Molecular epigenetics and genetics in neuro-oncology.
Gliomas arise through genetic and epigenetic alterations of normal brain cells, although the exact cell of origin for each glioma subtype is unknown. The alteration-induced changes in gene expression and protein function allow uncontrolled cell division, tumor expansion, and infiltration into surrounding normal brain parenchyma. The genetic and epigenetic alterations are tumor subtype and tumor-grade specific. Particular alterations predict tumor aggressiveness, tumor response to therapy, and patient survival. Genetic alterations include deletion, gain, amplification, mutation, and translocation, which result in oncogene activation and tumor suppressor gene inactivation, or in some instances the alterations may simply be a consequence of tumorigenesis. Epigenetic alterations in brain tumors include CpG island hypermethylation associated with tumor suppressor gene silencing, gene-specific hypomethylation associated with aberrant gene activation, and genome-wide hypomethylation potentially leading to loss of imprinting, chromosomal instability, and cellular hyperproliferation. Other epigenetic alterations, such as changes in the position of histone variants and changes in histone modifications are also likely to be important in the molecular pathology of brain tumors. Given that histone deacetylases are targets for drugs that are already in clinical trial, surprisingly little is known about histone acetylation in primary brain tumors. Although a majority of epigenetic alterations are independent of genetic alterations, there is interaction on specific genes, signaling pathways and within chromosomal domains. Next-generation sequencing technology is now the method of choice for genomic and epigenome profiling, allowing more comprehensive understanding of genetic and epigenetic contributions to tumorigenesis in the brain.
Nagarajan
Raman P
RP
Brain Tumor Research Center, Department of Neurosurgery, Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, California 94143, USA.
Costello
Joseph F
JF
D000818:Animals; D015415:Biomarkers; D001921:Brain / Q000378:metabolism; D001932:Brain Neoplasms / Q000209:etiology / Q000235:genetics* / Q000628:therapy; D002874:Chromosome Mapping; D004247:DNA / Q000378:metabolism; D019175:DNA Methylation; D015254:DNA Modification Methylases / Q000235:genetics / Q000378:metabolism; D045643:DNA Repair Enzymes / Q000235:genetics / Q000378:metabolism; D044127:Epigenesis, Genetic; D015972:Gene Expression Regulation, Neoplastic; D005910:Glioma / Q000209:etiology / Q000235:genetics* / Q000628:therapy; D006657:Histones / Q000235:genetics / Q000378:metabolism; D006801:Humans; D009367:Neoplasm Staging; D018911:Trinucleotide Repeats; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism
D015415:Biomarkers; D006657:Histones; D025521:Tumor Suppressor Proteins; D004247:DNA; D015254:DNA Modification Methylases; C515491:MGMT protein, human; D045643:DNA Repair Enzymes