Background and implications
Diffuse LGGs include World Health Organization (WHO) grade II astrocytoma, oligodendroglioma, and oligoastrocytoma, which usually exhibit relatively slow growth and are infiltrative brain tumors. The neoplastic cells of LGGs diffusely infiltrate to the surrounding/adjacent brain parenchyma (up to 3–4 cm from the “margin” of tumor resection), making it impossible to complete the surgical resection or neoplasia excision. Diagnosis is usually performed based on histological analysis; however, histological/phenotypic features often fail to offer sharp stratification between different grades of infiltrative tumors with astrocytic or oligodendroglial origin. In this context, there is increasing emphasis that the distinctive genetic signatures, especially those identified by comprehensive integrative analysis by The Cancer Genome Atlas (TCGA) platforms [1–4], and defined genetic entities suggested by the 2016 WHO grading system [5], should be used for circumscribed diagnosis.
Diffuse LGGs are characterized by mutually exclusive telomerase reverse transcriptase (TERT) and ATRX mutations, one of the best defined characteristic gene mutations such as isocitrate dehydrogenase 1,2 (IDH1/2) and tumor protein p53 (TP53) mutations and the combined deletion of 1p/19q regions. The IDH mutations are very early genetic events and are frequent in diffuse gliomas. Additionally, LGGs exhibit distinctly different CpG island methylator phenotype (G-CIMP). Of particular note, the G-CIMP status is strongly associated with IDH1 somatic mutations and is more prevalent in diffuse gliomas [6, 7]. Followed by the mutations in characteristic genes, the acquisition of epigenetic modifications may reinforce the classification criteria of LGG subtypes with astrocytic and oligodendroglial origins which otherwise are less likely to be established by histological features alone.
It is therefore clinically important to generate a prognostic classifier to better predict the sensitivity of LGG to radiotherapy and chemotherapy and therefore predict the prognosis of LGG patients. This standardized and rigorously validated classifier by integrating genetic, epigenetic, and histological features of LGG should be superior to histological classification alone.
References
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1.
Eckel-Passow JE, et al. Glioma groups based on 1p/19q, IDH, and TERT promoter mutations in tumors. N Engl J Med. 2015;372(26):2499–508.
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Cancer Genome Atlas Research Network. Comprehensive, integrative genomic analysis of diffuse lower-grade gliomas. N Engl J Med. 2015;372(26):2481–98.
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Ceccarelli M, et al. Molecular profiling reveals biologically discrete subsets and pathways of progression in diffuse glioma. Cell. 2016;164(3):550–63.
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Suzuki H, et al. Mutational landscape and clonal architecture in grade II and III gliomas. Nat Genet. 2015;47(5):458–68.
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Louis DN, et al. The 2016 World Health Organization classification of tumors of the central nervous system: a summary. Acta Neuropathol. 2016;131(6):803–20.
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Huse JT, Aldape KD. The evolving role of molecular markers in the diagnosis and management of diffuse glioma. Clin Cancer Res. 2014;20(22):5601–11.
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Noushmehr H, et al. Identification of a CpG island methylator phenotype that defines a distinct subgroup of glioma. Cancer Cell. 2010;17(5):510–22.
Submitters
Farah Fatima and Muhammad Nawaz.
Affiliation and email
Ribeirão Preto Medical School, Av. Bandeirantes 3900, Ribeirão Preto 14049-900, University of São Paulo, Brazil.
farah.fatima00@gmail.com; nawazm.edu@gmail.com