IDH1 encodes isocitrate dehydrogenase 1, which participates in the citric acid cycle and was recently reported to be mutated in 12% of glioblastomas. We assessed IDH1 mutations in 321 gliomas of various histological types and biological behaviors. A total of 130 IDH1 mutations was detected, and all were located at amino acid residue 132. Of these, 91% were G3 A mutations (Arg3 His). IDH1 mutations were frequent in low-grade diffuse astrocytomas (88%) and in secondary glioblastomas that developed through progression from low-grade diffuse or anaplastic astrocytoma (82%). Similarly, high frequencies of IDH1 mutations were found in oligodendrogliomas (79%) and oligoastrocytomas (94%). Analyses of multiple biopsies from the same patient (51 cases) showed that there were no cases in which an IDH1 mutation occurred after the acquisition of either a TP53 mutation or loss of 1p/19q, suggesting that IDH1 mutations are very early events in gliomagenesis and may affect a common glial precursor cell population. IDH1 mutations were co-present with TP53 mutations in 63% of low-grade diffuse astrocytomas and with loss of heterozygosity 1p/19q in 64% of oligodendrogliomas; they were rare in pilocytic astrocytomas (10%) and primary glioblastomas (5%) and absent in ependymomas. The frequent presence of IDH1 mutations in secondary glioblastomas and their nearcomplete absence in primary glioblastomas reinforce the concept that despite their histological similarities, these subtypes are genetically and clinically distinct entities. Gliomas are the most common primary brain tumors and show wide diversity with respect to location, morphology, genetic status, and response to therapy. Glioblastoma (World Health Organization [WHO]grade IV), the most frequent and most malignant glioma, may develop rapidly after a short clinical history and without evidence of a less malignant precursor lesion (primary or de novo glioblastoma), or slowly through progression from lowgrade diffuse or anaplastic astrocytoma (secondary glioblastoma).1-3 Both glioblastoma subtypes show frequent loss of heterozygosity (LOH) 10q (63% to 70%), but differ significantly with respect to the frequency of other genetic alterations: LOH 10p, EGFR amplification, MDM2 amplification, and PTEN mutations are typical of primary glioblastomas, 3,4 whereas TP53 mutations, LOH 19q, and LOH 22q are more frequent in secondary glioblastomas. 3,5 Low-grade diffuse astrocytomas (WHO grade II) are slowly growing, well-differentiated tumors, but they diffusely infiltrate into surrounding brain tissues and have an intrinsic tendency to progress to anaplastic astrocytoma (WHO grade III) and eventually to secondary glioblastoma. 6 In the genetic pathway to secondary glioblastoma, TP53 mutations are considered an early event, since their frequency in low-grade diffuse astrocytomas is similar to that in secondary glioblastomas. Recently, Parsons et al 7 analyzed 20,661 protein coding genes in 22 glioblastomas, and showed that 12% of cases contained mutations in the IDH1 gene. All were locat...

Purpose: To establish the frequency of IDH1 mutations in glioblastomas at a population level, and to assess whether they allow reliable discrimination between primary (de novo) glioblastomas and secondary glioblastomas that progressed from low-grade or anaplastic astrocytoma. Experimental Design: We screened glioblastomas from a population-based study for IDH1 mutations and correlated them with clinical data and other genetic alterations. Results: IDH1 mutations were detected in 36 of 407 glioblastomas (8.8%). Glioblastoma patients with IDH1 mutations were younger (mean, 47.9 years) than those with EGFR amplification (60.9 years) and were associated with significantly longer survival (mean, 27.1 versus 11.3 months; P < 0.0001). IDH1 mutations were frequent in glioblastomas diagnosed as secondary (22 of 30; 73%), but rare in primary glioblastomas (14 of 377; 3.7%: P < 0.0001). IDH1 mutations as genetic marker of secondary glioblastoma corresponded to the respective clinical diagnosis in 95% of cases. Glioblastomas with IDH1 mutation diagnosed as primary had clinical and genetic profiles similar to those of secondary glioblastomas, suggesting that they may have rapidly progressed from a less malignant precursor lesion that escaped clinical diagnosis and were thus misclassified as primary. Conversely, glioblastomas without IDH1 mutations clinically diagnosed as secondary typically developed from anaplastic rather than low-grade gliomas, suggesting that at least some were actually primary glioblastomas, that may have been misclassified, possibly due to histologic sampling error. Conclusion: IDH1 mutations are a strong predictor of a more favorable prognosis and a highly selective molecular marker of secondary glioblastomas that complements clinical criteria for distinguishing them from primary glioblastomas. (Clin Cancer Res 2009;15(19):6002-7) Glioblastomas, most frequent and malignant brain tumors, may develop rapidly after a short clinical history and without evidence of a less malignant precursor lesion (primary or de novo glioblastoma), or slowly through progression from low-grade diffuse or anaplastic astrocytoma (secondary glioblastoma; refs. 1-3). These glioblastoma subtypes constitute distinct disease entities that affect patients of different age, and develop through different genetic pathways (2, 3). Because they are usually indistinguishable histologically (2-4), the distinction between primary and secondary glioblastomas is currently based on clinical data. Tumors are considered primary glioblastomas if the glioblastoma diagnosis is made at the first biopsy, without clinical or histologic evidence of a preexisting, less malignant precursor lesion. The diagnosis of secondary glioblastoma requires histologic evidence of a preceding lowgrade or anaplastic astrocytoma. At the population level, only 5% of cases were classified as secondary glioblastoma (2). However, the possibility could not be excluded that some secondary glioblastomas rapidly progressed from less malignant precursor lesions, e...

The current World Health Organization classification recognizes three histological types of grade II lowgrade diffuse glioma (diffuse astrocytoma, oligoastrocytoma, and oligodendroglioma). However, the diagnostic criteria, in particular for oligoastrocytoma, are highly subjective. The aim of our study was to establish genetic profiles for diffuse gliomas and to estimate their predictive impact. In this study, we screened 360 World Health Organization grade II gliomas for mutations in the IDH1, IDH2, and TP53 genes and for 1p/19q loss and correlated these with clinical outcome. Most tumors (86%) were characterized genetically by TP53 mutation plus IDH1/2 mutation (32%), 1p/19q loss plus IDH1/2 mutation (37%), or IDH1/2 mutation only (17%). TP53 mutations only or 1p/19q loss only was rare (2 and 3%, respectively). The median survival of patients with TP53 mutation ؎ IDH1/2 mutation was significantly shorter than that of patients with 1p/19q loss ؎ IDH1/2 mutation (51.8 months vs. 58.7 months, respectively; P ‫؍‬ 0.0037).Multivariate analysis with adjustment for age and treatment confirmed these results (P ‫؍‬ 0.0087) and also revealed that TP53 mutation is a significant prognostic marker for shorter survival (P ‫؍‬ 0.0005) and 1p/19q loss for longer survival (P ‫؍‬ 0.0002), while IDH1/2 mutations are not prognostic (P ‫؍‬ 0.8737). The molecular classification on the basis of IDH1/2 mutation, TP53 mutation, and 1p/19q loss has power similar to histological classification and avoids the ambiguity inherent to the diagnosis of oligoastrocytoma. (Am J Pathol

Olig2 is a recently identified transcription factor in-

Central nervous system high-grade neuroepithelial tumors with BCOR alteration (CNS HGNET-BCOR) are a recently reported rare entity, identified as a small fraction of tumors previously institutionally diagnosed as so-called CNS primitive neuroectodermal tumors. Their genetic characteristic is a somatic internal tandem duplication in the 3' end of BCOR (BCOR ITD), which has also been found in clear cell sarcomas of the kidney (CCSK) and soft tissue undifferentiated round cell sarcomas/primitive myxoid mesenchymal tumors of infancy (URCS/PMMTI), and these BCOR ITD-positive tumors have been reported to share similar pathological features. In this study, we performed a clinicopathological and molecular analysis of six cases of CNS HGNET-BCOR, and compared them with their counterparts in the kidney and soft tissue. Although these tumors had histologically similar structural patterns and characteristic monotonous nuclei with fine chromatin, CNS HGNET-BCOR exhibited glial cell morphology, ependymoma-like perivascular pseudorosettes and palisading necrosis, whereas these features were not evident in CCSK or URCS/PMMTI. Immunohistochemically, diffuse staining of Olig2 with a mixture of varying degrees of intensity, and only focal staining of GFAP, S-100 protein and synaptophysin were observed in CNS HGNET-BCOR, whereas these common neuroepithelial markers were negative in CCSK and URCS/PMMTI. Therefore, although CNS HGNET-BCOR, CCSK and URCS/PMMTI may constitute a group of BCOR ITD-positive tumors, only CNS HGNET-BCOR has histological features suggestive of glial differentiation. In conclusion, we think CNS HGNET-BCOR are a certain type of neuroepithelial tumor relatively close to glioma, not CCSK or URCS/PMMTI occurring in the CNS.

Pleomorphic xanthoastrocytoma (PXA) is classified by the World Health Organization as a grade II astrocytic tumor with relatively favorable prognosis among gliomas. A valine-to-glutamic acid substitution at position 600 of the serine/threonine-protein kinase BRAF (BRAF V600E) mutation, which is commonly found in PXA, has recently been detected in approximately 50% of all epithelioid glioblastoma (GBM) cases. We herein report a case of epithelioid GBM developing at the site of a left temporal PXA 13 years after the treatment of the primary tumor. The BRAF V600E mutation was detected in both tumors. These findings suggest that epithelioid GBM may arise from a PXA with a BRAF V600E mutation.

One of the type VI intermediate filament proteins, nestin, is expressed in neuroepithelial stem cells during neural embryogenesis. Nestin is also expressed in a variety of neoplasms. Its expression in brain tumors has not been thoroughly studied. The objectives of this study were to survey nestin expression in different types of brain tumor, and to evaluate nestin as a marker for diagnosis and prognosis. We used tissue microarrays of 257 brain tumors for an immunohistochemical overview of nestin expression: nestin was frequently expressed in gliomas and schwannomas. Most of the gliomas that expressed high levels of nestin were high-grade gliomas (anaplastic astrocytomas, anaplastic oligodendrogliomas, anaplastic oligoastrocytomas, and glioblastomas). We then focused on high-grade gliomas and performed immunohistochemistry again, using whole-mount slides. As a result, we found (1) significantly different nestin expression between glioblastomas and other high-grade gliomas, and (2) worse overall survival for high-grade gliomas with high nestin expression. Our results suggest that: (1) nestin is a useful marker for diagnosis of high-grade gliomas, (2) nestin is helpful in diagnosis of schwannomas, and (3) nestin expression is related to poor prognosis in high-grade gliomas.

Astroblastoma is a rare, enigmatic tumor of the central nervous system (CNS) which shares some clinicopathologic aspects with other CNS tumors, especially ependymoma. To further clarify the nature of astroblastoma, we performed clinicopathologic and molecular genetic studies on eight cases of astroblastoma. The median age of the patients was 14.5 years, ranging from 5 to 60 years, and seven of the patients were female. All tumors arose in the cerebral hemisphere and radiologically appeared to be well-bordered, nodular tumors often associated with cystic areas and contrast-enhancement. Six of the seven patients with prognosis data survived without recurrences during the follow-up periods ranging from six to 76 months. One patient had multiple recurrences and died six years later. All tumors exhibited salient microscopic features, such as being well demarcated from the surrounding brain tissue, perivascular arrangement of epithelioid tumor cells (represented by "astroblastic" pseudorosettes, trabecular alignment, and pseudopapillary patterns), and hyalinized blood vessels. Immunoreactivity for GFAP, S-100 protein, Olig2, and EMA was variably demonstrated in all tumors, and IDH1 R132H and L1CAM were negative. Array comparative genomic hybridization revealed numerous heterozygous deletions on chromosome X in the four tumors studied, and break-apart fluorescence in situ hybridization demonstrated rearrangement of MN1 in five tumors with successful testing. The characteristic clinicopathologic and genetic findings support the idea that astroblastoma is distinct from other CNS tumors, in particular, ependymoma. In addition, MN1 rearrangement and aberrations of chromosome X may partly be involved in the pathogenesis of astroblastoma.