Finding
Immunohistochemical INA analysis can be used routinely and is a simple and valuable prognostic and predictive factor for adjuvant chemotherapy [8–10].
Paper
Can molecular markers help with decision making?
Citations: 1
Full textAbstract
WHO classification system remains unsatisfactory due to its lack of reproducibility [1] and lack of precision in terms of prognosis. Tumors that share identical histopathological features can actually represent multiple distinct molecular phenotypes. Several molecular markers provide prognostic information and may help in decision when providing predictive information. Early-retrospective studies suggested that the codeletion of chromosome 1p and 19q was a predictor of response to chemotherapy and longer progression-free survival in anaplastic oligodendrogliomas [2]. In both low-grade and anaplastic oligodendrogliomas, 1p19q codeletion was associated with longer progression-free survival and overall survival whatever the treatment [3–5]. Until recently, it was still unclear whether 1p19q loss was predictive for chemotherapy or merely indicates a different natural history [6, 7]: recent RTOG (Radiation Therapy Oncology Group) 9402 and EORTC 26951 update shows unambigously neardoubling of median survival times (14.7 versus 7.3 years in the RTOG study) of patients with 1p19q codeleted grade III gliomas treated with chemotherapy and radiation therapy (RT) versus RT alone, whereas patients without codeletion have a poor survival (2.6–2.7 years) and no substantial benefit of adjuvant chemotherapy (G. Cairncross and M. van den Bent, unpublished data). The 1p19q codeleted gliomas overexpress proneural genes: one of them is INA which encodes α-internexin (INA). Immunohistochemical INA analysis can be used routinely and is a simple and valuable prognostic and predictive factor for adjuvant chemotherapy [8–10]. The recurrent IDH1 mutation is restricted to the 132 residue of the IDH1 gene, the majority (>90%) being a CGT→ CAT change, leading to an Arg→His substitution [11]. Some patients without IDH1 mutations harbor a mutation in the analogous amino acid residue (Arg) of the mitochondrial isoform IDH2 [12]. IDH1/IDH2 mutation is inversely correlated with grade, affecting nearly 3/4 of WHO grade 2, half of WHO grade 3 gliomas, and only 5% of primary glioblastomas [13], whereas 80% of secondary glioblastomas are IDH1/IDH2 mutated [14]. IDH1/IDH2 mutations are extremely rare in non-glial malignancies and infrequent in pilocytic astrocytomas [12, 15]. IDH1/IDH2 mutational status is therefore also a useful diagnostic marker of glioma versus other intracranial tumors and may help to differentiate grade 2 gliomas from pilocytic astrocytomas, or secondary glioblastomas from primary glioblastomas [16]. This is considerably facilitated by the development of two monoclonal antibodies specifically targeted against the IDH1 R132H mutation [17, 18] and, above all, by non-invasive determination of IDH1/IDH2 mutational status, such as 2-HG dosage by Spectro-magnetic resonance imaging [19, 20]. IDH1/IDH2-mutated tumors have a better outcome, whatever grade considered [13, 14, 21]. Whether IDH1/IDH2 mutation can predict response to treatment in gliomas needs to be further investigated [22]. The mutation causes the loss of the isocitrate dehydrogenase function and the gain of an α-ketoglutarate reductase function leading to the cellular accumulation of D-2-hydroxyglutarate (D-2HG). The rate of D-2HG in IDH1-mutated tumors is increased by a factor of >100, thus representing a diagnostic marker (this change is almost specific for gliomas) and prognostic (mutated gliomas have longer survival) of interest. The accumulation of 2-HG is directly involved in histone and DNA methylkation. Interestingly IDH1/IDH2 mutations are tightly associated with genetic profile (IDH1 or IDH2 mutation is a constant feature in 1p19q-codeleted gliomas [23]) and with the methylation of MGMT promoter, and more generally with a methylation profile [24, 25]. MGMT removes alkyl groups from the O position of guanine [26] and is supposed to limit the effectiveness of alkylating agents [27]. Epigenetic silencing of the MGMT gene by promoter methylation is associated with the loss of MGMT expression [26]. Based on the initial studies in glioblastomas and on its biological role, MGMT promoter methylation has been mostly considered as a predictive factor of response to chemotherapy. In fact, recent studies showed that MGMT promoter methylation is also predictive of better response to radiotherapy, suggesting that it may be a marker of better therapeutic response [28]. In glioblastomas, the EORTC/NCIC 26981/22981 clinical trial showed a clear benefit of concomitant and adjuvant temozolomide (TMZ) to RT for patients with MGMT promoter methylation (overall survival = 27.2% at 2 years, 16.0% at 3 years, and 9.8% at 5 years versus 10.9%, 4.4%, and 3.0% for patients receiving radiotherapy alone) but not for *Correspondence to: Prof. M. Sanson, Department of Neurology, Groupe Hospitalier Pitié-Salpêtrière, UPMC, 75651, Paris cedex 13, France. Tel: +33-1-42-16-03-91; Fax: +33-1-42-16-03-75; E-mail: marc.sanson@psl.ap-hop-paris.fr sy m po si um ar tic le symposium article Annals of Oncology 23 (Supplement 10): x25–x27, 2012 doi:10.1093/annonc/mds320
Authors
M. Sanson
Journal
Annals of oncology : official journal of the European Society for Medical Oncology