Human Cancer Biology IDH1 Mutations as Molecular Signature and Predictive Factor of Secondary Glioblastomas

Purpose: To establish the frequency of IDH1mutations 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):OF1–6) 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, escaped clinical diagnosis, and were thus misclassified as primary glioblastomas. IDH1 mutations have recently been identified in an analysis of 20,661 protein-coding genes in glioblastomas (5). Interestingly, many of the glioblastomas carrying IDH1 mutations had features of secondary glioblastoma and contained TP53 mutations (5). Subsequent studies showed that low-grade astrocytomas, oligoastrocytomas, oligodendrogliomas, and secondary glioblastomas frequently (>70% of cases) carry an IDH1 mutation (6–8). IDH1 mutations have been reported rare or absent in primary glioblastomas, other nervous system tumors (6, 7), or a variety of neoplasms at other organ sites (8, 9). The objective of the present study was to establish the frequency of IDH1 mutations in glioblastomas at the population Authors' Affiliations: International Agency for Research on Cancer (IARC), Lyon, France, and Department of Pathology, University Hospital Zürich, Zürich, Switzerland Received 3/25/09; revised 6/19/09; accepted 7/1/09; published OnlineFirst 9/15/09. Grant support: Foundation for Promotion of Cancer Research, Japan. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be herebymarked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Requests for reprints: Hiroko Ohgaki, Molecular Pathology Section, IARC, 150 cours Albert Thomas, 69372 Lyon, France. Phone: 33-472-73-85-34; Fax: 33-472-73-86-98; E-mail: [email protected]. F 2009 American Association for Cancer Research. doi:10.1158/1078-0432.CCR-09-0715 OF1 Clin Cancer Res 2009;15(19) October 1, 2009 www.aacrjournals.org Published Online First on September 15, 2009 as 10.1158/1078-0432.CCR-09-0715 Research. on April 14, 2017. © 2009 American Association for Cancer clincancerres.aacrjournals.org Downloaded from Published OnlineFirst September 15, 2009; DOI: 10.1158/1078-0432.CCR-09-0715