Frequent ATRX, CIC, FUBP1 and IDH1 mutations refine the classification of malignant gliomas

Abstract

Mutations in the critical chromatin modifier ATRX and mutations in CIC and FUBP1, which are potent regulators of cell growth, have been discovered in specific subtypes of gliomas, the most common type of primary malignant brain tumors. However, the frequency of these mutations in many subtypes of gliomas, and their association with clinical features of the patients, is poorly understood. Here we analyzed these loci in 363 brain tumors. ATRX is frequently mutated in grade II-III astrocytomas (71%), oligoastrocytomas (68%), and secondary glioblastomas (57%), and ATRX mutations are associated with IDH1 mutations and with an alternative lengthening of telomeres phenotype. CIC and FUBP1 mutations occurred frequently in oligodendrogliomas (46% and 24%, respectively) but rarely in astrocytomas or oligoastrocytomas (<10%). This analysis allowed us to define two highly recurrent genetic signatures in gliomas: IDH1/ATRX (I-A) and IDH1/CIC/FUBP1 (I-CF). Patients with I-CF gliomas had a significantly longer median overall survival (96 months) than patients with I-A gliomas (51 months) and patients with gliomas that did not harbor either signature (13 months). The genetic signatures distinguished clinically distinct groups of oligoastrocytoma patients, which usually present a diagnostic challenge, and were associated with differences in clinical outcome even among individual tumor types. In addition to providing new clues about the genetic alterations underlying gliomas, the results have immediate clinical implications, providing a tripartite genetic signature that can serve as a useful adjunct to conventional glioma classification that may aid in prognosis, treatment selection, and therapeutic trial design.

Molecular classification of diffuse cerebral WHO grade II/III gliomas using genome- and transcriptome-wide profiling improves stratification of prognostically distinct patient groups

“…As expected [15,21,38], ATRX was among the top genes with higher expression in astrocytic versus oligodendroglial tumors as well as 1p/19q intact versus 1p/19q co-deleted tumors (Supplementary Tables 9-10). …”

“…Identified candidate genes included published markers such as ATRX [15,21,38] and alphainternexin (INA) [6], but also novel candidates (Supplementary Tables 7 and 8). The diagnostic utility of these candidate genes as surrogate markers for 1p/19q co-deletion, e.g.…”

“…Current molecular marker-based approaches explore the validity of a three-tiered approach delineating (i) IDH1/2-mutant tumors with 1p/19q co-deletion which often carry mutations in the Drosophila homolog of capicua (CIC) gene as well as the TERT promoter and predominantly include oligodendroglial tumors, (ii) IDH1/2 mutant tumors without 1p/19q co-deletion which often carry tumor protein p53 (TP53) as well as ATP-dependent X-linked helicase (ATRX) gene mutations and predominantly include astrocytic tumors, and (iii) IDH1/2 wild-type tumors that remain poorly characterized in terms of other molecular alterations [15,17,38]. In addition, recent data from exome sequencing of anaplastic astrocytomas suggested a distinct mutation profile from primary glioblastomas, including frequent mutations in Notch pathway genes [18].…”

Targeted genomic analysis of Müllerian adenosarcoma

“…Mutations in ATRX are common in various gliomas [37,38] and pancreatic neuroendocrine tumours [23,39]. The effect of ATRX mutation on prognosis is variable; several studies found an enhanced survival with ATRX mutation in some tumour types [39] but others report a worse prognosis [23,24].…”

Oligodendrogliomas: a short history of clinical developments

“…The clinical significance of these lesions is still unclear, and their functional impact remains speculative. Interest in telomerase activity has also been renewed in neuro-oncology, studies have shown that diffuse glioma are characterized by mutually exclusive TERT and ATRX mutations [28,29]. Surprisingly, 1p/19q co-deleted tumors have the same abnormality as glioblastoma (TERT mutations) whereas diffuse astrocytoma regardless of grade are characterized by ATRX mutations.…”