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Genetic and molecular epidemiology of adult diffuse glioma

Abstract

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.

Key points

  • 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.

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Fig. 1: The principal molecular subtypes included in the WHO 2016 classification of newly diagnosed adult diffuse glioma.
Fig. 2: Annual average age-adjusted incidence and relative survival data for non-glioblastoma and glioblastoma CNS tumours.
Fig. 3: Heritable germline risk factors for the WHO 2016 subtypes of adult glioma.
Fig. 4: Hypothesized pathways of glioma development.

References

  1. 1.

    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).

    PubMed  Google Scholar 

  2. 2.

    Ferlay, J. et al. Estimating the global cancer incidence and mortality in 2018: GLOBOCAN sources and methods. Int. J. Cancer 144, 1941–1953 (2019).

    CAS  PubMed  Google Scholar 

  3. 3.

    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).

    PubMed  Google Scholar 

  4. 4.

    Sanai, N., Alvarez-Buylla, A. & Berger, M. S. Neural stem cells and the origin of gliomas. N. Engl. J. Med. 353, 811–822 (2005).

    CAS  PubMed  Google Scholar 

  5. 5.

    Louis, D. N. et al. The 2007 WHO classification of tumours of the central nervous system. Acta Neuropathol. 114, 97–109 (2007).

    PubMed  PubMed Central  Google Scholar 

  6. 6.

    Cancer Genome Atlas Research Network. Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature 455, 1061–1068 (2008).

    Google Scholar 

  7. 7.

    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).

    CAS  PubMed  Google Scholar 

  8. 8.

    Yan, H. et al. IDH1 and IDH2 mutations in gliomas. N. Engl. J. Med. 360, 765–773 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. 9.

    Sturm, D. et al. Hotspot mutations in H3F3A and IDH1 define distinct epigenetic and biological subgroups of glioblastoma. Cancer Cell 22, 425–437 (2012).

    CAS  PubMed  Google Scholar 

  10. 10.

    Brennan, C. W. et al. The somatic genomic landscape of glioblastoma. Cell 155, 462–477 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. 11.

    Noushmehr, H. et al. Identification of a CpG island methylator phenotype that defines a distinct subgroup of glioma. Cancer Cell 17, 510–522 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. 12.

    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).

    PubMed  Google Scholar 

  13. 13.

    Alcantara Llaguno, S. et al. Cell-of-origin susceptibility to glioblastoma formation declines with neural lineage restriction. Nat. Neurosci. 22, 545–555 (2019).

    PubMed  Google Scholar 

  14. 14.

    Alcantara Llaguno, S. R. & Parada, L. F. Cell of origin of glioma: biological and clinical implications. Br. J. Cancer 115, 1445–1450 (2016).

    PubMed  PubMed Central  Google Scholar 

  15. 15.

    Lee, J. H. et al. Human glioblastoma arises from subventricular zone cells with low-level driver mutations. Nature 560, 243–247 (2018).

    CAS  PubMed  Google Scholar 

  16. 16.

    Paunu, N. et al. A novel low-penetrance locus for familial glioma at 15q23–q26.3. Cancer Res. 62, 3798–3802 (2002).

    CAS  PubMed  Google Scholar 

  17. 17.

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. 18.

    Jalali, A. et al. Targeted sequencing in chromosome 17q linkage region identifies familial glioma candidates in the Gliogene Consortium. Sci. Rep. 5, 8278 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. 19.

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. 20.

    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).

    CAS  PubMed  Google Scholar 

  21. 21.

    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).

    PubMed  Google Scholar 

  22. 22.

    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).

    PubMed  PubMed Central  Google Scholar 

  23. 23.

    Sturm, D. et al. New brain tumor entities emerge from molecular classification of CNS-PNETs. Cell 164, 1060–1072 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. 24.

    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).

    PubMed  PubMed Central  Google Scholar 

  25. 25.

    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).

    CAS  PubMed  Google Scholar 

  26. 26.

    Cancer Genome Atlas Research Network et al. Comprehensive, integrative genomic analysis of diffuse lower-grade gliomas. N. Engl. J. Med. 372, 2481–2498 (2015).

    Google Scholar 

  27. 27.

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. 28.

    Parsons, D. W. et al. An integrated genomic analysis of human glioblastoma multiforme. Science 321, 1807–1812 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. 29.

    Balss, J. et al. Analysis of the IDH1 codon 132 mutation in brain tumors. Acta Neuropathol. 116, 597–602 (2008).

    CAS  PubMed  Google Scholar 

  30. 30.

    Cohen, A., Holmen, S. & Colman, H. IDH1 and IDH2 mutations in gliomas. Curr. Neurol. Neurosci. Rep. 13, 345–345 (2013).

    PubMed  PubMed Central  Google Scholar 

  31. 31.

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. 32.

    Suzuki, H. et al. Mutational landscape and clonal architecture in grade II and III gliomas. Nat. Genet. 47, 458–468 (2015).

    CAS  PubMed  Google Scholar 

  33. 33.

    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).

    CAS  PubMed  Google Scholar 

  34. 34.

    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).

    PubMed  Google Scholar 

  35. 35.

    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).

    CAS  PubMed  Google Scholar 

  36. 36.

    Sahm, F. et al. Farewell to oligoastrocytoma: in situ molecular genetics favor classification as either oligodendroglioma or astrocytoma. Acta Neuropathol. 128, 551–559 (2014).

    CAS  PubMed  Google Scholar 

  37. 37.

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. 38.

    Aoki, K. et al. Prognostic relevance of genetic alterations in diffuse lower-grade gliomas. Neuro Oncol. 20, 66–77 (2018).

    CAS  PubMed  Google Scholar 

  39. 39.

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. 40.

    Rice, T. et al. Understanding inherited genetic risk of adult glioma — a review. Neurooncol. Pract. 3, 10–16 (2016).

    PubMed  Google Scholar 

  41. 41.

    Wu, G. et al. Somatic histone H3 alterations in pediatric diffuse intrinsic pontine gliomas and non-brainstem glioblastomas. Nat. Genet. 44, 251–253 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. 42.

    Schwartzentruber, J. et al. Driver mutations in histone H3.3 and chromatin remodelling genes in paediatric glioblastoma. Nature 482, 226–231 (2012).

    CAS  PubMed  Google Scholar 

  43. 43.

    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).

    PubMed  Google Scholar 

  44. 44.

    Louis, D. N. et al. cIMPACT-NOW update 1: not otherwise specified (NOS) and not elsewhere classified (NEC). Acta Neuropathol. 135, 481–484 (2018).

    PubMed  Google Scholar 

  45. 45.

    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).

    CAS  Google Scholar 

  46. 46.

    Ceccarelli, M. et al. Molecular profiling reveals biologically discrete subsets and pathways of progression in diffuse glioma. Cell 164, 550–563 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. 47.

    Leeper, H. E. et al. IDH mutation, 1p19q codeletion and ATRX loss in WHO grade II gliomas. Oncotarget 6, 30295–30305 (2015).

    PubMed  PubMed Central  Google Scholar 

  48. 48.

    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).

    CAS  PubMed  Google Scholar 

  49. 49.

    Capper, D. et al. DNA methylation-based classification of central nervous system tumours. Nature 555, 469–474 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. 50.

    Christensen, B. C. et al. DNA methylation, isocitrate dehydrogenase mutation, and survival in glioma. J. Natl Cancer Inst. 103, 143–153 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. 51.

    Turcan, S. et al. IDH1 mutation is sufficient to establish the glioma hypermethylator phenotype. Nature 483, 479–483 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. 52.

    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).

    PubMed  PubMed Central  Google Scholar 

  53. 53.

    Gerson, S. L. MGMT: its role in cancer aetiology and cancer therapeutics. Nat. Rev. Cancer 4, 296–307 (2004).

    CAS  PubMed  Google Scholar 

  54. 54.

    Wick, W. et al. MGMT testing — the challenges for biomarker-based glioma treatment. Nat. Rev. Neurol. 10, 372 (2014).

    CAS  PubMed  Google Scholar 

  55. 55.

    Hegi, M. E. et al. MGMT gene silencing and benefit from temozolomide in glioblastoma. N. Engl. J. Med. 352, 997–1003 (2005).

    CAS  PubMed  Google Scholar 

  56. 56.

    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).

    CAS  PubMed  Google Scholar 

  57. 57.

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. 58.

    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).

    PubMed  Google Scholar 

  59. 59.

    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).

    CAS  PubMed  Google Scholar 

  60. 60.

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. 61.

    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).

    PubMed  Google Scholar 

  62. 62.

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. 63.

    Wick, W. et al. Prognostic or predictive value of MGMT promoter methylation in gliomas depends on IDH1 mutation. Neurology 81, 1515–1522 (2013).

    CAS  PubMed  Google Scholar 

  64. 64.

    Yang, P. et al. IDH mutation and MGMT promoter methylation in glioblastoma: results of a prospective registry. Oncotarget 6, 40896–40906 (2015).

    PubMed  PubMed Central  Google Scholar 

  65. 65.

    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).

    CAS  PubMed  Google Scholar 

  66. 66.

    Perry, J. R. et al. Short-course radiation plus temozolomide in elderly patients with glioblastoma. N. Engl. J. Med. 376, 1027–1037 (2017).

    CAS  PubMed  Google Scholar 

  67. 67.

    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).

    CAS  PubMed  Google Scholar 

  68. 68.

    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).

    PubMed  Google Scholar 

  69. 69.

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  70. 70.

    Shirahata, M. et al. Novel, improved grading system(s) for IDH-mutant astrocytic gliomas. Acta Neuropathol. 136, 153–166 (2018).

    CAS  PubMed  Google Scholar 

  71. 71.

    Korshunov, A. et al. Integrated molecular characterization of IDH-mutant glioblastomas. Neuropathol. Appl. Neurobiol. 45, 108–118 (2019).

    CAS  PubMed  Google Scholar 

  72. 72.

    Ostrom, Q. T. et al. The epidemiology of glioma in adults: a “state of the science” review. Neuro Oncol. 16, 896–913 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  73. 73.

    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).

    PubMed  PubMed Central  Google Scholar 

  74. 74.

    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).

    PubMed  PubMed Central  Google Scholar 

  75. 75.

    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).

    PubMed  PubMed Central  Google Scholar 

  76. 76.

    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).

    PubMed  PubMed Central  Google Scholar 

  77. 77.

    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).

    CAS  PubMed  Google Scholar 

  78. 78.

    International Agency for Research on Cancer. Cancer Incidence in Five Continents Vol. X (eds Forman, D. et al.) (IARC, 2014).

  79. 79.

    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).

    PubMed  PubMed Central  Google Scholar 

  80. 80.

    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).

    PubMed  PubMed Central  Google Scholar 

  81. 81.

    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).

    PubMed  PubMed Central  Google Scholar 

  82. 82.

    US Department of Health and Human Services. SEER cancer statistics review (CSR) 1975–2015. SEER https://seer.cancer.gov/csr/1975_2015/ (2018).

  83. 83.

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  84. 84.

    Deltour, I. et al. Mobile phone use and incidence of glioma in the Nordic countries 1979–2008: consistency check. Epidemiology 23, 301–307 (2012).

    PubMed  Google Scholar 

  85. 85.

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  86. 86.

    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).

    PubMed  PubMed Central  Google Scholar 

  87. 87.

    Crocetti, E. et al. Epidemiology of glial and non-glial brain tumours in Europe. Eur. J. Cancer 48, 1532–1542 (2012).

    PubMed  Google Scholar 

  88. 88.

    Ho, V. K. et al. Changing incidence and improved survival of gliomas. Eur. J. Cancer 50, 2309–2318 (2014).

    PubMed  Google Scholar 

  89. 89.

    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).

    CAS  PubMed  Google Scholar 

  90. 90.

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  91. 91.

    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).

    CAS  PubMed  Google Scholar 

  92. 92.

    Wigertz, A. et al. Risk of brain tumors associated with exposure to exogenous female sex hormones. Am. J. Epidemiol. 164, 629–636 (2006).

    PubMed  Google Scholar 

  93. 93.

    Sanai, N., Mirzadeh, Z. & Berger, M. S. Functional outcome after language mapping for glioma resection. N. Engl. J. Med. 358, 18–27 (2008).

    CAS  PubMed  Google Scholar 

  94. 94.

    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).

    PubMed  Google Scholar 

  95. 95.

    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).

    PubMed  PubMed Central  Google Scholar 

  96. 96.

    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).

    CAS  PubMed  Google Scholar 

  97. 97.

    Claus, E. B. et al. Survival and low-grade glioma: the emergence of genetic information. Neurosurg. Focus 38, E6 (2015).

    PubMed  PubMed Central  Google Scholar 

  98. 98.

    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).

    CAS  PubMed  Google Scholar 

  99. 99.

    Dubrow, R. et al. Time trends in glioblastoma multiforme survival: the role of temozolomide. Neuro Oncol. 15, 1750–1761 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  100. 100.

    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).

    PubMed  Google Scholar 

  101. 101.

    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).

    PubMed  Google Scholar 

  102. 102.

    Koshy, M. et al. Improved survival time trends for glioblastoma using the SEER 17 population-based registries. J. Neurooncol. 107, 207–212 (2012).

    PubMed  Google Scholar 

  103. 103.

    Chinot, O. L. et al. Bevacizumab plus radiotherapy-temozolomide for newly diagnosed glioblastoma. N. Engl. J. Med. 370, 709–722 (2014).

    CAS  PubMed  Google Scholar 

  104. 104.

    Gilbert, M. R. et al. A randomized trial of bevacizumab for newly diagnosed glioblastoma. N. Engl. J. Med. 370, 699–708 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  105. 105.

    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).

    PubMed  PubMed Central  Google Scholar 

  106. 106.

    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).

    PubMed  Google Scholar 

  107. 107.

    Lindor, N. M. et al. Concise handbook of familial cancer susceptibility syndromes — second edition. J. Natl Cancer Inst. Monogr. 2008, 3–93 (2008).

    Google Scholar 

  108. 108.

    Kyritsis, A. P., Bondy, M. L., Rao, J. S. & Sioka, C. Inherited predisposition to glioma. Neuro Oncol. 12, 104–113 (2010).

    CAS  PubMed  Google Scholar 

  109. 109.

    D’Angelo, F. et al. The molecular landscape of glioma in patients with neurofibromatosis 1. Nat. Med. 25, 176–187 (2019).

    PubMed  Google Scholar 

  110. 110.

    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).

    PubMed  Google Scholar 

  111. 111.

    Hayes, J. et al. Genomic analysis of the origins and evolution of multicentric diffuse lower-grade gliomas. Neuro Oncol. 20, 632–641 (2018).

    CAS  PubMed  Google Scholar 

  112. 112.

    Ohgaki, H. & Kleihues, P. The definition of primary and secondary glioblastoma. Clin. Cancer Res. 19, 764–772 (2013).

    CAS  PubMed  Google Scholar 

  113. 113.

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  114. 114.

    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).

    CAS  PubMed  Google Scholar 

  115. 115.

    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).

    CAS  PubMed  Google Scholar 

  116. 116.

    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).

    PubMed  Google Scholar 

  117. 117.

    Malmer, B. et al. Genetic epidemiology of glioma. Br. J. Cancer 84, 429–434 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  118. 118.

    de Andrade, M. et al. Segregation analysis of cancer in families of glioma patients. Genet. Epidemiol. 20, 258–270 (2001).

    PubMed  Google Scholar 

  119. 119.

    Bainbridge, M. N. et al. Germline mutations in shelterin complex genes are associated with familial glioma. J. Natl Cancer Inst. 107, 384 (2015).

    PubMed  Google Scholar 

  120. 120.

    Wrensch, M. et al. Variants in the CDKN2B and RTEL1 regions are associated with high-grade glioma susceptibility. Nat. Genet. 41, 905–908 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  121. 121.

    Kinnersley, B. et al. Genome-wide association study identifies multiple susceptibility loci for glioma. Nat. Commun. 6, 8559 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  122. 122.

    Sanson, M. et al. Chromosome 7p11.2 (EGFR) variation influences glioma risk. Hum. Mol. Genet. 20, 2897–2904 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  123. 123.

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  124. 124.

    Enciso-Mora, V. et al. Deciphering the 8q24.21 association for glioma. Hum. Mol. Genet. 22, 2293–2302 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  125. 125.

    Eckel-Passow, J. E. et al. Using germline variants to estimate glioma and subtype risks. Neuro Oncol. 21, 451–461 (2019).

    PubMed  Google Scholar 

  126. 126.

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  127. 127.

    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).

    PubMed  PubMed Central  Google Scholar 

  128. 128.

    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).

    Google Scholar 

  129. 129.

    Ostrom, Q. T., Gittleman, H., Stetson, L., Virk, S. & Barnholtz-Sloan, J. Epidemiology of intracranial gliomas. Prog. Neurol. Surg. 30, 1–11 (2018).

  130. 130.

    Wang, L. E. et al. Polymorphisms of DNA repair genes and risk of glioma. Cancer Res. 64, 5560–5563 (2004).

    CAS  PubMed  Google Scholar 

  131. 131.

    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).

    CAS  PubMed  Google Scholar 

  132. 132.

    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).

    CAS  PubMed  Google Scholar 

  133. 133.

    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).

    PubMed  Google Scholar 

  134. 134.

    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).

    PubMed  PubMed Central  Google Scholar 

  135. 135.

    IARC Working Group on the Evaluation of Carcinogenic Risk to Humans. Non-Ionizing Radiation, Part 2: Radiofrequency Electromagnetic Fields Vol. 102 (IARC, 2013).

  136. 136.

    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).

    CAS  PubMed  Google Scholar 

  137. 137.

    Cardis, E. et al. The INTERPHONE study: design, epidemiological methods, and description of the study population. Eur. J. Epidemiol. 22, 647–664 (2007).

    PubMed  Google Scholar 

  138. 138.

    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).

    PubMed  Google Scholar 

  139. 139.

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  140. 140.

    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).

    Google Scholar 

  141. 141.

    Disney-Hogg, L. et al. Impact of atopy on risk of glioma: a mendelian randomisation study. BMC Med. 16, 42 (2018).

    PubMed  PubMed Central  Google Scholar 

  142. 142.

    Wiemels, J. L. et al. Reduced immunoglobulin E and allergy among adults with glioma compared with controls. Cancer Res. 64, 8468–8473 (2004).

    CAS  Google Scholar 

  143. 143.

    Wiemels, J. L. et al. History of allergies among adults with glioma and controls. Int. J. Cancer 98, 609–615 (2002).

    CAS  PubMed  Google Scholar 

  144. 144.

    Schwartzbaum, J. et al. Association between prediagnostic IgE levels and risk of glioma. J. Natl Cancer Inst. 104, 1251–1259 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  145. 145.

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  146. 146.

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  147. 147.

    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).

    CAS  PubMed  Google Scholar 

  148. 148.

    Grossman, S. A. et al. Immunosuppression in patients with high-grade gliomas treated with radiation and temozolomide. Clin. Cancer Res. 17, 5473–5480 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  149. 149.

    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).

    CAS  PubMed  Google Scholar 

  150. 150.

    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).

    CAS  PubMed  Google Scholar 

  151. 151.

    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).

    CAS  PubMed  Google Scholar 

  152. 152.

    Gabrusiewicz, K. et al. Glioblastoma-infiltrated innate immune cells resemble M0 macrophage phenotype. JCI Insight 1, e85841 (2016).

    PubMed Central  Google Scholar 

  153. 153.

    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).

    CAS  PubMed  Google Scholar 

  154. 154.

    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).

    PubMed  Google Scholar 

  155. 155.

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  156. 156.

    Wiencke, J. K. et al. Epigenetic biomarkers of T cells in human glioma. Epigenetics 7, 1391–1402 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  157. 157.

    Wiencke, J. K. et al. Immunomethylomic approach to explore the blood neutrophil lymphocyte ratio (NLR) in glioma survival. Clin. Epigenet. 9, 10 (2017).

    Google Scholar 

  158. 158.

    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).

    PubMed  PubMed Central  Google Scholar 

  159. 159.

    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).

    PubMed  PubMed Central  Google Scholar 

  160. 160.

    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).

    PubMed  Google Scholar 

  161. 161.

    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).

    PubMed  Google Scholar 

  162. 162.

    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).

    PubMed  PubMed Central  Google Scholar 

  163. 163.

    Niedermaier, T. et al. Body mass index, physical activity, and risk of adult meningioma and glioma: a meta-analysis. Neurology 85, 1342–1350 (2015).

    PubMed  Google Scholar 

  164. 164.

    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).

    CAS  PubMed  Google Scholar 

  165. 165.

    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).

    PubMed  PubMed Central  Google Scholar 

  166. 166.

    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).

    CAS  PubMed  Google Scholar 

  167. 167.

    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).

    CAS  PubMed  Google Scholar 

  168. 168.

    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).

    PubMed  Google Scholar 

  169. 169.

    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).

    PubMed  Google Scholar 

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Acknowledgements

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.).

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Nature Reviews Neurology thanks M. Hegi, W. Wick and J. Schwartzbaum for their contribution to the peer review of this work.

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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

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