Molecular pathogenesis of pituitary tumors.
Pituitary tumors are the result of a monoclonal outgrowth where the intrinsic genetic defects involve oncogenes, tumor suppressor genes (TSG), and most likely genes responsible for differentiation. In addition, hypothalamic and intrapituitary derived growth factors are imposed upon these aberrant cells, contributing to their growth characteristics. While histological examination will not identify those tumors likely to progress toward an invasive phenotype or those destined toward recurrence recent advances in the molecular pathology of these tumors holds significant promise for prediction of recurrence and the design of novel treatment strategies. Moreover, emerging data clearly indicate that different molecular mechanisms are involved in the pathogenesis of the various pituitary tumor subtypes. Until recently the gsp oncogene was the only oncogene significantly associated with pituitary tumors; however, emerging data have describe a role for PTTG and cyclin D1 in pituitary tumorigenesis. For known and putative TSG loci, allelic losses on the long arms of chromosomes 10, 11, and 13 are significantly associated with the transition from the noninvasive to the invasive and metastatic phenotype, while losses on chromosome 9p occur early in pituitary tumorigenesis. Studies of known TSG at these loci, including the menin gene and RB1, would suggest a limited role, if any, in pituitary tumors. However, loss of pRB is evident in a proportion of somatotropinomas but is not associated with allelic loss of an RB1 intragenic marker. The gene encoding p16/CDKN2A is neither deleted nor mutated in pituitary tumors; however, its associated CpG island is frequently methylated and is associated with a loss of p16 protein expression. Allelic losses on chromosome 9p, frequent methylation, and loss of p16 protein appear as early changes in nonfunctional tumors, whereas they are infrequent events in somatotropinomas. The functional consequence of enforced expression of p16/CDKN2A in the mouse corticotroph cell line AtT20 has shown that it is responsible for a profound reduction in cell proliferation and the mechanism is a G(1) arrest, mimicking the in vivo role of this cell cycle regulator in most tissues. The combined data from several groups show that the allelic losses reported at known TSG loci are not accompanied by mutation in the retained allele. However, since abnormal methylation patterns may precede and predispose toward genetic instability this could account for the allelic losses on these chromosomes. Equally, since DNA methylation may lead to reduced expression of a gene it might also account for the reduced expression of as yet unidentified TSGs implicated in pituitary tumorigenesis. Collectively these studies hold significant promise as markers predictive of tumor behavior and point to novel treatment strategies, which may include the reactivation of TSGs that are intact but silenced through epigenetic mechanisms.
Farrell
W E
WE
Centre for Cell and Molecular Medicine, University of Keele, North Staffordshire Hospital Thornburrow Drive, Stoke on Trent, ST4 7QB, United Kingdom. W.E.Farrell@keele.ac.uk
Clayton
R N
RN
D000483:Alleles; D002874:Chromosome Mapping; D017353:Gene Deletion; D016147:Genes, Tumor Suppressor / Q000502:physiology; D006801:Humans; D009857:Oncogenes / Q000502:physiology; D010911:Pituitary Neoplasms / Q000235:genetics*