Molecular pathogenesis of pituitary tumors

Pituitary tumors are the result of a monoclonal outgrowth. where the intrin sic genetic defects involve oncogenes, tumor suppressor genes (TSG), and mo st likely genes responsible for differentiation. In addition, hypothalamic and intrapituitary derived growth factors are imposed upon these aberrant c ells, contributing to their growth characteristics. While histological exam ination will not identify those tumors likely to progress toward an invasiv e phenotype or those destined toward recurrence recent advances in the mole cular pathology of these tumors holds significant promise for prediction of recurrence and the design of novel treatment strategies. Moreover, emergin g data clearly indicate that different molecular mechanisms are involved in the pathogenesis of the various pituitary tumor subtypes. Until recently t he gsp oncogene was the only oncogene significantly associated with pituita ry tumors; however, emerging data have describe a role for PTTG and cyclin D1 in pituitary tumorigenesis. For known and putative TSG loci, allelic los ses on the long arms of chromosomes 10, 11, and 13 are significantly associ ated with the transition from the noninvasive to the invasive and metastati c phenotype, while losses on chromosome 9p occur early in pituitary tumorig enesis. Studies of known TSG at these loci, including the menin gene and RB I, would suggest a limited role, if any, in pituitary tumors. However, loss of pRB is evident in a proportion of somatotropinomas but is not associate d with allelic loss of an RBI intragenic marker. The gene encoding p16/CDKN 2A is neither deleted nor mutated in pituitary tumors; however, its associa ted CPG island is frequently methylated and is associated with a loss of p1 6 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 cons equence of enforced expression of p16/CDKN2A in the mouse corticotroph cell line AtT20 has shown that it is responsible for a profound reduction in ce ll 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 s everal groups show that the allelic losses reported at known TSG loci are n ot 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, si nce DNA methylation may lead to reduced expression of a gene it might also account for the reduced expression of as yet unidentified TSGs implicated i n pituitary tumorigenesis. Collectively these studies hold significant prom ise as markers predictive of tumor behavior and point to novel treatment st rategics, which may include the reactivation of TSGs that are intact but si lenced through epigenetic mechanisms. (C) 2000 Academic Press.