progression was examined using a clonal analysis procedure in yeast. Malignant progression was accompanied by an increased percentage of mutant TP53 (red) yeast colonies resulting from monoclonal expansion of cells with mutated TP53. The presence of TP53 mutations in WHO grade II astrocytic tumors was associated with malignant progression (P=0.034, w 2 test) and shorter progression-free survival (PFS; 47.6+9.6 months for TP53-mutated tumors vs 67.8+8.2 months for TP53-wild type tumors, P50.05, log-rank test). Tumors from 22 patients (61%; type 2) were without TP53 mutations, and 64% of these recurred without a change in TP53 status, although 41% progressed to malignancy. This suggests that TP53 mutation is not an initiating or progression event in the majority of low grade astrocytic tumors. Our study also indicates that irradiation for WHO grade II astrocytic tumors might be associated with poor outcome (P50.0001) and this was independent of TP53 status. These ®ndings have important implications in the clinical management of patients with low grade astocytoma and provide new support to the clonal evolution model for tumor progression.

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Section: Relationship Between Tp53 Status and Outcomementioning

confidence: 89%

Cells with TP53 mutations in low grade astrocytic tumors evolve clonally to malignancy and are an unfavorable prognostic factor

Ishii¹,

Tada²,

Hamou³

et al. 1999

Oncogene

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“…2,31 Several workers have used proliferation index and p53 gene alterations for prediction of recurrence but results are controversial. 5,8,9,13,15,17,19,24,25,29 Similarly, the relationship between malignant progression and apoptosis is not clearly defined. 3,5,7,24,27 Nakamura et al 24 studied p53 protein expression, MIB-1 labeling index (MIB-1 LI) and apoptotic index (AI) in 46 recurrent anaplastic astrocytomas and reported that MIB-1 LI and AI were higher in the recurrent compared to the initial tumor.…”

Section: Introductionmentioning

confidence: 99%

Clinicopathological features, MIB-1 labeling index and apoptotic index in recurrent astrocytic tumors

Ralte

Sharma

Karak

et al. 2001

Pathol. Oncol. Res.

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“…However, the prognostic significance of p53 mutations in LGAs is unclear, with some studies showing it to be associated with malignant progression and shorter progressionfree and overall survival while others have not seen any significant association. 1,6,9,11,15,16 More recently, it has been shown that gemistocytic astrocytomas have a higher number of microglia, with more microglia being present when the fraction of gemistocytes is high. 8 Additionally gemistocytes were seen to be reactive for major histocompatibility complex Class II molecules.…”

mentioning

confidence: 99%

Low-grade astrocytomas: the prognostic value of fibrillary, gemistocytic, and protoplasmic tumor histology

Babu

Bagley

Park

et al. 2013

JNS

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Object Low-grade astrocytomas are slow-growing, infiltrative gliomas that over time may progress into more malignant tumors. Various factors have been shown to affect the time to progression and overall survival including age, performance status, tumor size, and the extent of resection. However, more recently it has been suggested that histological subtypes (fibrillary, protoplasmic, and gemistocytic) may impact patient outcome. In this study the authors have performed a large comparative population-based analysis to examine the characteristics and survival of patients with the various subtypes of WHO Grade II astrocytomas. Methods Patients diagnosed with fibrillary, protoplasmic, and gemistocytic astrocytomas were identified through the Surveillance, Epidemiology, and End Results (SEER) database. The chi-square test and Student t-test were used to evaluate differences in patient and treatment characteristics between astrocytoma subtypes. Kaplan-Meier analysis was used to assess overall survival, and the log-rank test was used to evaluate the differences between survival curves. Univariate and multivariate analyses were also performed to determine the effect of various patient, tumor, and treatment variables on overall survival. Results A total of 500 cases were included in the analysis, consisting of 326 fibrillary (65.2%), 29 protoplasmic (5.8%), and 145 gemistocytic (29%) variants. Gemistocytic astrocytomas presented at a significantly older age than the fibrillary variant (46.8 vs 37.7 years, p < 0.0001), with protoplasmic and fibrillary subtypes having a similar age. Although protoplasmic and fibrillary variants underwent radiotherapy at similar rates, gemistocytic tumors more frequently received radiotherapy (p = 0.0001). Univariate analysis revealed older age, larger tumor size, and the use of radiotherapy to be poor prognostic factors, with resection being associated with improved survival. The gemistocytic subtype (hazard ratio [HR] 1.62 [95% CI 1.27–2.07], p = 0.0001) also resulted in significantly worse survival than fibrillary tumors. Bivariate analyses demonstrated that older age, the use of radiotherapy, and resection significantly influenced median survival. Tumor subtype also affected median survival; patients who harbored gemistocytic tumors experienced less than half the median survival of fibrillary and protoplasmic tumors (38 vs 82 months, p = 0.0003). Multivariate analysis revealed increasing age (HR 1.05 [95% CI 1.04–1.05], p < 0.0001), larger tumor size (HR 1.02 [95% CI 1.01–1.03], p = 0.0002), and the use of resection (HR 0.70 [95% CI 0.52–0.94], p = 0.018) to be independent predictors of survival. Examination of tumor subtype revealed that the gemistocytic variant (HR 1.30 [95% CI 0.98–1.74], p = 0.074) was associated with worse patient survival than fibrillary tumors, although this only approached significance. The protoplasmic subtype did not affect overall survival (p = 0.33). Conclusions Gemistocytic tumor histology was associated with worse survival than fibrillary and protoplasmic astrocytomas. As protoplasmic astrocytomas have a survival similar to fibrillary tumors, there may be limited utility to the identification of this rare variant. However, increased attention should be paid to the presence of gemistocytes in low-grade gliomas as this is associated with shorter time to progression, increased malignant transformation, and reduced overall survival.

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TP53 alterations and clinical outcome in low grade astrocytomas

Cited by 57 publications

References 14 publications

Cells with TP53 mutations in low grade astrocytic tumors evolve clonally to malignancy and are an unfavorable prognostic factor

Cells with TP53 mutations in low grade astrocytic tumors evolve clonally to malignancy and are an unfavorable prognostic factor

Clinicopathological features, MIB-1 labeling index and apoptotic index in recurrent astrocytic tumors

Low-grade astrocytomas: the prognostic value of fibrillary, gemistocytic, and protoplasmic tumor histology

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