Epigenetic Mechanisms of Tumorigenesis

Abstract

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 Gsα, 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 Gsα 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.

Key words

Epigenetics - Pituitary tumors - Familial - TSG (Tumor-suppressor gene)

References

• 1 Baylin S B, Herman J G. DNA hypermethylation in tumorigenesis.  Trends in Genet. 2000;  16 168-173
• 2 Jones P A, Laird P W. Cancer epigenetics comes of age.  Nature. Genetics1999;  21 163-167
• 3 Baylin S B, Herman J G, Graff J R, Vertino P M, Issa J-P. Alterations in DNA methylation: a fundamental aspect of neoplasia. In: Vande Woude GF, Kleine G (eds) Advances in Cancer Research. San Diego, CA; Academic Press 1998: 141-196
• 4 Zingg J-M, Jones P. Genetic and epigenetic aspects of DNA methylation on genome expression, evolution, mutation and carcinogenesis.  Carcinog. 1997;  21 461-467
• 5 Kass S U, Pruss D, Wolffe A P. How does DNA methylation repress transcription?.  Trends in Genetics. 1997;  12 444-449
• 6 Jones P L, Veenstra G JC, Wade P A, Vermaak D, Kass S U, Landsberger N, Strouboulis J, Wolffe A P. Methylated DNA and MeCP2 recruit histone deacetylase to repress transcription.  Nature Genetics. 1999;  19 87-191
• 7 Momparler R L. Cancer epigenetics.  Oncogene. 2003;  22 6479-6483
• 8 Jones P A, Baylin S B. The fundamental role of epigenetic events in cancer.  Nature Reviews Genetics. 2002;  3 415-428
• 9 Li E. Chromatin modification and epigenetic reprogramming in mammalian development.  Nat Rev Genet. 2002;  3 662-673
• 10 Tate P H, Bird A P. Effects of DNA methylation on DNA-binding proteins and gene expression.  Curr Opin Genet Dev. 1993;  3 226-231
• 11 Sherr C. Cancer cell cycles.  Science. 1996;  274 1672-1677
• 12 Esteller M, Fraga M F, Guo M Z, Garcia-Foncillas J, Hedenfalk I, Godwin A K, Trojan J, Vaurs-Barriere C, Bignon Y J, Ramus S, Benitez J, Caldes T, Akiyama Y, Yuasa Y, Launonen V, Canal M J, Rodriguez R, Capella G, Peinado M A, Borg A, Aaltonen L A, Ponder B A, Baylin S B, Herman J G. DNA methylation patterns in hereditary human cancers mimic sporadic tumorigenesis.  Hum Mol Genet. 2001;  10 3001-3007
• 13 Greger V, Passarge E, Hopping W, Messmer E, Horsthemke B. Epigenetic changes may contribute to the formation and spontaneous regression of retinoblastoma.  Hum Genet. 1989;  83 155-158
• 14 Sakai T, Toguchida J, Ohtani N, Yandell D W, Rapaport J M, Dryja T P. Allele-specific hypermethylation of the retinoblastoma tumor-suppressor gene.  Am J Hum Genet. 1991;  48 880-888
• 15 Woloschak M, Yu A, Post K D. Frequent inactivation of the p16 gene in human pituitary tumors by gene methylation.  Molec Carcinogen. 1997;  19 221-224
• 16 Simpson D J, Bicknell J E, McNicol A M, Clayton R N, Farrel W E. Hypermethylation of the p16/CDKN2A/MTS1 gene and loss of protein expression is associated with non-functional pituitary adenomas but not somatotrophinomas Genes.  Chromosomes and Cancer. 1999;  24 328-336
• 17 Yoshimoto K, Tanaka C, Yamada S, Kimura T, Iwahana H, Sano T, Itakura M. Infrequent mutation of p16INK4A and p15INK4B genes in human pituitary adenomas.  Eur J Endocrinol. 1997;  136 74-80
• 18 Jaffrain-Rea M L, Ferretti E, Toniato E, Cannita K, Santoro A, di Stefano D, Ricevuto E, Maroder M, Tamburrano G, Cantore G, Gulino A, Martinotti S. p16 (INK4^a , MTS-1) gene polymorphism and methylation status in human pituitary tumors.  Clinical Endocrinology. 1999;  51 317-325
• 19 Seemann N, Kuhn D, Wrocklage C, Keyvani K, Hackl W, Buchfelder M, Fahlbusch R, Paulus W. CDKN2A/p16 inactivation is related to pituitary adenoma type and size.  J Pathol. 2001;  193 491-497
• 20 Ruebel K H, Jin L, Zhang S, Scheithauer B W, Lloyd R V. Inactivation of p16 gene in human pituitary non-functioning tumors by hypermethylation is more common in null cell adenomas.  Endocrine Pathol. 2001;  12 281-289
• 21 Burke C W, Adams C B, Esiri M M, Morris C, Bevan J S. Transsphenoidal surgery for Cushing’s disease: does what is removed determine the endocrine outcome?.  Clin Endocrinol (Oxf). 1990;  33 525-537
• 22 Kruse A, Klinken L, Holck S, Lindholm J. Pituitary histology in Cushing’s disease.  Clin Endocrinol. 1992;  37 254-259
• 23 Yap L B, Turner H E, Adams C B, Wass J A. Undetectable postoperative cortisol does not always predict long-term remission in Cushing’s disease: a single centre audit.  Clin Endocrinol (Oxf). 2002;  56 25-28
• 24 Bloodworth J MB. Assessment of the pituitary hyperplasia/neoplasia interface.  Path Res Pract. 1988;  183 626-630
• 25 Horvath E, Kovacs K, Scheithauer B W. Pituitary hyperplasia.  Pituitary. 1999;  1 69-179
• 26 Simpson D J, McNicol A M, Murray D C, Bahar A, Turner H E, Wass J AH, Esiri M M, Clayton R N, Farrell W E. Molecular pathology shows p16 methylation in nonadenomatous pituitaries from patients with Cushing’s disease.  Clin Can Res. 2004;  10 1780-1788
• 27 Herman J G, Graff J R, Myohanen S, Nelkin B D, Baylin S B. Methylation-specific PCR: a novel PCR assay for methylation status of CpG islands.  Proc Natl Acad Sci USA. 1996;  93 9821-9826
• 28 Farrell W E, Clayton R N. Molecular pathogenesis of pituitary tumors.  Frontiers in Neuroendocrinology. 2000;  21 174-198
• 29 Simpson D J, Magnay J, Bicknell J E, Barkan A L, McNicol A M, Clayton R N, Farrell W E. Chromosome 13q deletion mapping in pituitary tumors: infrequent loss of the retinoblastoma susceptibility gene (RB1) locus despite loss of RB1 protein product in somatotrophinomas.  Cancer Res. 1999;  59 1562-1566
• 30 Simpson D J, Hibberts N A, McNicol A M, Clayton R N, Farrell W E. Loss of pRb expression in pituitary adenomas is associated with methylation of the RB1 CpG island.  Cancer Res. 2000;  60 1211-1216
• 31 Gonzalez-Gomez P, Bello M J, Alonso M E, Lomas J, Arjona D, de Campos J M, Vaquero J, Isla A, Lassaletta L, Gutierrez M, Sarasa J L, Rey J A. CpG island methylation in sporadic and neurofibromatis type 2-associated schwannomas.  Clin Can Res. 2003;  9 5601-5606
• 32 Edamoto Y, Hara A, Biernat W, Terracciano L, Cathomas G, Riehle H M, Matsuda M, Fujii H, Scoazec J Y, Ohgaki H. Alterations of RB1, p53 and Wnt pathways in hepatocellular carcinomas associated with hepatitis C, hepatitis B and alcoholic liver cirrhosis.  Int J Can. 2003;  106 334-341
• 33 Gonzalez-Gomez P, Bello M J, Alonso M E, Arjona D, Lomas J, de Campos J M, Isla A, Rey J A. CpG island methylation status and mutation analysis of the RBI gene essential promoter region and protein-binding pocket domain in nervous system tumours.  British J Cancer. 2003;  88 109-114
• 34 Raveh T, Droguett G, Horwitz M S, DePinho R A, Kimichi A. DAP kinase activates a p19(ARF)/p53-mediated apoptotic checkpoint to suppress oncogenic transformation.  Nat Cell Biol. 2001;  3 1-7
• 35 Simpson D J, Clayton R N, Farrell W E. Methylation and loss of Death Associated Protein Kinase gene in sporadic pituitary tumors.  Oncogene. 2002;  21 1217-1224
• 36 Zhang X, Sun H, Danila D C, Johnson S R, Zhou Y, Swearingen B, Klibanski A. Loss off expression of GADD45γ , a growth inhibitory gene, in human pituitary adenomas: implications for tumorigenesis.  J Clin Endocrinol Metab. 2002;  87 1262-1267
• 37 Bahar A, Bicknell J E, Simpson D J, Clayton R N, Farrell W E. Loss of expression of the growth inhibitory gene GADD45 gamma, in human pituitary adenomas, is associated with CpG island methylation.  Oncogene. 2004;  23 936-944
• 38 Surani M AH, Barton S C, Norris M L. Development of reconstituted mouse eggs suggests imprinting of the genome during gametogenesis.  Nature. 1984;  308 548-550
• 39 McGrath J, Solter D. Completion of mouse embryogenesis requires both the maternal and paternal genomes.  Cell. 1984;  37 79-183
• 40 Rainier S, Johnson L A, Dobry C J, Ping A J, Grundy P E, Feinberg A P. Relaxation of imprinted genes in human cancer.  Nature. 1993;  362 747-749
• 41 Ogawa O, Eccles M R, Szeto J, McNoe L A, Yun K, Maw M A, Smith P J, Reeve A E. Relaxation of insulin-like growth factor-ii gene imprinting implicated in wilms-tumor.  Nature. 1993;  362 749-751
• 42 Melmed S. Mechanisms for pituitary Tumorigenesis: the plastic pituitary.  J Clin Invest. 2003;  112 1603-1618
• 43 Weinstein L S, Chen M, Liu J. Gs(alpha) mutations and imprinting defects in human disease.  Ann NY Acad Sci. 2002;  968 173-197
• 44 Hayward B E, Barlier A, Korbonits M, Grossman A B, Jacquet P, Enjalbert A, Bonthron D T. Imprinting of the G(s) alpha gene GNAS in the pathogenesis of acromegaly.  J Clin Invest. 2001;  107 R31-R36
• 45 Gonzalgo M L, Liang G, Spruck C H, Zingg J M, Rideout W H, Jones P A. Identification and characterisation of differentially methylated regions of genomic DNA by methylation-sensitive arbitrarily primed PCR.  Can Res. 1997;  57 594-599
• 46 Bahar A, Simpson D J, Cutty S J, Bicknell J E, Hoban P R, Holley S, Mourtada-Maarabouni M, Williams G T, Clayton R N, Farrell W E. Isolation and Characterization of a Novel Pituitary Tumor Apoptosis Gene (PTAG).  Mol Endo. 2004;  18 1827-1839
• 47 Gardiner-Garden M, Frommer M. CpG islands in vertebrate genomes.  J Molec Biol. 1987;  196 261-282
• 48 Yin D, Tamaki N, Kokunai T, Yasuo K, Yonezawa K. Bromocriptine-induced apoptosis in pituitary adenoma cells: relationship to p53 and bcl-2 expression.  Journal Clin Neurosci. 1999;  6 326-331
• 49 Yin D, Kondo S, Takeuchi J, Morimura T, Vaux D L. Bcl-2 gene prevents apoptosis in murine ACTH-secreting adenoma cells induced by bromocriptine.  International J Oncol. 1994;  4 187-191
• 50 Wheeler J MD, Loukola A, Aaltonen L A, Mortensen N JM, Bodmer W F. The role of hypermethylation of the hMLH1 promoter region in HNPCC versus MSI plus sporadic colorectal cancers.  J Med Genet. 2000;  37 588-592
• 51 Kuismanen S A, Holmberg M T, Salovaara R, de la Chapelle A, Peltomaki P. Genetic and epigenetic modification of MLH1 accounts for a major share of microsatellite-unstable colorectal cancers.  Am J Pathol. 2000;  156 1773-1779
• 52 Grady W M, Willis J, Guilford P J, Dunbier A K, Toro T T, Lynch H, Wiesner G, Ferguson K, Eng C, Park J G, Kim S J, Markowitz S. Methylation of the CDH1 promoter as the second genetic hit in hereditary diffuse gastric cancer.  Nat Genet. 2000;  26 16-17
• 53 Prowse A H, Webster A R, Richards F M, Richard S, Olschwang S, Resche F, Affara N A, Maher E R. Somatic inactivation of the VHL gene in Von Hippel-Lindau disease tumors.  Am J Hum Genet. 1997;  60 765-771
• 54 Yuen S T, Chan T L, Ho J WC, Chan A SY, Chung L P, Lam P WY, Tse C W, Wyllie A H, Leung S Y. Germline, somatic and epigenetic events underlying mismatch repair deficiency in colorectal and HNPCC-related cancers.  Oncogene. 2002;  21 7585-7592