The WHO 2007 glioma classification system (based primarily on tumour histology) resulted in considerable interobserver variability and substantial variation in patient survival within grades. Furthermore, few risk factors for glioma were known. Discoveries over the past decade have deepened our understanding of the molecular alterations underlying glioma and have led to the identification of numerous genetic risk factors. The advances in molecular characterization of glioma have reframed our understanding of its biology and led to the development of a new classification system for glioma. The WHO 2016 classification system comprises five glioma subtypes, categorized by both tumour morphology and molecular genetic information, which led to reduced misclassification and improved consistency of outcomes within glioma subtypes. To date, 25 risk loci for glioma have been identified and several rare inherited mutations that might cause glioma in some families have been discovered. This Review focuses on the two dominant trends in glioma science: the characterization of diagnostic and prognostic tumour markers and the identification of genetic and other risk factors. An overview of the many challenges still facing glioma researchers is also included.
Glioma incidence differs by age, sex, ethnicity and geography whereas glioma survival varies by tumour subtype, age and sex.
In the past decade, multiple discoveries have expanded our understanding of glioma and led to a new classification system (WHO 2016) that integrates molecular alterations and histology.
The WHO 2016 classification system defines five glioma subtypes that have improved homogeneity in their clinical outcomes.
Twenty-five risk loci for glioma and several rare inherited mutations that might cause glioma in some families have been identified; however, ionizing radiation is the only confirmed environmental risk factor.
Subscribe to Journal
Get full journal access for 1 year
only $4.92 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Bray, F. et al. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin. 68, 394–424 (2018).
Ferlay, J. et al. Estimating the global cancer incidence and mortality in 2018: GLOBOCAN sources and methods. Int. J. Cancer 144, 1941–1953 (2019).
Miranda-Filho, A., Pineros, M., Soerjomataram, I., Deltour, I. & Bray, F. Cancers of the brain and CNS: global patterns and trends in incidence. Neuro Oncol. 19, 270–280 (2017).
Sanai, N., Alvarez-Buylla, A. & Berger, M. S. Neural stem cells and the origin of gliomas. N. Engl. J. Med. 353, 811–822 (2005).
Louis, D. N. et al. The 2007 WHO classification of tumours of the central nervous system. Acta Neuropathol. 114, 97–109 (2007).
Cancer Genome Atlas Research Network. Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature 455, 1061–1068 (2008).
Killela, P. J. et al. TERT promoter mutations occur frequently in gliomas and a subset of tumors derived from cells with low rates of self-renewal. Proc. Natl Acad. Sci. USA 110, 6021–6026 (2013).
Yan, H. et al. IDH1 and IDH2 mutations in gliomas. N. Engl. J. Med. 360, 765–773 (2009).
Sturm, D. et al. Hotspot mutations in H3F3A and IDH1 define distinct epigenetic and biological subgroups of glioblastoma. Cancer Cell 22, 425–437 (2012).
Brennan, C. W. et al. The somatic genomic landscape of glioblastoma. Cell 155, 462–477 (2013).
Noushmehr, H. et al. Identification of a CpG island methylator phenotype that defines a distinct subgroup of glioma. Cancer Cell 17, 510–522 (2010).
Louis, D. N. et al. The 2016 World Health Organization classification of tumors of the central nervous system: a summary. Acta Neuropathol. 131, 803–820 (2016).
Alcantara Llaguno, S. et al. Cell-of-origin susceptibility to glioblastoma formation declines with neural lineage restriction. Nat. Neurosci. 22, 545–555 (2019).
Alcantara Llaguno, S. R. & Parada, L. F. Cell of origin of glioma: biological and clinical implications. Br. J. Cancer 115, 1445–1450 (2016).
Lee, J. H. et al. Human glioblastoma arises from subventricular zone cells with low-level driver mutations. Nature 560, 243–247 (2018).
Paunu, N. et al. A novel low-penetrance locus for familial glioma at 15q23–q26.3. Cancer Res. 62, 3798–3802 (2002).
Shete, S. et al. Genome-wide high-density SNP linkage search for glioma susceptibility loci: results from the Gliogene Consortium. Cancer Res. 71, 7568–7575 (2011).
Jalali, A. et al. Targeted sequencing in chromosome 17q linkage region identifies familial glioma candidates in the Gliogene Consortium. Sci. Rep. 5, 8278 (2015).
Melin, B. S. et al. Genome-wide association study of glioma subtypes identifies specific differences in genetic susceptibility to glioblastoma and non-glioblastoma tumors. Nat. Genet. 49, 789–794 (2017).
Brat, D. J. et al. cIMPACT-NOW update 3: recommended diagnostic criteria for “Diffuse astrocytic glioma, IDH-wildtype, with molecular features of glioblastoma, WHO grade IV”. Acta Neuropathol. 136, 805–810 (2018).
Ostrom, Q. T. et al. CBTRUS statistical report: primary brain and other central nervous system tumors diagnosed in the United States in 2011–2015. Neuro Oncol. 20, iv1–iv86 (2018).
van den Bent, M. J. Interobserver variation of the histopathological diagnosis in clinical trials on glioma: a clinician’s perspective. Acta Neuropathol. 120, 297–304 (2010).
Sturm, D. et al. New brain tumor entities emerge from molecular classification of CNS-PNETs. Cell 164, 1060–1072 (2016).
Ellison, D. W. et al. Histopathological grading of pediatric ependymoma: reproducibility and clinical relevance in European trial cohorts. J. Negat. Results Biomed. 10, 7 (2011).
Wiestler, B. et al. Integrated DNA methylation and copy-number profiling identify three clinically and biologically relevant groups of anaplastic glioma. Acta Neuropathol. 128, 561–571 (2014).
Cancer Genome Atlas Research Network et al. Comprehensive, integrative genomic analysis of diffuse lower-grade gliomas. N. Engl. J. Med. 372, 2481–2498 (2015).
Eckel-Passow, J. E. et al. Glioma groups based on 1p/19q. IDH, and TERT promoter mutations in tumors. N. Engl. J. Med. 372, 2499–2508 (2015).
Parsons, D. W. et al. An integrated genomic analysis of human glioblastoma multiforme. Science 321, 1807–1812 (2008).
Balss, J. et al. Analysis of the IDH1 codon 132 mutation in brain tumors. Acta Neuropathol. 116, 597–602 (2008).
Cohen, A., Holmen, S. & Colman, H. IDH1 and IDH2 mutations in gliomas. Curr. Neurol. Neurosci. Rep. 13, 345–345 (2013).
Lai, A. et al. Evidence for sequenced molecular evolution of IDH1 mutant glioblastoma from a distinct cell of origin. J. Clin. Oncol. 29, 4482–4490 (2011).
Suzuki, H. et al. Mutational landscape and clonal architecture in grade II and III gliomas. Nat. Genet. 47, 458–468 (2015).
Jenkins, R. B. et al. A t(1;19)(q10;p10) mediates the combined deletions of 1p and 19q and predicts a better prognosis of patients with oligodendroglioma. Cancer Res. 66, 9852–9861 (2006).
Hartmann, C. et al. Patients with IDH1 wild type anaplastic astrocytomas exhibit worse prognosis than IDH1-mutated glioblastomas, and IDH1 mutation status accounts for the unfavorable prognostic effect of higher age: implications for classification of gliomas. Acta Neuropathol. 120, 707–718 (2010).
Weller, M. et al. Molecular classification of diffuse cerebral WHO grade II/III gliomas using genome- and transcriptome-wide profiling improves stratification of prognostically distinct patient groups. Acta Neuropathol. 129, 679–693 (2015).
Sahm, F. et al. Farewell to oligoastrocytoma: in situ molecular genetics favor classification as either oligodendroglioma or astrocytoma. Acta Neuropathol. 128, 551–559 (2014).
Pekmezci, M. et al. Adult infiltrating gliomas with WHO 2016 integrated diagnosis: additional prognostic roles of ATRX and TERT. Acta Neuropathol. 133, 1001–1016 (2017).
Aoki, K. et al. Prognostic relevance of genetic alterations in diffuse lower-grade gliomas. Neuro Oncol. 20, 66–77 (2018).
Reuss, D. E. et al. IDH mutant diffuse and anaplastic astrocytomas have similar age at presentation and little difference in survival: a grading problem for WHO. Acta Neuropathol. 129, 867–873 (2015).
Rice, T. et al. Understanding inherited genetic risk of adult glioma — a review. Neurooncol. Pract. 3, 10–16 (2016).
Wu, G. et al. Somatic histone H3 alterations in pediatric diffuse intrinsic pontine gliomas and non-brainstem glioblastomas. Nat. Genet. 44, 251–253 (2012).
Schwartzentruber, J. et al. Driver mutations in histone H3.3 and chromatin remodelling genes in paediatric glioblastoma. Nature 482, 226–231 (2012).
Louis, D. N. et al. cIMPACT-NOW update 2: diagnostic clarifications for diffuse midline glioma, H3 K27M-mutant and diffuse astrocytoma/anaplastic astrocytoma. IDH-mutant. Acta Neuropathol. 135, 639–642 (2018).
Louis, D. N. et al. cIMPACT-NOW update 1: not otherwise specified (NOS) and not elsewhere classified (NEC). Acta Neuropathol. 135, 481–484 (2018).
Reifenberger, G., Wirsching, H. G., Knobbe-Thomsen, C. B. & Weller, M. Advances in the molecular genetics of gliomas — implications for classification and therapy. Nat. Rev. Clin. Oncol. 14, 434–452 (2017).
Ceccarelli, M. et al. Molecular profiling reveals biologically discrete subsets and pathways of progression in diffuse glioma. Cell 164, 550–563 (2016).
Leeper, H. E. et al. IDH mutation, 1p19q codeletion and ATRX loss in WHO grade II gliomas. Oncotarget 6, 30295–30305 (2015).
Wiestler, B. et al. ATRX loss refines the classification of anaplastic gliomas and identifies a subgroup of IDH mutant astrocytic tumors with better prognosis. Acta Neuropathol. 126, 443–451 (2013).
Capper, D. et al. DNA methylation-based classification of central nervous system tumours. Nature 555, 469–474 (2018).
Christensen, B. C. et al. DNA methylation, isocitrate dehydrogenase mutation, and survival in glioma. J. Natl Cancer Inst. 103, 143–153 (2011).
Turcan, S. et al. IDH1 mutation is sufficient to establish the glioma hypermethylator phenotype. Nature 483, 479–483 (2012).
Hovestadt, V. et al. Robust molecular subgrouping and copy-number profiling of medulloblastoma from small amounts of archival tumour material using high-density DNA methylation arrays. Acta Neuropathol. 125, 913–916 (2013).
Gerson, S. L. MGMT: its role in cancer aetiology and cancer therapeutics. Nat. Rev. Cancer 4, 296–307 (2004).
Wick, W. et al. MGMT testing — the challenges for biomarker-based glioma treatment. Nat. Rev. Neurol. 10, 372 (2014).
Hegi, M. E. et al. MGMT gene silencing and benefit from temozolomide in glioblastoma. N. Engl. J. Med. 352, 997–1003 (2005).
Weller, M. et al. Molecular predictors of progression-free and overall survival in patients with newly diagnosed glioblastoma: a prospective translational study of the German Glioma Network. J. Clin. Oncol. 27, 5743–5750 (2009).
Gilbert, M. R. et al. Dose-dense temozolomide for newly diagnosed glioblastoma: a randomized phase III clinical trial. J. Clin. Oncol. 31, 4085–4091 (2013).
Malmstrom, A. et al. Temozolomide versus standard 6-week radiotherapy versus hypofractionated radiotherapy in patients older than 60 years with glioblastoma: the Nordic randomised, phase 3 trial. Lancet Oncol. 13, 916–926 (2012).
Stupp, R. et al. Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC–NCIC trial. Lancet Oncol. 10, 459–466 (2009).
Baumert, B. G. et al. Temozolomide chemotherapy versus radiotherapy in high-risk low-grade glioma (EORTC 22033–26033): a randomised, open-label, phase 3 intergroup study. Lancet Oncol. 17, 1521–1532 (2016).
Bell, E. H. et al. Association of MGMT promoter methylation status with survival outcomes in patients with high-risk glioma treated with radiotherapy and temozolomide: an analysis from the NRG Oncology/RTOG 0424 trial. JAMA Oncol. 4, 1405–1409 (2018).
Leu, S. et al. IDH/MGMT-driven molecular classification of low-grade glioma is a strong predictor for long-term survival. Neuro Oncol. 15, 469–479 (2013).
Wick, W. et al. Prognostic or predictive value of MGMT promoter methylation in gliomas depends on IDH1 mutation. Neurology 81, 1515–1522 (2013).
Yang, P. et al. IDH mutation and MGMT promoter methylation in glioblastoma: results of a prospective registry. Oncotarget 6, 40896–40906 (2015).
Nguyen, H. N. et al. Human TERT promoter mutation enables survival advantage from MGMT promoter methylation in IDH1 wild-type primary glioblastoma treated by standard chemoradiotherapy. Neuro Oncol. 19, 394–404 (2017).
Perry, J. R. et al. Short-course radiation plus temozolomide in elderly patients with glioblastoma. N. Engl. J. Med. 376, 1027–1037 (2017).
Wick, W. et al. Temozolomide chemotherapy alone versus radiotherapy alone for malignant astrocytoma in the elderly: the NOA-08 randomised, phase 3 trial. Lancet Oncol. 13, 707–715 (2012).
Hegi, M. E. et al. MGMT promoter methylation cutoff with safety margin for selecting glioblastoma patients into trials omitting temozolomide: a pooled analysis of four clinical trials. Clin. Cancer Res. 25, 1809–1816 (2018).
Reis, G. F. et al. CDKN2A loss is associated with shortened overall survival in lower-grade (World Health Organization Grades II-III) astrocytomas. J. Neuropathol. Exp. Neurol. 74, 442–452 (2015).
Shirahata, M. et al. Novel, improved grading system(s) for IDH-mutant astrocytic gliomas. Acta Neuropathol. 136, 153–166 (2018).
Korshunov, A. et al. Integrated molecular characterization of IDH-mutant glioblastomas. Neuropathol. Appl. Neurobiol. 45, 108–118 (2019).
Ostrom, Q. T. et al. The epidemiology of glioma in adults: a “state of the science” review. Neuro Oncol. 16, 896–913 (2014).
Ostrom, Q. T. et al. CBTRUS statistical report: primary brain and central nervous system tumors diagnosed in the United States in 2006–2010. Neuro Oncol. 15, ii1–ii56 (2013).
Arora, R. S. et al. Age-incidence patterns of primary CNS tumors in children, adolescents, and adults in England. Neuro Oncol. 11, 403–413 (2009).
Lee, C. H., Jung, K. W., Yoo, H., Park, S. & Lee, S. H. Epidemiology of primary brain and central nervous system tumors in Korea. J. Korean Neurosurg. Soc. 48, 145–152 (2010).
Dobes, M. et al. Increasing incidence of glioblastoma multiforme and meningioma, and decreasing incidence of schwannoma (2000–2008): findings of a multicenter Australian study. Surg. Neurol. Int. 2, 176 (2011).
Gousias, K. et al. Descriptive epidemiology of cerebral gliomas in northwest Greece and study of potential predisposing factors, 2005–2007. Neuroepidemiology 33, 89–95 (2009).
International Agency for Research on Cancer. Cancer Incidence in Five Continents Vol. X (eds Forman, D. et al.) (IARC, 2014).
Leece, R. et al. Global incidence of malignant brain and other central nervous system tumors by histology, 2003–2007. Neuro Oncol. 19, 1553–1564 (2017).
Jacobs, D. et al. Leveraging ethnic group incidence variation to investigate genetic susceptibility to glioma: a novel candidate SNP approach. Front. Genet. 3, 203 (2012).
Ostrom, Q. T., Cote, D. J., Ascha, M., Kruchko, C. & Barnholtz-Sloan, J. S. Adult glioma incidence and survival by race or ethnicity in the United States from 2000 to 2014. JAMA Oncol. 4, 1254–1262 (2018).
US Department of Health and Human Services. SEER cancer statistics review (CSR) 1975–2015. SEER https://seer.cancer.gov/csr/1975_2015/ (2018).
Little, M. P. et al. Mobile phone use and glioma risk: comparison of epidemiological study results with incidence trends in the United States. BMJ 344, e1147 (2012).
Deltour, I. et al. Mobile phone use and incidence of glioma in the Nordic countries 1979–2008: consistency check. Epidemiology 23, 301–307 (2012).
Surawicz, T. S. et al. Descriptive epidemiology of primary brain and CNS tumors: results from the Central Brain Tumor Registry of the United States, 1990–1994. Neuro Oncol. 1, 14–25 (1999).
Ostrom, Q. T. et al. Sex-specific glioma genome-wide association study identifies new risk locus at 3p21.31 in females, and finds sex-differences in risk at 8q24.21. Sci. Rep. 8, 7352 (2018).
Crocetti, E. et al. Epidemiology of glial and non-glial brain tumours in Europe. Eur. J. Cancer 48, 1532–1542 (2012).
Ho, V. K. et al. Changing incidence and improved survival of gliomas. Eur. J. Cancer 50, 2309–2318 (2014).
Benson, V. S., Kirichek, O., Beral, V. & Green, J. Menopausal hormone therapy and central nervous system tumor risk: large UK prospective study and meta-analysis. Int. J. Cancer 136, 2369–2377 (2015).
Kabat, G. C., Park, Y., Hollenbeck, A. R., Schatzkin, A. & Rohan, T. E. Reproductive factors and exogenous hormone use and risk of adult glioma in women in the NIH-AARP diet and health study. Int. J. Cancer 128, 944–950 (2011).
Zong, H. et al. Reproductive factors in relation to risk of brain tumors in women: an updated meta-analysis of 27 independent studies. Tumour Biol. 35, 11579–11586 (2014).
Wigertz, A. et al. Risk of brain tumors associated with exposure to exogenous female sex hormones. Am. J. Epidemiol. 164, 629–636 (2006).
Sanai, N., Mirzadeh, Z. & Berger, M. S. Functional outcome after language mapping for glioma resection. N. Engl. J. Med. 358, 18–27 (2008).
Sanai, N., Polley, M. Y., McDermott, M. W., Parsa, A. T. & Berger, M. S. An extent of resection threshold for newly diagnosed glioblastomas. J. Neurosurg. 115, 3–8 (2011).
Marko, N. F. et al. Extent of resection of glioblastoma revisited: personalized survival modeling facilitates more accurate survival prediction and supports a maximum-safe-resection approach to surgery. J. Clin. Oncol. 32, 774–782 (2014).
Jakola, A. S. et al. Comparison of a strategy favoring early surgical resection versus a strategy favoring watchful waiting in low-grade gliomas. JAMA 308, 1881–1888 (2012).
Claus, E. B. et al. Survival and low-grade glioma: the emergence of genetic information. Neurosurg. Focus 38, E6 (2015).
Stupp, R., van den Bent, M. J. & Hegi, M. E. Optimal role of temozolomide in the treatment of malignant gliomas. Curr. Neurol. Neurosci. Rep. 5, 198–206 (2005).
Dubrow, R. et al. Time trends in glioblastoma multiforme survival: the role of temozolomide. Neuro Oncol. 15, 1750–1761 (2013).
Johnson, D. R., Ma, D. J., Buckner, J. C. & Hammack, J. E. Conditional probability of long-term survival in glioblastoma: a population-based analysis. Cancer 118, 5608–5613 (2012).
Darefsky, A. S., King, J. T. Jr & Dubrow, R. Adult glioblastoma multiforme survival in the temozolomide era: a population-based analysis of Surveillance, Epidemiology, and End Results registries. Cancer 118, 2163–2172 (2012).
Koshy, M. et al. Improved survival time trends for glioblastoma using the SEER 17 population-based registries. J. Neurooncol. 107, 207–212 (2012).
Chinot, O. L. et al. Bevacizumab plus radiotherapy-temozolomide for newly diagnosed glioblastoma. N. Engl. J. Med. 370, 709–722 (2014).
Gilbert, M. R. et al. A randomized trial of bevacizumab for newly diagnosed glioblastoma. N. Engl. J. Med. 370, 699–708 (2014).
Porter, K. R., McCarthy, B. J., Berbaum, M. L. & Davis, F. G. Conditional survival of all primary brain tumor patients by age, behavior, and histology. Neuroepidemiology 36, 230–239 (2011).
Farah, P. et al. Conditional survival after diagnosis with malignant brain and central nervous system tumor in the United States, 1995–2012. J. Neurooncol. 128, 419–429 (2016).
Lindor, N. M. et al. Concise handbook of familial cancer susceptibility syndromes — second edition. J. Natl Cancer Inst. Monogr. 2008, 3–93 (2008).
Kyritsis, A. P., Bondy, M. L., Rao, J. S. & Sioka, C. Inherited predisposition to glioma. Neuro Oncol. 12, 104–113 (2010).
D’Angelo, F. et al. The molecular landscape of glioma in patients with neurofibromatosis 1. Nat. Med. 25, 176–187 (2019).
Hartmann, C. et al. Type and frequency of IDH1 and IDH2 mutations are related to astrocytic and oligodendroglial differentiation and age: a study of 1,010 diffuse gliomas. Acta Neuropathol. 118, 469–474 (2009).
Hayes, J. et al. Genomic analysis of the origins and evolution of multicentric diffuse lower-grade gliomas. Neuro Oncol. 20, 632–641 (2018).
Ohgaki, H. & Kleihues, P. The definition of primary and secondary glioblastoma. Clin. Cancer Res. 19, 764–772 (2013).
Robertson, L. B. et al. Survey of familial glioma and role of germline p16 INK4A /p14 ARF and p53 mutation. Fam. Cancer 9, 413–421 (2010).
Malmer, B., Gronberg, H., Bergenheim, A. T., Lenner, P. & Henriksson, R. Familial aggregation of astrocytoma in northern Sweden: an epidemiological cohort study. Int. J. Cancer 81, 366–370 (1999).
Wrensch, M. et al. Familial and personal medical history of cancer and nervous system conditions among adults with glioma and controls. Am. J. Epidemiol. 145, 581–593 (1997).
Hemminki, K., Tretli, S., Sundquist, J., Johannesen, T. B. & Granstrom, C. Familial risks in nervous-system tumours: a histology-specific analysis from Sweden and Norway. Lancet Oncol. 10, 481–488 (2009).
Malmer, B. et al. Genetic epidemiology of glioma. Br. J. Cancer 84, 429–434 (2001).
de Andrade, M. et al. Segregation analysis of cancer in families of glioma patients. Genet. Epidemiol. 20, 258–270 (2001).
Bainbridge, M. N. et al. Germline mutations in shelterin complex genes are associated with familial glioma. J. Natl Cancer Inst. 107, 384 (2015).
Wrensch, M. et al. Variants in the CDKN2B and RTEL1 regions are associated with high-grade glioma susceptibility. Nat. Genet. 41, 905–908 (2009).
Kinnersley, B. et al. Genome-wide association study identifies multiple susceptibility loci for glioma. Nat. Commun. 6, 8559 (2015).
Sanson, M. et al. Chromosome 7p11.2 (EGFR) variation influences glioma risk. Hum. Mol. Genet. 20, 2897–2904 (2011).
Jenkins, R. B. et al. A low-frequency variant at 8q24.21 is strongly associated with risk of oligodendroglial tumors and astrocytomas with IDH1 or IDH2 mutation. Nat. Genet. 44, 1122–1125 (2012).
Enciso-Mora, V. et al. Deciphering the 8q24.21 association for glioma. Hum. Mol. Genet. 22, 2293–2302 (2013).
Eckel-Passow, J. E. et al. Using germline variants to estimate glioma and subtype risks. Neuro Oncol. 21, 451–461 (2019).
Labreche, K. et al. Diffuse gliomas classified by 1p/19q co-deletion. TERT promoter and IDH mutation status are associated with specific genetic risk loci. Acta Neuropathol. 135, 743–755 (2018).
Killedar, A. et al. A common cancer risk-associated allele in the hTERT locus encodes a dominant negative inhibitor of telomerase. PLOS Genet. 11, e1005286 (2015).
Telomeres Mendelian Randomization Collaboration et al. Association between telomere length and risk of cancer and non-neoplastic diseases: a mendelian randomization study. JAMA Oncol. 3, 636–651 (2017).
Ostrom, Q. T., Gittleman, H., Stetson, L., Virk, S. & Barnholtz-Sloan, J. Epidemiology of intracranial gliomas. Prog. Neurol. Surg. 30, 1–11 (2018).
Wang, L. E. et al. Polymorphisms of DNA repair genes and risk of glioma. Cancer Res. 64, 5560–5563 (2004).
Preston, D. L. et al. Tumors of the nervous system and pituitary gland associated with atomic bomb radiation exposure. J. Natl Cancer Inst. 94, 1555–1563 (2002).
Sadetzki, S. et al. Long-term follow-up for brain tumor development after childhood exposure to ionizing radiation for tinea capitis. Radiat. Res. 163, 424–432 (2005).
Neglia, J. P. et al. New primary neoplasms of the central nervous system in survivors of childhood cancer: a report from the Childhood Cancer Survivor Study. J. Natl Cancer Inst. 98, 1528–1537 (2006).
Pearce, M. S. et al. Radiation exposure from CT scans in childhood and subsequent risk of leukaemia and brain tumours: a retrospective cohort study. Lancet 380, 499–505 (2012).
IARC Working Group on the Evaluation of Carcinogenic Risk to Humans. Non-Ionizing Radiation, Part 2: Radiofrequency Electromagnetic Fields Vol. 102 (IARC, 2013).
Grayson, J. K. Radiation exposure, socioeconomic status, and brain tumor risk in the US Air Force: a nested case–control study. Am. J. Epidemiol. 143, 480–486 (1996).
Cardis, E. et al. The INTERPHONE study: design, epidemiological methods, and description of the study population. Eur. J. Epidemiol. 22, 647–664 (2007).
Vila, J. et al. Occupational exposure to high-frequency electromagnetic fields and brain tumor risk in the INTEROCC study: an individualized assessment approach. Environ. Int. 119, 353–365 (2018).
Amirian, E. S. et al. Approaching a scientific consensus on the association between allergies and glioma risk: a report from the glioma international case–control study. Cancer Epidemiol. Biomarkers Prev. 25, 282–290 (2016).
Linos, E., Raine, T., Alonso, A. & Michaud, D. Atopy and risk of brain tumors: a meta-analysis. J. Natl Cancer Inst. 99, 1544–1550 (2007).
Disney-Hogg, L. et al. Impact of atopy on risk of glioma: a mendelian randomisation study. BMC Med. 16, 42 (2018).
Wiemels, J. L. et al. Reduced immunoglobulin E and allergy among adults with glioma compared with controls. Cancer Res. 64, 8468–8473 (2004).
Wiemels, J. L. et al. History of allergies among adults with glioma and controls. Int. J. Cancer 98, 609–615 (2002).
Schwartzbaum, J. et al. Association between prediagnostic IgE levels and risk of glioma. J. Natl Cancer Inst. 104, 1251–1259 (2012).
Wiemels, J. L. et al. IgE, allergy, and risk of glioma: update from the San Francisco Bay Area Adult Glioma Study in the temozolomide era. Int. J. Cancer 125, 680–687 (2009).
Brooks, W. H., Roszman, T. L., Mahaley, M. S. & Woosley, R. E. Immunobiology of primary intracranial tumours. II. Analysis of lymphocyte subpopulations in patients with primary brain tumours. Clin. Exp. Immunol. 29, 61–66 (1977).
Dix, A. R., Brooks, W. H., Roszman, T. L. & Morford, L. A. Immune defects observed in patients with primary malignant brain tumors. J. Neuroimmunol. 100, 216–232 (1999).
Grossman, S. A. et al. Immunosuppression in patients with high-grade gliomas treated with radiation and temozolomide. Clin. Cancer Res. 17, 5473–5480 (2011).
Hughes, M. A., Parisi, M., Grossman, S. & Kleinberg, L. Primary brain tumors treated with steroids and radiotherapy: low CD4 counts and risk of infection. Int. J. Radiat. Oncol. Biol. Phys. 62, 1423–1426 (2005).
Bambury, R. M. et al. The association of pre-treatment neutrophil to lymphocyte ratio with overall survival in patients with glioblastoma multiforme. J. Neurooncol. 114, 149–154 (2013).
Dubinski, D. et al. CD4+ T effector memory cell dysfunction is associated with the accumulation of granulocytic myeloid-derived suppressor cells in glioblastoma patients. Neuro Oncol. 18, 807–818 (2016).
Gabrusiewicz, K. et al. Glioblastoma-infiltrated innate immune cells resemble M0 macrophage phenotype. JCI Insight 1, e85841 (2016).
Gielen, P. R. et al. Increase in both CD14-positive and CD15-positive myeloid-derived suppressor cell subpopulations in the blood of patients with glioma but predominance of CD15-positive myeloid-derived suppressor cells in glioma tissue. J. Neuropathol. Exp. Neurol. 74, 390–400 (2015).
Mason, M. et al. Neutrophil–lymphocyte ratio dynamics during concurrent chemo-radiotherapy for glioblastoma is an independent predictor for overall survival. J. Neurooncol. 132, 463–471 (2017).
Chongsathidkiet, P. et al. Sequestration of T cells in bone marrow in the setting of glioblastoma and other intracranial tumors. Nat. Med. 24, 1459–1468 (2018).
Wiencke, J. K. et al. Epigenetic biomarkers of T cells in human glioma. Epigenetics 7, 1391–1402 (2012).
Wiencke, J. K. et al. Immunomethylomic approach to explore the blood neutrophil lymphocyte ratio (NLR) in glioma survival. Clin. Epigenet. 9, 10 (2017).
Ruder, A. M. et al. The Upper Midwest Health Study: industry and occupation of glioma cases and controls. Am. J. Ind. Med. 55, 747–755 (2012).
Yiin, J. H. et al. The Upper Midwest Health Study: a case–control study of pesticide applicators and risk of glioma. Environ. Health 11, 39 (2012).
Li, H. X. et al. A meta-analysis of association between pesticides exposure and glioma risk in adults. J. Craniofac. Surg. 26, e672–e673 (2015).
Wiedmann, M. K. H. et al. Overweight, obesity and height as risk factors for meningioma, glioma, pituitary adenoma and nerve sheath tumor: a large population-based prospective cohort study. Acta Oncol. 56, 1302–1309 (2017).
Kitahara, C. M., Gamborg, M., Rajaraman, P., Sorensen, T. I. & Baker, J. L. A prospective study of height and body mass index in childhood, birth weight, and risk of adult glioma over 40 years of follow-up. Am. J. Epidemiol. 180, 821–829 (2014).
Niedermaier, T. et al. Body mass index, physical activity, and risk of adult meningioma and glioma: a meta-analysis. Neurology 85, 1342–1350 (2015).
Braganza, M. Z. et al. Cigarette smoking, alcohol intake, and risk of glioma in the NIH-AARP Diet and Health Study. Br. J. Cancer 110, 242–248 (2014).
Li, H. X. et al. Cigarette smoking and risk of adult glioma: a meta-analysis of 24 observational studies involving more than 2.3 million individuals. Onco Targets Ther. 9, 3511–3523 (2016).
Inskip, P. D., Mellemkjaer, L., Gridley, G. & Olsen, J. H. Incidence of intracranial tumors following hospitalization for head injuries (Denmark). Cancer Causes Control 9, 109–116 (1998).
Nygren, C. et al. Primary brain tumors following traumatic brain injury — a population-based cohort study in Sweden. Cancer Causes Control 12, 733–737 (2001).
Chen, Y. H., Keller, J. J., Kang, J. H. & Lin, H. C. Association between traumatic brain injury and the subsequent risk of brain cancer. J. Neurotrauma 29, 1328–1333 (2012).
Munch, T. N., Gortz, S., Wohlfahrt, J. & Melbye, M. The long-term risk of malignant astrocytic tumors after structural brain injury — a nationwide cohort study. Neuro Oncol. 17, 718–724 (2015).
The authors thank K. Probst for his artistic support and T. Rice, S. Lin, G. Warrier, P. Chunduru and Y. Zhang for their analytical support. The authors also thank L. McCoy, J. Phillips, J. Clarke, P. Bracci, Q. Ostrom, J. Barnholtz-Sloan, C. Kruchko, R. Jenkins, J. Eckel-Passow, A. Perry, M. Pekmezci, S. Chang and M. Berger for help with data, their ongoing insights and intellectual support. The authors’ research work is supported by NIH grant number P50CA09725 and the loglio collective (to all four authors), R01 CA207360 (to A.M.M., J.K.W. and M.R.W.), the Lewis Chair in Brain Tumor Research (held by M.R.W.) and the Robert Magnin Newman Chair in Neuro-oncology (held by J.K.W.).
Nature Reviews Neurology thanks M. Hegi, W. Wick and J. Schwartzbaum for their contribution to the peer review of this work.
The authors declare no competing interests.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
About this article
Cite this article
Molinaro, A.M., Taylor, J.W., Wiencke, J.K. et al. Genetic and molecular epidemiology of adult diffuse glioma. Nat Rev Neurol 15, 405–417 (2019). https://doi.org/10.1038/s41582-019-0220-2
Cancer & Metabolism (2021)
Mutation-based clustering and classification analysis reveals distinctive age groups and age-related biomarkers for glioma
BMC Medical Informatics and Decision Making (2021)
Focused ultrasound mediated blood–brain barrier opening is safe and feasible in a murine pontine glioma model
Scientific Reports (2021)
Functional connectivity of the default mode, dorsal attention and fronto-parietal executive control networks in glial tumor patients
Journal of Neuro-Oncology (2021)
High-dose salvage re-irradiation for recurrent/progressive adult diffuse glioma: healing or hurting?
Clinical and Translational Oncology (2021)