Molecular hallmarks of gliomas

Abstract

Gliomas are a heterogeneous group of neoplasias that account for the majority of primary tumors of the central nervous system, of which glioblastoma multiforme is by far the most common and malignant subtype. These are particularly dramatic diseases, as they rank first among all human tumor types for the tumor‐related average years of life lost, and for which curative therapies are not yet available. Their etiology remains mostly undetermined: so far, only exposure to high‐dose therapeutic radiation has been firmly established as a risk factor, but other plausible causes include genetic syndromes, familial aggregation, and genetic polymorphisms. Equally mysterious are truly clinically‐relevant prognostic factors of glioma patients; patient age at diagnosis and clinical performance status are classic features associated with patient outcome, but recent evidences suggest that tumor’s molecular traits are also major determinants of prognosis. The outcome of glioblastoma patients is remarkably variable and unpredictable. Regardless, all patients are equally treated with a standardized therapeutic approach. It is widely acknowledged that a set of molecular (genetic and epigenetic) markers predictive of patient outcome, and/or tumor response to specific therapies, will be the basis of a molecular stratification of subgroups of glioblastoma and may prove crucial in rationalizing treatment decisions. However, well-established and clinically relevant biomarkers of prognosis of glioblastoma patients are still lacking. The methylation status of the promoter region of MGMT is currently the most promising, but has not reached clinical applicability. In this context, one of the most important research fields in neuro-oncology today is the identification of molecular determinants of survival and therapy response in glioma patients. This is very relevant because if patients with poor prognosis could be identified at the time of surgery, they would be followed more closely and would be promptly directed to potentially effective experimental therapies, rather than suffering the effects of ineffective and expensive treatments. Identifying new molecular markers and understanding their functional mechanisms in these aggressive therapy-insensitive gliomas may also be the first step in designing novel therapies. The general aim of this chapter is to review some of the most relevant genetic and epigenetic hallmarks of glial tumors, with a particular emphasis on those molecular alterations that have been suggested to affect the prognosis of glioma patients. Naturally, a special focus will be given to glioblastoma, one of the highest devastating human tumors. The chapter is organized in individual subsections, which are more interrelated than autonomous, starting with a brief summary of the classification, epidemiology, and treatment of gliomas. Subsequently, the different types of molecular alterations are defined and discussed in the context of brain gliomas, as well as the interaction between these different features. The molecular alterations are specific to tumor subtype and grade, and may be genetic, including deletion, gain, amplification, mutation, and translocation, or epigenetic, such as DNA CpG island hypermethylation, gene-specific and global genome-wide hypomethylation, and aberrant post-translational histone modifications. Together, these molecular aberrations result in altered gene expression profiles, including oncogene activation, tumor suppressor gene inactivation, loss of imprinting, and chromosomal instability, which ultimately culminate in uncontrolled cell division, deregulation of programmed cell death mechanisms, and limitless replication potential, favoring tumor expansion, angiogenesis, and infiltration into surrounding normal brain tissue. Although epigenetic alterations are usually studied independently of genetic alterations, there is interaction on specific genes, signaling pathways and within chromosomal domains. For example, we recently found that a chromosomal domain of transcriptional aberrant activation encompassing the HOXA genes is present in a subgroup of glioblastoma, and demonstrated that a PI3K‐associated epigenetic mechanism reversibly regulates this domain via histone modifications. In addition, we showed that reactivation of HOXA9 expression, one of the genes within this domain, is a novel, independent, and negative prognostic factor in glioblastoma patients, highlighting the clinical relevance of concurrent genetic and epigenetic events in brain tumors. A particular emphasis will be given to some of the currently most promising biomarkers of glioma prognosis (e.g., MGMT promoter methylation, IDH genes mutations, HOXA genes activation), and some of the challenges for future studies in the field of glioma biomarkers will be discussed.