Regular Article
Molecular Pathogenesis of Pituitary Tumors

https://doi.org/10.1006/frne.1999.0195Get rights and content

Abstract

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 G1 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.

References (98)

  • SL Asa et al.

    Pituitary adenomas in mice transgenic for growth-hormone-releasing hormone

    Endocrinology

    (1992)
  • SL Asa et al.

    The cytogenesis and pathogenesis of Pituitary Adenomas

    Endocr Rev

    (1998)
  • SL Asa et al.

    The MEN-1 gene is rarely down-regulated in pituitary adenomas

    J Clin Endocrinol Metab

    (1998)
  • AS Bates et al.

    Allelic deletion in pituitary adenomas reflects aggressive biological activity and has potential value as a prognostic marker

    J Clin Endocrinol Metab

    (1997)
  • H Battifora

    p53 immunohistochemistry: A word of caution

    Hum Pathol

    (1994)
  • SB Baylin et al.

    Alteration in DNA methylation: A fundamental aspect of neoplasia

  • J Bertherat et al.

    The cyclic adenosine 3′3′-monophosphate-responsive factor CREB is constitutiveley activated in human somatotroph adenomas

    Mol Endocrinol

    (1995)
  • DC Betticher et al.

    Prognostic significance of CCND1 (cyclin D1) overexpression in primary non-small cell lung cancer

    Br J Cancer

    (1996)
  • DC Betticher et al.

    Alternate splicing produces a novel cyclin D1 transcript

    Oncogene

    (1995)
  • MD Boggild et al.

    Molecular genetic studies of sporadic pituitary tumors

    J Clin Endocrinol Metab

    (1994)
  • E Borreli et al.

    Pituitary hyperplasia induced by ectopic expression of nerve growth factor

    Proc Natl Acad Sci USA

    (1992)
  • N Buckley et al.

    p53 protein accumulation in Cushings adenoma and invasive non functional adenomas

    J Clin Endocrinol Metab

    (1994)
  • C Bystrom et al.

    Localisation of the MEN1 gene to a small region within chromosome 11q13 by deletion mapping in tumors

    Proc Natl Acad Sci USA

    (1990)
  • SC Chandrasekharappa et al.

    Positional cloning of the gene for multiple endocrine neoplasia-type 1

    Science

    (1997)
  • RN Clayton et al.

    Human Pituitary Tumors Have Multiclonal Origins

    (1999)
  • E Clementi et al.

    A new constitutively activating mutation in Gs protein α subunit-gsp oncogene is found in human pituitary tumors

    Oncogene

    (1990)
  • JF Costello et al.

    Silencing of p16/CDKN2 expression in human gliomas by methylation and chromatin condensation

    Cancer Res

    (1996)
  • VL Cryns et al.

    The retinoblastoma gene in human pituitary tumors

    J Clin Endocrinology Metab

    (1993)
  • P LM Dahia et al.

    Investigation of the cell cycle regulator p27/kip1 gene in ACTH-secreting tumors: Lack of correlation with the “knockout” animal model

    J Endocrinol

    (1997)
  • P LM Dahia et al.

    Mutation and expression analysis of p27/kip1 gene in corticotroph-secreting tumors

    Oncogene

    (1998)
  • Q Dong et al.

    Screening of candidate oncogenes in human thyrotroph tumors: Absence of activation mutations in Gαq, Gα11, Gαs or thyrotropin-releasing hormone receptor genes

    J Clin Endocrinol Metab

    (1996)
  • Hum Mol Genet

    (1997)
  • S Ezzat et al.

    Somatotroph hyperplasia without pituitary adenoma associated with a long standing growth hormone-releasing-hormone-producing bronchial carcinoid

    J Clin Endocrinol Metab

    (1994)
  • WE Farrell et al.

    Chromosome 9p deletions in invasive and non invasive non-functional pituitary adenomas: The deleted region involves markers outside of the MTS1 and MTS2 gene

    Cancer Res

    (1997)
  • WE Farrell et al.

    Sequence analysis and transcript expression of the MEN1 gene in sporadic pituitary tumors

    Br J Cancer

    (1999)
  • WE Farrell et al.

    Genomic sequence analysis of a key residue (Arg183) in human Gαq in invasive non-functional pituitary adenomas

    Clin Endocrinol

    (1997)
  • SJ Frost et al.

    Transfection of an inducible p16/CDKN2A construct mediated reversible growth inhibition and G1 arrest in the AtT20 pituitary tumor cell line

    Mol Endocrinol

    (1999)
  • Gonzalez-Zulueta et al.

    Methylation of the 5′ CpG island of the p16/CDKN2 tumor suppressor gene in normal and transformed human tissues correlates with gene silencing

    Cancer Res

    (1995)
  • ML Gonzalgo et al.

    The role of DNA methylation in expression of the p19/p16 locus in human bladder cancer cell lines

    Cancer Res

    (1998)
  • C Heppner et al.

    Somatic mutations of the MEN1 gene in parathyroid tumors

    Nature Genet

    (1997)
  • JG Herman et al.

    Inactivation of the CDKN2/p16/MTS1 gene is frequently associated with aberrant DNA methylation in all common human cancers

    Cancer Res

    (1995)
  • V Herman et al.

    Molecular screening of pituitary adenomas for gene mutations and rearrangements

    J Clin Endocrinol Metab

    (1993)
  • V Herman et al.

    Clonal origin of pituitary adenomas

    J Clin Endocrinol Metab

    (1990)
  • NA Hibberts et al.

    Analysis of cyclin D1 (CCND1) allelic imbalance and overexpression in sporadic pituitary tumors

    Clin Cancer Res

    (1999)
  • N-P Hu et al.

    Hetrozygous Rb-1Δ20/+mice are predisposed to tumors of the pituitary gland with nearly complete penetrance

    Oncogene

    (1994)
  • T Jacks et al.

    Effect of an Rb mutation in mouse

    Nature

    (1992)
  • L Jin et al.

    Transforming growth factor-β, Transforming growth factor-β Receptor 11, and p27kip1 expression in nontumorous and neoplastic human pituitaries

    Am J Pathol

    (1997)
  • P Jones

    Methylation errors and cancer

    Cancer Res

    (1996)
  • Cited by (76)

    • Association between intracranial aneurysm and meningiomas: An integrative survival Analysis with identification of prognostic factors

      2020, Clinical Neurology and Neurosurgery
      Citation Excerpt :

      This occurrence was an obvious independent predictor for survival. This fact should draw attention to the urgency of the proper management of these patients, who in themselves already have factors that may contribute to increased intracranial pressure due to the presence of the tumor [7,10,19]. Regarding treatment, most patients had tumor-related symptoms and surgical treatment subsequent to diagnosis showed an impact on overall survival, however, one should take into account the patient's previous conditions, surgical indications, and prognostic factors [6,23].

    • Relationship between expression of vascular endothelial growth factor and the proliferation of prolactinomas

      2017, Clinical Neurology and Neurosurgery
      Citation Excerpt :

      Furthermore, prolactinomas have the highest rate of recurrence post-surgery as compared with other pituitary adenomas [23]. Many factors may influence the proliferation of pituitary adenomas, such as angiogenesis, apoptosis, growth factors, oncogenes, tumor suppressor genes, and hormone receptors [25,26]. However, little is known about the role of VEGF expression in the process of the growth of prolactinomas.

    • CAMP signalling in the normal and tumorigenic pituitary gland

      2014, Molecular and Cellular Endocrinology
      Citation Excerpt :

      Gain-of-function mutations in this oncoprotein result in a constitutively active G protein coupled receptor, inhibition of intrinsic α subunit GTPase activity, increased AC activity in response to ligand binding and ultimately higher cAMP levels (Vallar et al., 1987; Landis et al., 1989). Mutations within this gene are mostly found in two hotspots, at residues 201 and 227 on the maternally imprinted allele (Farrell and Clayton, 2000). However, sommatotropinoma patients with GNAS mutations have been reported to have higher (Harris, 1988), lower (Buchfelder et al., 1999; Yang et al., 1996; Adams et al., 1993) or unchanged plasma GH levels (Yasufuku-Takano et al., 2006) compared to patients with no GNAS mutations.

    • Differential expression of cyclin D1 in human pituitary tumors: Relation to MIB-1 and p27/Kip1 labeling indices

      2011, Journal of the Egyptian National Cancer Institute
      Citation Excerpt :

      However in addition to amplification, inappropriate cyclin D1 expression may be due to another principal mechanism which is cytogenic inversion as described in parathyroid tumors [30]. This is further highlighted in the few reports on the cyclin D1 overexpression and its genetic alteration in pituitary adenomas suggesting that the overexpression of cyclin D1 occurs early and late in pituitary tumorigenesis and this is not necessarily associated with cyclin D1 gene allelic imbalance [13,16,31]. In our study, a significant positive correlation was noted between cyclin D1 and tumor recurrence, which was previously described in squamous cell carcinoma of the head and neck [9].

    • Pathology of the Pituitary and Sellar Region

      2010, Practical Surgical Neuropathology: A Diagnostic Approach A Volume in the Pattern Recognition Series, Expert Consult: Online and Print
    View all citing articles on Scopus

    Address reprint requests to W. E. Farrell. Fax: (44) 17 82 74 73 19. E-mail: [email protected].

    View full text