Epigenetic mechanisms of tumorigenesis.
In the majority of human cancers, heritable loss of gene function through cell division may be mediated as often by epigenetic as by genetic abnormalities. Epigenetic modification occurs through a process of interrelated changes in CpG island methylation and histone modifications. Candidate gene approaches of cell cycle, growth regulatory and apoptotic genes have shown epigenetic modification associated with loss of cognate proteins in sporadic pituitary tumors. A search for novel genes on the basis of their differential methylation has led to the isolation and functional characterization of a pro-apoptotic mediator--a pituitary tumor apoptosis gene ( PTAG). Although PTAG expression is significantly underexpressed in most pituitary adenomas, mechanisms in addition to methylation most likely account for its loss. The GNAS gene is imprinted in normal pituitary, and activating mutations within Gsalpha, referred to as the gsp oncogene, are almost invariably associated with the maternal expressed allele in somatotrophic adenomas. In addition, epigenetic modification, manifesting as relaxation of imprinting, leads to biallelic expression of Gsalpha irrespective of gsp status. Pituitary tumors as components of familial syndromes represent a rare entity, and the role of epigenetic modification in their evolution and outgrowth is not known. Although speculative, these studies might provide new insight since methylation-associated gene silencing is a feature of other familial tumor types.
Institute of Science and Technology in Medicine, School of Medicine, Keele University, Stoke on Trent, Staffordshire, UK. w.e.farrell@keele.ac.uk
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D000818:Animals; D051017:Apoptosis Regulatory Proteins; D018899:CpG Islands / Q000235:genetics*; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D020868:Gene Silencing; D006801:Humans; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D010911:Pituitary Neoplasms / Q000151:congenital / Q000235:genetics* / Q000503:physiopathology
D051017:Apoptosis Regulatory Proteins; D009363:Neoplasm Proteins; C496066:RHBDD3 protein, human