Abstract
Compatible with contemporary paradigms of the role of genetic aberrations in the progression of human tumors, the growth of pituitary tumors into a state of invasiveness appears to be due to genetic alterations. Amplification of H-ras and c-myc oncogenes and mutations of p53, nm23 and Rb genes have been identified disproportionately more in aggressive tumors and, in the case of Rb gene, in pituitary carcinomas, providing evidence that amplification of these oncogenes (H-ras and c-myc) and inactivation of tumor suppressor genes (p53, nm23 and Rb) seem to be at least one mechanism by which pituitary tumors progress. The current level of management of invasive pituitary adenomas should become more comprehensive as the advances in our understanding of genetic basis of pituitary adenoma invasiveness becomes translated into development of novel chemotherapy or gene transferbreak technique.
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References
Thapar K, Kovacs K, Horvath E, Asa SL: Classification and pathology of pituitary tumors. In: Wilkins RH, Rengachary S (eds) Neurosurgery 2nd edn. McGraw-Hill Co., New York, 1996, pp 1273–1289
Bishop JM: The molecular genetics of cancer. Science 235: 305–311, 1987
Ponder BA: Genetics and cancer. Biochim Biophys Acta 605: 369–410, 1980
Rowley JD: Biological implications of consistent chromosome rearrangements in leukemia and lymphoma. Cancer Res 44: 3159–3168, 1984
Yunis JJ: The chromosomal basis of human neoplasia. Science 221: 224–236, 1983
Dirks PB, Rutka JT: Current concept of in neuro-oncology. The cell cycle – a review. Neurosurgery 40: 1000–1013, 1997
Schwab M: Oncogene amplification in solid tumors. Semin Cancer Biol 9: 319–325, 1999
Winter E, Perucho M: Oncogene amplification during tumorigenesis of established rat fibroblasts reversibly transformed by activated human ras oncogenes. Mol Cell Biol 6: 2562–2570, 1986
Oshimura M, Gilmer TM, Barrett JC: Non-random loss of chromosome 15 in Syrian hamster tumours induced by V-Ha-ras plus V-myc oncogenes. Nature 316: 636–639, 1985
Vousden KH, Marshall CJ: Three different activated ras gene in mouse tumours; evidence for oncogene activation during the progression of a mouse lymphoma. EMBO J 3: 913–917, 1984
Boggild MD, Jenkinson S, Pistorello M, Bascaro M, Scanarini M, McTernan P, Perrett CW, Thakker RN, Clayton RN: Molecular genetic studies of sporadic pituitary tumors. J Clin Endocrinol Metab 78: 387–392, 1994
Hollstein M, Rice K, Greenblatt MS, Soussi T, Fuchs R, Sorlie T, Hovig E, Smith-Sorensen B, Montesano R, Harris CL: Data base of p53 gene somatic mutations in human tumors and cell lines. Nucl Acid Res 22: 3551–3555, 1994
Levine A: p53, the cellular gatekeeper for growth and division. Cell 88: 323–331, 1997
Donehover LA, Godley LA, Aldaz CM, Pyle R, Shi YP, Pinkel D, Gray J, Bradley A, Demina D, Varmus HE: Deficiency of p53 accelerates mammary tumorigenesis in Wnt-1 transgenic mice and promotes chromosomal instability. Genes Dev 9: 882–895, 1995
Cho Y, Gorina S, Jeffrey PD, Pavletich NP: Crystal structure of a p53 tumor suppressor–DNAcomplex: understanding tumorigenic mutations. Science 265: 346–355, 1994
Jayaraman L, Prives C: Activation of p53 sequence-specific DNA binding by short-single strands of DNA sequences the p53 C-terminus. Cell 81: 1021–1029, 1995
Walker KK, Levine AJ: Identification of a novel p53 functional domain which is necessary for efficient growth suppression. Proc Natl Acad Sci USA 93: 15335–15340, 1996
Polyak K, Waldman T, He TC, Kinzler KW, Vogelstein B: Genetic determinants of p53-induced apoptosis and growth arrest. Genes Dev 10: 1945–1952, 1996
Karen-Tal I, Suh BS, Dantes A, Linder S, Oren M, Amsterdam A: Involvement of p53 expression in apoptosis in immortalized granulosa cells. Exp Cell Res 218: 283–295, 1995
Lowe SW, Schmitt EM, Smith SW, Osborne BA, Jacks T: p53 is required for radiation induced apoptosis in mouse thymocytes. Nature 362: 847–849, 1993
Donehover LA, Harvey M, Slagle BL, McArthur MJ, Montgomery CA, Butel JS, Bradley A: Mice deficient for p53 are developmentally normal but susceptible for spontaneous tumours. Nature 356: 215–221, 1992
Lutzker S, Levine AJ: A functionally inactive p53 proteins in embryonal carcinoma cells is activated by DNA damaged or cellular differentiation. Nature Med 2: 804–810, 1996
Thapar K, Scheithauer BW, Kovacs K, Pernicone PJ, Laws ER: p53 expression in pituitary adenomas and carcinomas: correlation with invasiveness and tumor growth fraction. Neurosurgery 38: 763–770, 1996
Buckley N, Bates AS, Broome JC, Strange RC, Perrett CW, Burke CW, Clayton RN: p53 protein accumulation in Cushing's adenomas and invasive non-functional adenomas. J Clin Endocrinol Metab 79: 1513–1516, 1994
Clayton RN, Boggild M, Bates AS, Bicknell J, Simpson D, Farrell W: Tumor suppressor genes in the pathogenesis of human pituitary tumors. Horm Res 47: 185–193, 1997
Amsterdam A, Karen-Tal I, Aharoni D: Cross-talk between cAMP and p53-generated signals in induction of differentiation and apoptosis in steroidogenic granulosa cells. Steroids 61: 252–256, 1996
Gilman AG: G protein and regulation of adenylcyclase. Nobel Lecture, December 8, 1994. In: Ringertz N (ed) Nobel Lectures in Physiology or Medicine 1991–1995. World Scientific Publ. Co., Singapore, 1997, pp 182–212
Sutherland EW: Studies on the mechanism of hormone action: Nobel lecture December 11, 1971. In: Lindsten J (ed) Nobel Lectures in Physiology or Medicine 1971–1980. World Scientific Publ. Co., Singapore, 1992, pp 5–22
Lee WH, Bookstein R, Hong F, Young LJ, Shew JY, Lee EY: Human retinoblastoma susceptibility gene: cloning, identification, and sequence. Science 235: 1394–1399, 1987
Sherr CJ: Cancer cell cycles. Science 274: 1672–1677, 1996
Cavanee WK, Dryja TP, Phillips RA, Benedict WF, Godbout R, Galllie B, Murphree AL, Strong LC, White RL: Expression of recessive alleles by chromosomal mechanisms in retinoblastoma. Nature 305: 779–784, 1983
Knudson AG: Mutation and cancer: Statistical study of retinoblastoma. Proc Natl Acad Sci USA 68: 820–823, 1971
Marshall CJ: Tumor suppressor genes. Cell 64: 313–326, 1991
Hu Q, Dyson N, Harlow E: The regions of the retinoblastoma protein needed for binding to adenovirus E1A or SV 40 large T-antigen are common sites for mutations. EMBO J 9: 1147–1155, 1990
Hunter T: Oncoprotein network. Cell 88: 333–346, 1997
Jacks T, Fazali A, Schmitt EM, Bronson RT, Goodell MA, Weinberg RA: Effects of an Rb mutation in the mouse. Nature 359: 295–300, 1992
Riley DJ, Lee EY-HP, Lee W-H: Retinoblastoma protein: more than a tumor suppressor. Annu Rev Cell Biol 10: 1–29, 1994
Beijersbergen RL, Bernards R: Cell cycle regulation by the retinoblastoma family of growth inhibitory proteins. Biochim Biophys Acta 1287: 103–120, 1996
Farnham PJ, Slansky JE, Kollmar R: The role of E2F in the mammalian cell cycle. Biochim Biophys Acta 1155: 125–131, 1993
Nevins JR: E2F: A link between the Rb tumor suppressor protein and viral oncoproteins. Science 258: 424–429, 1992
Sidle A, Palaty C, Dirks P, Wiggan O, Kiess M, Gill RM, Wong AK, Hamel P: Activity of the retinoblastoma family proteins, pRb, p107, and p130, during cellular proliferation and differentiation. Crit Rev Biochem Mol Biol 31: 237–271, 1996
Weinberg RA: Tumor suppressor genes. Science 254: 1138–1146, 1991
Hu N, Gutsmann A, Herbert DC, Bradley A, Lee W-H, Lee EY-HP: Heterozygous Rb-1 delta + / – mice are predisposed to tumors of the pituitary gland with a nearly complete penetrance. Oncogene 9: 1021–1027, 1994
Huang S, Wang NP, Tseng BY, Lee W-H, Lee EY-HP: Two distinct and frequently mutated regions of the retinoblastoma protein are required for binding to SV 40 T antigen. EMBO J 9: 1815–1822, 1990
Cryns VL, Alexander JM, Klibanski A, Arnold A: The retinoblastoma gene in human pituitary tumors. J Clin Endocrinol Metab 77: 644–646, 1993
Pei L, Melmed S, Scheithauer B, Kovacs K, Benedict WF, Prager D: Frequent loss of heterozygosity at the retinoblastoma susceptibility gene (Rb) locus in aggressive pituitary tumors: evidence for a chromosome 13 tumor suppressor gene other than Rb. Cancer Res 55: 1613–1616, 1995
Woloschak M, Yu A, Xiao J, Post KD: Abundance and state of phosphorylation of the Rb gene product in human pituitary tumors. Int J Cancer 67: 16–19, 1996
Zhu J, Leon SP, Beggs AH, Busque L, Gilliland DG, Black PM: Human pituitary adenomas show no loss of heterozygosity at the retinoblastoma gene locus. J Clin Endocrinol Metab 78: 922–927, 1994
Dang CV, Regar LM, Emison E, Kim S, Li Q, Precott JE, Wonsey D, Zeller K: Function of the c-myc oncogenic transcription factor. Exp Cell Res 253: 63–77, 1999
Dalla-Favera R, Bregni M, Erikson J, Patterson D, Gallo RC, Croce CM: Human c-myc oncogene is located on the region of chromosome 8 that is translocated in Burkitt lymphoma cells. Proc Natl Acad Sci USA 79: 7824–7827, 1982
Pledger WJ, Stiles CD, Antoniades HN, Scher CD: Induction of DNA synthesis in BALB/c3T3 cells by serum components of the commitment process. Proc Natl Acad Sci USA 74: 4481–4485, 1977
Pledger WJ, Siles CD, Antoniades HN, Scher CD: An ordered sequence of event is required before BALB/c3T3 cells become committed to DNA synthesis. Proc Natl Acad Sci USA 75: 2839–2843, 1978
Shan-Ong GC, Keath EJ, Picolli SP, Cole MD: Novel myc oncogene RNA from abortive immunoglobulin gene recombined in plasmocytoma. Cell 31: 443–452, 1982
Lutterbach B, Hann SR: Hierarchical phosphorylation at N-terminal transformation-sensitive sites in c-myc protein is regulated by mitogen and in mitosis. Mol Cell Biol 14: 5510–5522, 1994
Dang CV, Dam HV, Buckmire M, Lee WMF: DNA-binding domain of human c-myc produced in Escherichia coli. Mol Cell Biol 9: 2477–2486, 1989
Dang CV, Lee WMF: Identification of the human c-myc protein nuclear translocation signal. Mol Cell Biol 8: 4048–4054, 1988
Hann SR, Eisenman RN: Proteins encoded by the human c-myc oncogene: differential expression in neoplastic cells. Mol Cell Biol 4: 2486–2497, 1984
Hann SR, King MW, Bentley DL, Anderson CW, Eisenman RN: Anon-AU6 translational initiation in c-myc exon 1 generates an N-terminally distinct protein whose synthesis is disrupted in Burkitt's lymphoma. Cell 52: 185–195, 1988
Luscher B, Eisenman RN: New light on myc and myb. Part I. Myc. Genes Dev 4: 2025–2035, 1990
Luscher B, Kuenzel EA, Krebs EG, Eisenman RN: Myc oncoproteins are phosphorylated by casein kinase II. EMBO J 8: 1111–1119, 1989
Marcu KB: myc function and regulation. Annu Rev Biochem 61: 809–860, 1992
Persson H, Leder P: Nuclear localization and DNA binding properties of a protein expressed by human c-myc oncogene. Science 225: 728–731, 1984
Rustgi AK, Dyson N, Bernards R: Amino-terminal domains of c-myc and N-myc proteins mediate binding of the retinoblastoma gene product. Nature 352: 541–544, 1991
Beijersbergen RL, Hijmens EM, Zhu L, Bernards E: Interaction of c-myc with the pRb related protein p107 results in inhibition of c-myc mediated transactivation. EMBO J 13: 4080–4086, 1994
Gu Y, Rosenblatt J, Morgan DO: Cell-cycle regulation of cdk 2 activity by phosphorylation of Thr 160 and Thy 15. EMBO J 17: 3995–4005, 1992
Pellici G, Pagliacci M, Lanfrancore L, Pellici PG, Grignani F, Nicoletti I: Inhibitory of the somatostatin analog octreotide on rat pituitary tumor cells (GH3) proliferation in vitro. J Endocrinol Invest 13: 657–662, 1990
Woloschak M, Roberts JL, Post K: c-myc, c-fos and c-myb gene expression in human pituitary tumors. J Clin Endocrinol Metab 79: 253–257, 1994
Panno JP, McKeown BA: Expression and regulation of the myc protooncogene in the pituitary gland of rainbow trout. Mol Cell Endocrinol 134: 81–90, 1997
Berczi I, Nagy E, deToledo SM, Matusik KS, Frieser HG: Pituitary hormones regulate c-myc and DNA synthesis in lymphoid tissue. J Immunol 146: 2201–2206, 1991
Chernavsky AL, Chervin A, Vitale M, Basso A, Burdman JA: Human pituitary tumors: studies on gene expression. Neurol Res 15: 2–6, 1993
Wilson TM, Yu-Lee LY, Kelley MR: Coordinate gene expression of luteinizing hormone-releasing hormone (LHRH) and the LHRH receptor after prolactin stimulation in the rat Nb2-T cell line: implication of a role in immunomodulation and cell cycle gene expression. Mol Endocrinol 9: 44–53, 1995
Yu-Lee LY: Prolactin stimulates transcription of growth related genes in Nb2T lymphoma cells. Mol Cell Endocrinol 68: 21–28, 1990
Chernavsky AL, Valerani AV, Burdman JA: Haloperidol and estrogen induce c-myc and c-fos expresion in the anterior pituitary gland of the rat. Neurol Res 15: 339–343, 1993
Ponch I, Hallstorm I, Svenson D, Blank A: Sexdifferentiated deoxychollic and protein in rat liver carcinogenesis is under pituitary control. Carcinogenesis 12: 2035–2040, 1991
Hurel SJ, Harris PE, McNicol AM, Foster S, Kelly WF, Bayliss PH: Metastatic prolactinoma: effect of octreotide, cabergoline, carboplatin and etoposide: immunocytochemical analysis of proto-oncogene expression. J Clin Endocrinol Metab 82: 2962–2965, 1997
Ikeda H, Yoshimoto T: Relationship between c-myc protein expression: The bromodeoxyuridine labeling index and the biological behaviour of pituitary adenoma. Acta Neuropathol 83: 361–364, 1992
Wang DG, Johnston CF, Atkinson AB, Hearey AP, Mitakhur M, Buchanan KP: Expression of bcl-2 oncoprotein in pituitary tumors: comparison with c-myc. J Clin Pathol 49: 795–797, 1996
Raghavan R, Harrison D, Ince PG, James RA, Daniels M, Birsch P: Oncoprotein immunoreactivity in human pituitary tumors. Clin Endocrinol 40: 114–126, 1994
Thapar K, Kovacs K, Stefaneanu L, Scheithauer B, Killinger DW, Lloyd RV, Smyth HS, Barr A, Thorner MO, Gaylinn B, Laws ER: Over-expression of the growthhormone-releasing hormone gene in acromegalyassociated pituitary tumors. An event associated with neoplastic progression and aggressive behavior. Am J Pathol 151: 769–784, 1997
degli Uberti EC, Henau S, Rossi R, Piva R, Margutti A, Transforini G, Passini G, del Senno L: Somatostatin reduces 3H-thymidine incorporation and c-myc, but not thyroglobulin ribonucleic acid levels in human thyroid follicular cells in vitro. J Clin Endocrinol Metab 72: 1364–1371, 1991
Graham SM, Cox AD, Drivas G, Rush MG, D'Eustachio P, Der CJ: Aberrant function of the ras-related protein TC12 R-Ras 2 triggers malignant transformation. Mol Cell Biol 14: 4108–4115, 1994
Saez R, Chan AM, Miki T, Aaronson SA: Oncogenic activation of human R-ras by point mutation analogous to those of prototype H-ras oncogenes. Oncogene 9: 2977–2982, 1994
Magee T, Marshall C: New insight into the interaction of ras with the plasma membrane. Cell 98: 9–12, 1999
Quilliam LA, Khosravi-Far R, Huff SY, Der CJ: Guanine nucleotide exchange factors: activators of the Ras superfamily of proteins. Bioessays 17: 395–404, 1995
Khosravi-Far R, White MA, Westwick JK, Solski PA, Chrzanowska-Wodnicka M, Van Aelst L, Wigler MH, Der CJ: Oncogenic Ras activation of Raf/mitogen activated protein kinase-independent pathways is sufficient to cause tumorigenic transformation. Mol Cell Biol 16: 3923–3933, 1996
White MA, Nicolette C, Minder MH, Polverino A, Van Aelst L, Karin M, Wigler MH: Ras function can contribute to mammalian cell transformation. Cell 80: 533–541, 1995
Karga HJ, Alexander JM, Hedley-Whyte ET, Klibanski A, Jameson JL: Ras mutation in human pituitary tumors. J Clin Endocrinol Metab 74: 914–919, 1992
Pei L, Melmed S, Scheithauer B, Kovacs K, Prager D: H-ras mutation in human pituitary carcinoma metastasis. J Clin Endocrinol Metab 78: 842–846, 1994
Choy E, Chiu VK, Siletti J, Feoktistov M, Morimoto T, Michaelson D, Ivanov IE, Philips MR: Endomembrane trafficking of Ras: The CAAX motif targets proteins to the ER and Golgi. Cell 98: 69–80, 1999
Gibbs JB, Oliff A, Kohl NE: Fernesyltransferase inhibitors: Ras research yields a potential cancer therapeutic. Cell 77: 175–178, 1994
Martin KK, Pilkington GJ: Nm23: an invasion suppressor gene in CNS tumors? Anti Cancer Res 18: 919–926, 1998
Stahl JA, Leone A, Rosengard AM, Porter L, King CR, Steeg PS: Identification of a second human nm23 gene, nm23-H2. Cancer Res 51: 445–449, 1991
Engel M, Theisinger B, Seib T, Seitz G, Huwer H, Zang KD, Welter C, Dooley S: High levels of nm23-H1 and nm23-H2 messenger RNA overexpression in human small cell lung carcinoma are associated with poor differentiation and advanced tumor stages. Int J Cancer 55: 375–379, 1993
Fujii K, Yasui W, Shimamoto F, Yokozaki H, Nakayama H, Kajiyama G, Tahara E: Immunohistochemical analysis of nm23 gene product in human gallbladder carcinoma. Virchow Archives 426: 355–359, 1995
Gazzeri S, Brambilla E, Negoescu A, Thoraval D, Veron M, Moro D, Brambilla C: Overexpression of nucleoside diphosphate/kinase A/nm23-H1 protein in human lung tumors: association with tumor progression in squamous cell carcinoma. Lab Invest 74: 158–167, 1996
Huwer H, Engel M, Welter C, Dooley S, Kalweit G, Feindt P, Games E: Squamous cell carcinoma of the lung: does the nm23 gene expression correlate to the tumor stage? Thor Cardiovasc Surg 42: 298–301, 1994
Mandai M, Konishi I, Komatsu T, Mori T, Arao S, Nomura H, Kanda Y, Hiai H, Fukumoto M: Mutation of the nm23 gene, loss of heterozygosity at the nm23 locus and K-ras mutation in ovarian carcinoma: correlation with tumour progression and nm23 gene expression. Br J Cancer 72: 691–695, 1995
Nakasu S, Nakasu Y, Nioka H, Nakajima M, Handa J: bcl-2 protein expression in tumors of the central nervous system. Acta Neuropathol 88: 520–526, 1994
Anciaux H, VanDoMellen K, Willems R, Royarans D, Slegers H: Inhibition of nucleoside diphosphate kinase (NPPK/nm23) by cAMP analogues. FEBS Lett 400: 75–79, 1997
Hsieh TC, Wu JM: Changes in cell growth, cyclin kinase, endogenous phosphoprotein and nm23 gene expression in human prostate JCA 1 cells treated with modified citruspectin. Biochem Mol Biol Int 37: 833–841, 1995
Takino H, Herman V, Weiss M, Melmed S: Purine-binding factor (nm23) gene expression in pituitary tumors: marker of adenoma invasiveness. J Clin Endocrinol Metab 80: 1733–1738, 1995
Farrell WE, Simpson DJ, Bicknell JE, Talbot AJ, Bates AS, Clayton RN: Chromosome 9p deletion in invasive and noninvasive non-functional pituitary adenomas: The deleted region involves markers outside of the MTS 1 and MTS 2 genes. Cancer Res 57: 2703–2709, 1997
U HS, Kelley PS, Lee WH: Abnormalities of the human growth hormone genes and proto-oncogenes in some pituitary adenomas. Mol Endocrinol 2: 85–89, 1988
Le Riche VK, Asa SL, Ezzat S: Epidermal growth factor and its receptor (EGF-R) in human pituitary adenomas: EGF-R correlates with tumor aggressiveness. J Clin Endocrinol Metab 81: 656–662, 1996
Ezzat S, Horvath E, Kovacs K, Smyth HS, Singer W, Asa SL: Basic fibroblast growth factor expression by two prolactin and thyrotropin producing pituitary adenomas. Endocr Pathol 6: 125–134, 1995
Abbass SA, Asa SL, Ezzat S: Altered expression of fibroblast growth factor in human pituitary adenomas. J Clin Endocrinol Metab 82: 1160–1166, 1997
Alvaro V: Invasive human pituitary tumors express a pointmutated alpha-protein kinase C. J Clin Endocrinol Metab 77: 1125–1129, 1993
Alvaro V, Touraine P, Raisman-Vozari R, Bai-Gremmer F, Birman F, Joubert D: Protein kinase C activity and expression in normal and adenomatous pituitaries. Int J Cancer 50: 724–730, 1992
Assert R, Naiem A, Schiemann U, Schatz H, Pfeiffer A: Effects of a mutation of protein kinase Ca (PKCa) in pituitary and thyroid neoplasia on enzyme activity. Exp Clin Endocrinol Diab 106 (Abstract): 51A, 1991
Atkins SZ, Landolt AM, Jeffreys RV, Diver M, Radcliffe J, White MC: Basic fibroblast growth factor stimulates prolactin secretion from human anterior pituitary adenomas without affecting adenoma cell proliferation. J Clin Endocrinol Metab 77: 831–837, 1993
Inoue K, Sakai T, Hattori M: The cell-adhesive effect of basic fibroblast growth factor on pituitary cells in vitro. J Endocrinol 130: 381–386, 1991
Muller W, Saeger W, Wellhausen L, Derwahl KM, Hamacher C, Lüdecke DK: Markers of function and proliferation in non-invasive bi-and pluri-hormonal adenomas of patients with acromegaly: an immunohistochemical study. Pathol Res Pract 195: 595–603, 1999
Prysor-Jones RA, Silverlight JJ, Jenkins JS: Oestradiol, vasoactive intestinal peptide and fibroblast growth factor in the growth of human pituitary tumour cells in vitro. J Endocrinol 120: 171–177, 1989
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Suhardja, A., Kovacs, K. & Rutka, J. Genetic Basis of Pituitary Adenoma Invasiveness: A Review. J Neurooncol 52, 195–204 (2001). https://doi.org/10.1023/A:1010655419332
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DOI: https://doi.org/10.1023/A:1010655419332