**3. The genetic risk of glioma**

The lifetime risk of gliomas is 4-5 per 1000 of the general population. Thus, inheriting of one of the low penetrance glioma risk variants may increase the risk by 20-40% to approximately 6 per 1000 [2]. The risk loci of glioma variants have been identified as ten inherited variants near eight genes, 2 with stratification leading to an increase in the risk of developing gliomas.

The common inherited variants are named for the nearby genes of TERC, TERT, EGFR, CDKN2B, PHLDB1, CCDC26, TP53 and RTEL1, and are not directly involved in protein coding [3]. Of interest, these variants increase the odds ratio of gliomagenesis on a scale of 1.2– 1.4. TERT, TERC, and RTEL1 are involved in telomere maintenance, and it has been hypothe‐ sized that a longer telomere length may possibly contribute to risk of gliomas [4, 5]. Additionally, of note, is the predictive and prognostic value of gliomas with TERT gene promoter mutations in association with isocitrate dehydrogenase (IDH) mutations and loss of heterozygosity of 1p/19q [4]. The less common risk loci are noted to correlate with higher odds ratios, and these are located near TP53 (2.4-fold increase in relative risk) and CCDC26 (6.3-fold increase in relative risk) especially in the presence of an IDH mutation or an oligodendro‐ glial component. Moreover, the UCSF Adult Glioma Study noted that population screening for the risk loci near the CCDC26 yielded significantly more false positives than true posi‐ tives, and hence the yield for undertaking this screening test of risk loci was extremely low [2].

At this point, with our current knowledge arsenal, the authors advise the following three acquired molecular glioblastoma markers to be identified and then further correlate to survival and outcome: IDH mutation, 1p/19q, and TERT promoter mutation. These molecular glio‐ blastoma markers are then further subdivided into five glioma subgroups to further elicit the pathways of gliomas in pathways: TERT mutated only (most common in approximately half of the cases), IDH mutated only, TERT and IDH mutation (least common), triple negative and triple positive [6, 7]. Of note, the IDH mutation status was analyzed in the BELOB trial, which showed a lower median overall survival for patients with wild-type IDH (8 months) com‐ pared with median survival of 20 months for patients with an IDH mutational status [8]. We also note here, in our clinical role as Neurosurgical Oncologists, of the recent landmark paper associating a definite survival benefit after maximal surgical resection, including both enhancing and nonenhancing tumor, resulting in an improved prognosis observed in the IDH1 mutant subgroup [9]. Thus, individualized surgical strategies for high-grade gliomas must be considered on the molecular IDH marker status of the tumor [10].

The recent development of a targeted next-generation sequencing panel (GlioSeq) provides simultaneous, highly accurate and comprehensive genetic profiling of a wide array of central nervous system (CNS) tumors on an increasingly smaller volumes of biopsies in a single workflow format [11]. This next-generation assay allows simultaneous detection of the major mutations (>1360 hot spots in 30 CNS tumor-related genes) in addition to 14 gene fusions and 24 gene copy number changes in a rapid and cost-effective manner. We look forward to the incorporation of the versatile GlioSeq as a high throughput technological advance to rapidly identify a variety of genetic alterations and small deletions, thereby assisting in diagnosis and prognostic stratification of brain tumors.

Finally, the Neuro-Oncology community looks forward to the Glioma International Case-Control Consortium undertaking the important task of identification of new risk loci by the genotyping of 4000 glioma and 4000 nonglioma patients in the Epi4K project (epgb.org/epi4k).
