Genetic alterations in adult diffuse glioma: occurrence, significance, and prognostic implications

Abstract

Our understanding of diffuse glioma development and progression has expanded remarkably over the past decade. As the genetic alterations responsible for these tumors are identified, molecular models of glioma pathogenesis are emerging and hold great promise to explain the biologic mechanisms of these neoplasms. Although these models continue to evolve and remain highly simplified, some of the genetic alterations that they encompass appear to be prognostically useful. Among the astrocytic gliomas, age and tumor grade are the most powerful indicators of patient survival, however, a wide range of variability remains, particularly among the lowgrade and anaplastic astrocytomas. Recent reports indicate that alterations of the PTEN tumor suppressor gene are independent predictors of overall survival for anaplastic astrocytoma patients, helping to distinguish the cases with behavior resembling their more malignant counterparts, the glioblastomas.Among the oligodendroglial tumors, alterations of the 1p and 19q chromosome arms have emerged as potentially powerful predictors of overall patient survival and in vivo chemotherapeutic response, while alterations of the p16/CDKN2A tumor suppressor gene suggest shorter overall survival. As our molecular models continue to improve, through functional analyses and the identification of additional genetic contributors, we will expand our capacity to more effectively prognose these patients and to design rational therapeutic strategies. INTRODUCTIONDiffuse gliomas exhibit an inherent tendency to progress to more malignant phenotypes and a broad range of clinical behavior. Classification of diffuse gliomas by histologic subtype (figure 1) and malignancy grade (figure 2),

Identification of genomic aberrations associated with shorter overall survival in patients with oligodendroglial tumors

“…This is of particular interest, as patients with oligodendrogliomas were traditionally thought to have a better outcome than patients with oligoastrocytomas or astrocytomas. [3][4][5]41 Considering that the histopathological distinction between ''pure'' oligodendrogliomas and mixed oligoastrocytomas is difficult and quite subjective, our data indicate that genetic analyses may be more important to stratify oligodendroglial tumors with respect to patient outcome.…”

“…1 In addition, patients with pure oligodendrogliomas are thought to have a better prognosis than patients with mixed gliomas. [3][4][5] The hallmark genetic aberration in oligodendrogliomas is the loss of genetic material from chromosome arms 1p and 19q, which is found in 60-80% of oligodendrogliomas and 50% of oligoastrocytomas. 6 Recently, it was described that the combined deletions of 1p and 19q in oligodendroglial tumors are mediated by an unbalanced translocation t(1;19) (q10;p10).…”

Profile of a Malignant Brain Tumor in Jamaica: an Eight Year Review, 2005 to 2012

“…However, it is well known that despite multimodal aggressive therapy even in the best of treatment centres, the median survival time after diagnosis remains approximately 12 months (19,20).…”

Dynamics of chemosensitivity and chromosomal instability in recurrent glioblastoma

“…With respect to chromosomal aberrations deletions of 1p, 9p, 10, 13q, 17p, 19q, and 22q, and gains of chromosome 7 ( Liu et al, 1997;Rasheed et al, 1997;Duerr et al, 1998;Smith and Jenkins, 2000) are the most common in gliomas. Several genes have been identified to be associated with tumorigenesis and anaplastic progression of glioblastoma subgroups including, besides the already mentioned p16/Cdkn2/Ink4, EGFR, PTEN, p53, and HDM2 also for example cdk4, cyclin D1, PDGFRa, k-ras, N-myc, gli, c-myc, and myb (Mao and Hamoudi, 2000;Zhu and Parada, 2002).…”