Population-based studies on incidence, survival rates, and genetic alterations in astrocytic and oligodendroglial gliomas.
ABSTRACT Published data on prognostic and predictive factors in patients with gliomas are largely based on clinical trials and hospital-based studies. This review summarizes data on incidence rates, survival, and genetic alterations from population-based studies of astrocytic and oligodendrogliomas that were carried out in the Canton of Zurich, Switzerland (approximately 1.16 million inhabitants). A total of 987 cases were diagnosed between 1980 and 1994 and patients were followed up at least until 1999. While survival rates for pilocytic astrocytomas were excellent (96% at 10 years), the prognosis of diffusely infiltrating gliomas was poorer, with median survival times (MST) of 5.6 years for low-grade astrocytoma WHO grade II, 1.6 years for anaplastic astrocytoma grade III, and 0.4 years for glioblastoma. For oligodendrogliomas the MSTwas 11.6 years for grade II and 3.5 years for grade III. TP53 mutations were most frequent in gemistocytic astrocytomas (88%), followed by fibrillary astrocytomas (53%) and oligoastrocytomas (44%), but infrequent (13%) in oligodendrogliomas. LOH 1p/19q typically occurred in tumors without TP53 mutations and were most frequent in oligodendrogliomas (69%), followed by oligoastrocytomas (45%), but were rare in fibrillary astrocytomas (7%) and absent in gemistocytic astrocytomas. Glioblastomas were most frequent (3.55 cases per 100,000 persons per year) adjusted to the European Standard Population, amounting to 69% of total incident cases. Observed survival rates were 42.4% at 6 months, 17.7% at one year, and 3.3% at 2 years. For all age groups, survival was inversely correlated with age, ranging from an MST of 8.8 months (<50 years) to 1.6 months (>80 years). In glioblastomas, LOH 10q was the most frequent genetic alteration (69%), followed by EGFR amplification (34%), TP53 mutations (31%), p16INK4a deletion (31%), and PTEN mutations (24%). LOH 10q occurred in association with any of the other genetic alterations, and was the only alteration associated with shorter survival of glioblastoma patients. Primary (de novo) glioblastomas prevailed (95%), while secondary glioblastomas that progressed from low-grade or anaplastic gliomas were rare (5%). Secondary glioblastomas were characterized by frequent LOH 10q (63%) and TP53 mutations (65%). Of the TP53 mutations in secondary glioblastomas, 57% were in hot-spot codons 248 and 273, while in primary glioblastomas, mutations were more evenly distributed. G:C-->A:T mutations at CpG sites were more frequent in secondary than primary glioblastomas, suggesting that the acquisition of TP53 mutations in these glioblastoma subtypes may occur through different mechanisms.
SourceAvailable from: Eran Blacher[Show abstract] [Hide abstract]
ABSTRACT: Glioblastoma multiforme (GBM) is one of the most lethal human cancers, accounting for about 15% of all primary brain tumors in adults. Tumor-associated microglia/macrophages (TMMs) are a major constituent of the tumor mass and the tumor microenvironment where they support tumor progression. We previously demonstrated that the NAD + utilizing ectoenzyme CD38 regulates microglia activation and that loss of CD38 inhibits glioma progression and extends the survival of glioma-bearing mice. These results indicated that targeting CD38 in the tumor microenvironment may serve as a novel therapeutic approach to treat glioma. To test this hypothesis, we identified small molecules that inhibit CD38 enzymatic activity (NAD + glycohydrolase): the natural anthranoid rhein, its water-soluble tri-potassium salt (K-rhein), and the polyphenol tannic acid (TA). Microglial properties regulated by CD38 (e.g., NO secretion and LPS/IFNγ activation induced cell death) were inhibited in primary microglia treated with rhein in a CD38-dependent manner. Furthermore, wild-type mice intracranially injected with GL261 mouse glioma cells and intranasally treated with K-rhein or TA, exhibited significant reduction in tumor volume and prolonged lifespan compared to vehicle treated mice. On the other hand, these inhibitors had only a modest effect on tumor-bearing Cd38 −/− mice. Taken together, our results demonstrate that small molecule CD38 inhibitors such as K-rhein and TA can target CD38 in the tumor microenvironment and offer a novel and useful strategy for glioma treatment.
[Show abstract] [Hide abstract]
ABSTRACT: Z Glioblastoma multiform beyin tümörleri içerisinde en sık rastlanan histolojik tiptir. Gliomaların genetik özellikleri Nörofibromatöz ve Li-Fraumeni sendromunun moleküler temellerinin açıklandığı 1980'lerin son dönemlerinden bugüne kadar yapılan çalışmalarla ortaya konulmaya çalışılmaktadır.Genetik alt yapının ortaya konması hem karsinogenez sürecini anlamamıza yardımcı olurken aynı zamanda olguların tümör tiplerinin, prognozun ve tedaviye yönelik hassasiyetlerinin belirlenmesi açısından da büyük önem taşımaktadır. Glioblastomalar günümüzde moleküler temelde primer ve sekonder olarak iki altgruba ayrılmakta ve biyolojik ve genetik olarak farklı genetik alt yapıya sahiptirler. Aynı zamanda GBM'de birçok genin epigenetik olarak inaktivasyonu saptanmıştır. Bu genler hücre siklusu gibi hücresel fonksiyonlarda, DNA tamiri ve genom bütünlüğünü sağlamada, tümör invazyonu ve apoptozisde anahtar rolü olan genlerdir. ABSTRACT Glioblastoma multiforme is the most common histological brain tumor type. The genetic characteristics of gliomas have been described in the late 1980s. The demonstration of the genetic background can help us understand the process of carcinogenesis of these tumor types and also their prognosis and sensitivity to treatment. Glioblastomas are divided as a two subgroups as primary and secondary, with distinct biological and genetic backgrounds. Epigenetic inactivation of many genes in GBM has also been identified. These genes play a key role in cellular functions such as the cell cycle and DNA repair, ensuring the integrity of the genome, tumor invasion, and apoptosis.
[Show abstract] [Hide abstract]
ABSTRACT: The alteration of the epidermal growth factor receptor (EGFR)-driven signaling network is a characteristic feature of glioblastomas (GBM), and its inhibition represents a treatment strategy. However, EGFR-targeted interventions have been largely ineffective. Complex perturbations in this system are likely to be central to tumor cells with high adaptive capacity and resistance to therapies. We review key concepts and mechanisms relevant to EGFR-targeted treatment resistance at a systems level. Our understanding of treatment resistance as a systems-level phenomenon is necessary to develop effective therapeutic options for GBM patients. This is allowing us to go beyond the notion of therapeutic targets as single molecular components, into strategies that can weaken cancer signaling robustness and boost inherent network-level vulnerabilities.Cell Communication and Signaling 03/2015; 13. DOI:10.1186/s12964-015-0098-6 · 4.67 Impact Factor