Molecular Features of Adult Glioma Associated with Patient Race/Ethnicity, Age, and a Polymorphism inO6-Methylguanine-DNA-Methyltransferase

Abstract

Background: Risk factors for adult glioma in the San Francisco Bay Area include well-known demographic features such as age and race/ethnicity, and our previous studies indicated that these characteristics are associated with the TP53 mutation status of patients' tumors. We enlarged our study to assess the relationships of risk factors with TP53 as well as epidermal growth factor receptor (EGFR) and murine double minute-2 (MDM2) gene amplification and expression and the germ line Leu84Phe polymorphism in the DNA repair protein O 6 -methylguanine-DNA-methyltransferase (MGMT). MGMT expression may depend on the TP53 status of cells. Methods: Molecular analyses were carried out on 556 incident astrocytic tumors. MGMT genotype data were collected on germ line DNA from 260 of these cases. Results: The tumor data confirm the inverse relationships between TP53 mutation and MDM2 (P = 0.04) or EGFR (P = 0.004) amplification and that patients whose tumors contain TP53 mutations are younger than those without (P < 0.001). Although there was little difference in age of patient by EGFR amplification or expression among glioblastoma multiforme cases, EGFR gene amplification was associated with much older age of onset of anaplastic astrocytoma; for example, EGFR-amplified anaplastic astro-

Differential inactivation of polymorphic variants of human O6-alkylguanine-DNA alkyltransferase

“…However, at present, these are not clearly established. There are a substantial number of epidemiological and biochemical reports on the properties of these variants (reviewed in [48]) but these do not provide a consistent picture with some studies showing increased risk of tumor development and others not [19,20,22,23,25,26,29,31,[45][46][47]. This may be a consequence of the small sample size in most of these studies.…”

“…Variants W65C [15,16], L84F [15][16][17][18][19][20][21][22][23][24][25][26][27][28], I143V/ K178R [17][18][19][20][21][22][23][24]27,[29][30][31] and G160R [29,32] have been reported by multiple laboratories. These reports raise the possibility that there may be individual variation in response to hAGT inactivators.…”

Molecular Hallmarks of Gliomas

“…Studying genetic variants in this panoply of DNA repair genes might contribute to a better understanding of gliomagenesis, progression, and response to therapy (mostly DNA targeting agents). Some of the most intriguing and consistent findings of the past decade of neuro-oncology research are the statistically significant inverse associations between risk of gliomas in adults and histories of allergies and/or chickenpox, IgG antibodies to varicella-zoster virus, and levels of serum IgE (Wiemels et al, 2004;Wrensch et al, 2001;2005). A later study used germline polymorphisms in genes associated with asthma and allergies (IL-4RA, IL-13 and ADAM33) as biomarkers for the presence of these conditions, as genetic polymorphisms could not be influenced by the presence of glioma.…”

“…Studies using elegant mouse models have recently shown that the specific inactivation of PTEN in the mouse brain caused its overgrowth and abnormal proliferation of astrocytes (Fraser et al, 2004). Also in mouse studies, inactivation of PTEN has been associated with increased angiogenesis, closely paralleling the progression from low-grade to high-grade astrocytomas in humans, which coincides with PTEN loss (Andrew Xiao et al, 2002;2005). Aberrant PI3K signaling commonly results in activation of Akt via phosphorylation of two key residues, T308 and S473, by PDK1 and the mammalian target of rapamycin (mTOR), respectively (Mora et al, 2004;Sarbassov et al, 2005).…”

“…Because DNA repair is a mechanism of utmost importance in preserving genomic integrity, genes involved in this pathway have been extensively studied in human tumors. Glioma and some histological subtypes have been associated with specific polymorphic variants of particular DNA repair genes, such as ERCC1 (excision repair cross-complementing 1), ERCC2 (excision repair cross-complementing 2), GLTSCR1 (glioma tumor suppressor candidate region gene 1), PRKDC (protein kinase, DNA-activated, catalytic), and MGMT (O 6 -methylguanine-DNA methyltransferase) Wiencke et al, 2005;Yang et al, 2005). However, the clear reliability of these findings is still requiring further studies to assess consistency.…”