The Evolving Molecular Genetics of Low-grade Glioma

Abstract

Low-grade gliomas (LGG) constitute grade I and grade II tumors of astrocytic and grade II tumors of oligodendroglial lineage. Although these tumors are typically slow growing, they may be associated with significant morbidity and mortality due to recurrence and malignant progression, even in the setting of optimal resection. LGG in pediatric and adult age groups are currently classified by morphologic criteria. Recent years have heralded a molecular revolution in understanding brain tumors, including LGG. Next generation sequencing has definitively demonstrated that pediatric and adult LGG fundamentally differ in their underlying molecular characteristics, despite being histologically similar. Pediatric LGG show alterations in FGFR1 and BRAF in pilocytic astrocytomas and FGFR1 alterations in diffuse astrocytomas, each converging on the MAP kinase-signaling pathway. Adult LGG are characterized by IDH1/2 mutations and ATRX mutations in astrocytic tumors and IDH1/2 mutations and 1p/19q codeletions in oligodendroglial tumors. TERT promoter mutations are also noted in LGG and are mainly associated with oligodendrogliomas. These findings have considerably refined approaches to classifying these tumors. Moreover, many of the molecular alterations identified in LGG directly impact on prognosis, tumor biology, and the development of novel therapies.

Increased expression of von Willebrand factor gene is associated with poorer survival in primary lower grade glioma

“…[9,10] Among these tumors, as noted above, patients with astrocytomas have poorer survival than patients with oligoastrocytomas or oligodendrogliomas; prognosis of oligoastrocytomas or oligodendrogliomas is approximately equivalent. When we analyzed the data with Cox regression, expression had a significant effect on survival ( P = 0.02) that was unrelated to the effect of IDH1 expression ( P = 0.062), TP53 expression ( P = 0.135), independent of ATRX expression ( P = 0.021), and histology (astrocytoma versus ohgoastrocytoma and oligodendroglioma, P = 0.002).…”

“…[13] Recently, tumor genome has proven to be a prognostic factor,[9,10] as well as F13Al copy number segments. [14]…”

Non-invasive metabolic imaging of brain tumours in the era of precision medicine

“…More than 70% of intermediate-grade (grade II and III) gliomas (including astrocytomas and oligodendrogliomas) in adults bear mutations in isocitrate dehydrogenase (IDH) 1/2 (Table 1). IDH mutant gliomas tend to occur in younger adults and are associated with a favorable prognosis relative to their wild-type counterparts 10 (Table 1). IDH 1/2 mutant gliomas that progress to GBM are termed secondary GBM.…”

“…Low-grade gliomas in children and young adults such as pilocytic astrocytomas show constitutive activation of BRAF. Oncogenic fusion of the kinase domain of BRAF with KIAA1549 is seen in 30–70% of pilocytic astrocytomas (with varying frequency depending on cortical versus cerebellar tumor location) 10 . Likewise, activating BRAF point mutations (V600E) are observed in other low-grade pediatric brain tumors like pleomorphic xanthoastrocytomas (70%), gangliogliomas (20%) and at lower frequencies in pilocytic astrocytomas and diffuse astrocytomas 10 .…”

Overexpression of FZD7 promotes glioma cell proliferation by upregulating TAZ

“…Gliomas are divided into several histological subtypes, including astrocytomas, ependymomas and oligodendrogliomas [3, 4]. Astrocytomas are the largest group of gliomas, representing 75% of all gliomas [2, 5].…”