The aim of the present review is to give new insights into the pathogenesis of retinoblastoma, by applying the principles of Epigenetics to the analysis of clinical, epidemiological, and biological data concerning the disease. As an emerging new scientific approach linking the genome to the environment, Epigenetics, as applied to the interpretation of clinical, epidemiological and biological data in retinoblastoma, can not only explain the inconsistencies of the mutational (“two hit”) model, but also open new outstanding scenarios in the fields of diagnosis, treatment and prevention of this eye tumour. This review is both a collection of literature data arguing against the role of the mutational (“two hit”) model in the genesis of retinoblastoma, and a documented evaluation of how the Epigenetic, rather than the genetic model fit the variegated phenotypic expression of the disease. The epigenetic model in the genesis of retinoblastoma, proposed herein, emphasizes the role of environment and the interaction of the environment with the genome, in generating reti-noblastoma in young children. Environmental toxicants, including radiations, wrong diets, and infectious diseases, among others, all play a major role in conditioning the degree of DNA methylation in embryos and foetuses during pregnancy, thus leading to stable, functional alterations of the genome, which, on the other hand, can be also transmit-ted from generation to generation, thus mimicking a hereditary disease. An accurate analysis of the currently available literature on both retinoblastoma and Epigenetics, coupled with the knowledge of the variegated phenotypic expression of the disease, can easily lead to the conclusion that retinoblastoma is an epigenetic, rather than a genetic disease.
D. Mastrangelo, A. Di Leonardo, L. Lentini, S. De Francesco and T. Hadjistilianou, “Missing Evidences in Cancer Genetics: The Retinoblastoma Paradigm,” Cellular Oncology, Vol. 30, No. 6, 2008. pp. 509-510.
A. G. Knudson, “Mutation and Cancer: Statistical Study of Rb,” Proceedings of the National Academy of Sciences, Vol. 68, No. 4, 1971, pp. 820-823. doi:10.1073/pnas.68.4.820
S. H. Friend, R. Bernards, S. Rogelj, R. A. Weinberg, J. M. Rapaport, D. M. Albert, et al., “A Human DNA Segment with Properties of the Gene that Predisposes to Retinoblastoma and Osteosarcoma,” Nature, Vol. 323, 1986, pp. 643-646. doi:10.1038/323643a0
D. R. Lohmann and B. L. Gallie, “Retinoblastoma,” In: R. A. Pagon, T. C. Bird, C. R. Dolan and K. Stephens, Eds., Gene Reviews, University of Washington, Seattle, 2010.
G. Gaidano, A. Serra, A. Guerrasio, G. Rege-Cambrin, U. Mazza and G. Saglio, “Genetic Analysis of p53 and RB1 Tumor-Suppressor Genes in Blast Crisis of Chronic Myeloid Leukaemia,” Annals of Hematology, Vol. 68, No. 1, 1994, pp. 3-7. doi:10.1007/BF01695912
A. G. Knudson, “Heredity and Human Cancer,” American Journal of Pathology, Vol. 77, No. 1, 1974, pp. 77-84.
A. G. Knudson, “A Personal Sixty-Year Tour of Genetics and Medicine,” Annual Review of Genomics and Human Genetics, Vol. 6, 2005, pp. 1-14. doi:10.1146/annurev.genom.6.080604.162320
R. H. Li, A. Sonik, R. Stindl, D. Rasnick and P Duesberg, “Aneuploidy vs. Gene Mutation Hypothesis of Cancer: Recent Study Claims Mutation but is Found to Support Aneuploidy,” Proceedings of the National Academy of Sciences USA, Vol. 97, No. 7, 2000, pp. 3236-3241. doi:10.1073/pnas.040529797
P. Duesberg, C. Rausch, D. Rasnick and R. Hehlmann, “Genetic Instability of Cancer Cells is Proportional to Their Degree of Aneuploidy,” Proceedings of the National Academy of Sciences USA, Vol. 95, No. 23, 1998, pp. 13692-13697. doi:10.1073/pnas.95.23.13692
P. Duesberg, R. Li, D. Rasnik, C. Rausch, A. Willer, A. Kraemer, et al., “Aneuploidy Precedes and Segregates with Chemical Carcinogenesis,” Cancer Genetics and Cytogenetics, Vol. 119, No. 2, 2000, pp. 83-93. doi:10.1016/S0165-4608(99)00236-8
P. Duesberg, R. Stindl, R. H. Li, R. Hehlmann and D. Rasnick, “Aneuploidy versus Gene Mutation as Cause of Cancer,” Current Science, Vol. 81, No. 5, 2001, pp. 490-500.
P. Duesberg, R. Li and D. Rasnick, “Aneuploidy Approaching a Perfect Score in Predicting and Preventing Cancer,” Cell Cycle, Vol. 3, No. 6, 2004, pp. 823-828. doi:10.4161/cc.3.6.938
P. Duesberg, “Does Aneuploidy or Mutation Start Cancer?” Science, Vol. 307, No. 41, 2005, p. 5706.
P. Duesberg, R. Li, A. Fabarius, and R. Hehlmann, “The Chromosomal Basis of Cancer,” Cellular Oncology, Vol. 27, No. 5-6, 2005, pp. 293-318.
P. Duesberg, “Chromosomal Chaos and Cancer,” Scientific American, Vol. 296, 2007, pp. 52-59. doi:10.1038/scientificamerican0507-52
D. Mastrangelo, S. De Francesco, A. Di Leonardo, L. Lentini and T. Hadjistilianou, “Does the Evidence Matter in Medicine? The Rb Paradigm,” International Journal of Cancer, Vol. 121, No. 11, 2007, pp. 2501-2505. doi:10.1002/ijc.22944
D. Mastrangelo, S. De Francesco, A. Di Leonardo, L. Lentini and T. Hadjistilianou, “Rb Epidemiology: Does the Evidence Matter?” European Journal of Cancer, Vol. 43, No. 10, 2007, pp. 1596-1603. doi:10.1016/j.ejca.2007.04.019
D. Mastrangelo, T. Hadjistilianou, S. De Francesco and C. Loré, “Retinoblastoma and the Genetic Theory of Cancer: an Old Paradigm Trying to Survive to the Evidence,” Journal of Cancer Epidemiology, Vol. 2009, 2009. doi:10.1155/2009/301973
D. Mastrangelo, S. De Francesco, A. Di Leonardo, L. Lentini and T. Hadjistilianou, “The Retinoblastoma Paradigm Revisited,” Medical Science Monitor, Vol. 14, No. 12, 2008, pp. 231-240.
C. H. Waddington, “Organisers and Genes,” Cambridge University Press, Cambridge, 1940.
R. Holliday and J. C. Pugh, “DNA Modification Mechanisms and Gene Activity during Development,” Science, Vol. 187, 1975, pp. 226-232.
R. Holliday, “DNA Methylation and Epigenotypes,” Biochemistry, Vol. 70, No. 5, 2005, pp. 500-504.
V. Blanquet, C. Turleau, M.S. Gross-Morand, C. Semanaud-Beaufort, F. Doz and C. Besmond, “Spectrum of Germline Mutations in the RB1 Gene: A Study of 232 Patients with Hereditary and Non Hereditary Rb,” Human Molecular Genetics, Vol. 4, No. 3, 1995, pp. 383-388. doi:10.1093/hmg/4.3.383
Cancer Genetics Web: “Rb1, Retinoblastoma,” 2009. http://www.cancerindex.org/geneweb//RB1.htm
F. Cetani, E. Pardi, P. Vacava, G. Di Pollina, G. Fanelli, A. Picone, et al., “A Reappraisal of the Rb1 Gene Abnormalities in the Diagnosis of Parathyroid Cancer,” Clinical Endocrinology, Vol. 60, No. 1, 2004, pp. 99-106.
J. I. Herschkowitz, X He, C. Fan, C. M. Perou, “The Functional Loss of the Retinoblastoma Tumour Suppressor is a Common Event in Basal-Like and Luminal B Breast Carcinomas,” Breast Cancer Research, Vol. 10, No. 5, 2008, pp. 1-13. doi:10.1186/bcr2142
P. S. Lai, P. Y. Cheah, P. Kadam, C. Li-Ming Chua, D. Khun Hong Lie, H. H. Li, et al., “Overexpression of RB1 Transcript is Significantly Correlated with 13q14 Allelic Imbalance in Colorectal Carcinomas,” International Journal of Cancer, Nol. 119, No. 5, 2006, pp. 1061-1066.
D. M. Parkin and C. A. Stiller, “Childhood Cancer in Developing Countries: Environmental Factors,” International Journal of Pediatric Hematology/Oncology, Vol. 2, 1995, pp. 411-417.
D. M. Parkin, P. Pisani and J. Ferlay, “Global Cancer Statistics,” CA Cancer Journal for Clinicians, Vol. 49, No. 1, 1999, pp. 33-64. doi:10.3322/canjclin.49.1.33
C. A. Stiller and D. M. Parkin, “Geographic and Ethnic Variations in the Incidence of Childhood Cancer,” British Medical Bulletin, Vol. 52, No. 4, 1996, pp. 682-703.
I. Ajioka, R. A. Martins, I. T. Bayazitov, S. Donovan, D. A. Johnson, S. Frase, et al., “Differentiated Horizontal Interneurons Clonally Expand to Form Metastatic Retinoblastoma in Mice,” Cell, Vol. 131, No. 2, 2007, pp. 378-390. doi:10.1016/j.cell.2007.09.036
J. Madhavan, A. Ganesh, J. Roy, J. Biswas and G. Kumaramanickavel, “The Relationship between Tumor Cell Differentiation and Age at Diagnosis in Retinoblastoma,” Journal of Pediatric Ophthalmology & Strabismus, Vol. 45, No. 1, 2008, pp. 22-25. doi:10.3928/01913913-20080101-16
D. C. Dolinoy, “Epigenetic Gene Regulation: Early Environmental Exposures,” Pharmacogenomics, Vol. 8, No. 1, 2007, pp. 5-10. doi:10.2217/14622416.8.1.5
R. L. Jirtle and M. K. Skinner, “Environmental Epigenomics and Disease Susceptibility,” Nature Reviews Genetics, Vol. 8, 2007, pp. 253-262. doi:10.1038/nrg2045
D. C. Dolinoy, J. R. Weidman and R. L. Jirtle, “Epigenetic Gene Regulation: Linking Early Developmental Environment to Adult Disease,” Reproductive Toxicology, Vol. 23, No. 3, 2007, pp. 297-307. doi:10.1016/j.reprotox.2006.08.012
D. C. Dolinoy, R. Das, J. R. Weidman and R. L. Jirtle, “Metastable Epialleles, Imprinting, and the Fetal Origins of Adult Diseases,” Pediatric Research, Vol. 61, No. 5, 2007, pp. 31-37.
Genetics Home Reference. http://ghr.nlm.nih.gov/glossary=housekeepinggene
F. Iovino, L. Lentini, A. Amato and A. Di Leonardo, “RB Acute Loss Induces Centrosomes Amplification and aneuploidy in Murine Primary Fi Broblasts,” Molecular Cancer, Vol. 5, 2006, p. 38. doi:10.1186/1476-4598-5-38
E. Hernando, Z. Nahle, G. Juan, E. Diaz-Rodriguez, M. Alaminos, M. Hemann, et al., “Rb Inactivation Promotes Genomic Instability by Uncoupling Cell Cycle Progression from Mitotic Control,” Nature, Vol. 430, No. 7001, 2004, pp. 797-802. doi:10.1038/nature02820
N. Ohtani-Fujita, T. Fujita, A. Aoike, N. E. Osifchin, P. D. Robbins and T. Sakai, “CpG Methylation Inactivates the Promoter Activity of the Human Retinoblastoma Tumor-Suppressor Gene,” Oncogene, Vol. 8, No. 4, 1993, pp. 1063-1067.
N. Ohtani-Fujita, T. P. Dryja, J. M. Rapaport, T. Fujita, S. Matsumura, K. Ozasa, et al., “Hypermethylation in the Retinoblastoma Gene Is Associated with Unilateral, Sporadic Retinoblastoma,” Cancer Genetics and Cytogenetics, Vol. 98, No. 1, 1997, pp. 43-49. doi:10.1016/S0165-4608(96)00395-0
M. J. Bello, P. Gonzalez-Gomez, M. Eva Alonso, N. P. Anselmo, D. Arjona, C. Ami?oso, et al., “Methylation Analysis of Cell Cycle Control Genes RB1, p14ARF and p16INK4a in Human Gliomas,” Cancer Therapy, Vol. 2, 2004, pp. 187-194.
P. R. Moreira, M. M. Guimar?es, C. C. Gomes, M. G. Diniz, J. A. Brito, W. H. de Castro, et al., “Methylation Frequencies of Cell-Cycle Associated Genes in Epithelial Odontogenic Tumours,” Archives of Oral Biology, Vol. 54, No. 10, 2009, pp. 893-897. doi:10.1016/j.archoralbio.2009.07.006
K. Malekzadeh, R. C. Sobti, M. Nikbakht, M. Shekari, S. A.Hosseini, D. K. Tamandani, et al., “Methylation Patterns of Rb1 and Casp-8 Promoters and Their Impact on Their Expression in Bladder Cancer,” Cancer Investigation, Vol. 27, No. 1, 2009, pp. 70-80. doi:10.1080/07357900802172085
K. Bastide, M. N. Guilly, J. F. Bernaudin, C. Joubert, B. Lectard, C. Levalois, et al., “Molecular Analysis of the Ink4a/Rb1-Arf/Tp53 Pathways in Radon-Induced Rat Lung Tumors,” Lung Cancer, Vol. 63, No. 3, 2009, pp. 348-353. doi:10.1016/j.lungcan.2008.06.007
C. S. Chim, K. Y. Wong, F. Loong, W. W. Lam and G. Srivastava, “Frequent Epigenetic Inactivation of Rb1 in Addition to p15 and p16 in Mantle Cell and Follicular Lymphoma,” Human Pathology, Vol. 38, No. 12, 2007, pp. 1849-1857. doi:10.1016/j.humpath.2007.05.009
K. Amara, M. Trimeche, S. Ziadi, A. Laatiri, M. Hachana, B. Sriha, et al., “Presence of Simian Virus 40 DNA Sequences in Diffuse Large B-cell Lymphomas in Tunisia Correlates with Aberrant Promoter Hypermethylation of Multiple Tumor Suppressor Genes,” International Journal of Cancer, Vol. 121, No. 12, 2007, pp. 2693-2702. doi:10.1002/ijc.23038
Y. F. Zhao, Y. G. Zhang, X. X. Tian, J. Du and J. Zheng, “Aberrant Methylation of Multiple Genes in Gastric Carcinomas,” International Journal of Surgical Pathology, Vol. 15, No. 3, 2007, pp. 242-251. doi:10.1177/1066896907302117
M. B. Michalowski, F. de Fraipont, D. Plantaz, S. Michelland, V. Combaret and M. C. Favrot, “Methylation of Tumor-Suppressor Genes in Neuroblastoma: The RASSF1A Gene is almost Always Methylated in Primary Tumors,” Pediatric Blood Cancer, Vol. 50, No. 1, 2008, 29-32. doi:10.1002/pbc.21279
A. Yoshino, Y. Katayama, A. Ogino, T. Watanabe, K. Yachi, T. Ohta, et al., “Promoter Hypermethylation Profile of Cell Cycle Regulator Genes in Pituitary Adenomas,” Journal of Neurooncology, Vol. 83, No. 2, 2007, pp. 153-162. doi:10.1007/s11060-006-9316-9
E. N. Tolmacheva, A. A. Kashevarova, N. N. Sukhanova, E. A. Sazhenova and I. N. Lebedev, “Epigenetic Inactivation of the RB1 Gene as a Factor of Genomic Instability: A Possible Contribution to Etiology of Chromosomal Mosaicism during Human Embryo Development,” Russian Journal of Genetics, Vol. 44, No. 11, 2008, pp. 1266-1271. doi:10.1134/S1022795408110033
H. Shigematsu, M. Suzuki, T. Takahashi, K. Miyajima, S. Toyooka, N. Shivapurkar, et al., “Aberrant Methylation of HIN-1 (High in Normal-1) is a Frequent Event in Many Human Malignancies,” International Journal of Cancer, Vol. 113, No. 4, 2005, pp. 600-604. doi:10.1002/ijc.20622
A. Rathi, A. K. Virmani, K. Harada, C. F.Timmons, K. Miyajima, R. J. Hay, et al., “Aberrant Methylation of the HIC1 Promoter Is a Frequent Event in Specific Pediatric Neoplasms,” Clinical Cancer Research, Vol. 9, No. 10, 2003, pp. 3674-3678.
K. Harada, S. Toyooka, N. Shivapurkar, A. Maitra, J. L. Reddy, H. Matta, et al., “Deregulation of Caspase 8 and 10 Expression in Pediatric Tumors and Cell Lines,” Cancer Research, Vol. 62, No. 20, 2002, pp. 5897-5901.
K. Harada, S. Toyooka, A. Maitra, R. Maruyama, K. O. Toyooka, C. F. Timmons, et al., “Aberrant Promoter Methylation and Silencing of the RASSF1A Gene in Pediatric Tumors and Cell Lines,” Oncogene, Vol. 21, No. 27, 2002, pp. 4345-4349. doi:10.1038/sj.onc.1205446
D. C. Dolinoy and R. L. Jirtle, “Environmental Epigenomics in Human Health and Disease,” Environmental Molecular Mutagenesis, Vol. 49, No. 1, 2008, pp. 4-8. doi:10.1002/em.20366
K. E. Nichols, S. Walther, E. Chao, C. Shields and A. Ganguly, “Recent Advances in Retinoblastoma Genetic Research,” Current Opinion in Ophthalmology, Vol. 20, No. 5, 2009, pp. 351-355. doi:10.1097/ICU.0b013e32832f7f25
D. Knaber, T. Berulava, O. Ammerpohl, D. Mitter, J Richter, R Siebert, et al., “The Human Retinoblastoma Gene Is Imprinted,” PLoS Genetics, Vol. 5, No. 12, 2009.
G. E. Sanbor, J. J. Augsburger and J. A. Shields, “Spontaneous Regression of Bilateral Retinoblastoma,” British Journal of Ophthalmology, Vol. 66, No. 11, 1982, pp. 685-690. doi:10.1136/bjo.66.11.685
R. C. Eagle, J. A. Shields, L. Donoso and R. S. Milner, “Malignant Transformation of Spontaneously Regressed Retinoblastoma, Retinoma/Retinocytoma Variant,” Ophthalmology, Vol. 96, No. 9, 1989, pp. 1389-1395.
J. K. Steward, J. L. S. Smith and E. L. Arnold, “Spontaneous Regression of Retinoblastoma,” British Journal of Ophthalmology, Vol. 40, 1956, pp. 449-461. doi:10.1136/bjo.40.8.449
A. Raj, S. A. Rifkin, E. Andersen and A. van Oudenaarden, “Variability in Gene Expression Underlies Incomplete Penetrance,” Nature, Vol. 463, 2010, pp. 913-918. doi:10.1038/nature08781
N. Zamudio and D. Bourc’his, “Transposable Elements in the Mammalian Germline: A Comfortable Niche or a Deadly Trap?” Heredity, Vol. 105, No. 1, 2010, pp. 92-104. doi:10.1038/hdy.2010.53
T. H. Bestor, “Cytosine Methylation Mediates Sexual Conflict,” Trends in Genetics, Vol. 19, No. 4, 2003, pp. 185-190. doi:10.1016/S0168-9525(03)00049-0
J. A. Yoder, C. P. Walsh and T. H. Bestor, “Cytosine Methylation and the Ecology of Intragenomic Parasite,” Trends in Genetics, Vol. 13, No. 8, 1997, pp. 335-340. doi:10.1016/S0168-9525(97)01181-5
D. C. Dolinoy, J. Wiedman, R. Waterland and R. L. Jirtle, “Maternal Genistein Alters Coat Color And Protects Avy Mouse Offspring from Obesity by Modifying the Fetal Epigenome,” Environmental Health Perspectives, Vol. 114, 2006, pp. 567-572. doi:10.1289/ehp.8700
H. Abouzeid, D. F. Schorderet, A. Balmer and F. L. Munier, “Germline Mutations in Retinoma Patients: Relevance to Low Penetrance and Low-Expressivity Molecular Basis,” Molecular Vision, Vol. 15, 2009, pp. 771-777.
G. Morgan, “Diffuse Infiltrating Retinoblastoma,” British Journal of Ophthalmology, Vol. 55, No. 9, 1971, pp. 600-606. doi:10.1136/bjo.55.9.600
C. L. Shields, F. Ghassemi, S. Tuncer, A. Thangappan and J. A. Shields, “Clinical Spectrum of Diffuse Infiltrating Retinoblastoma in 34 Consecutive Eyes,” Ophthalmology, Vol. 115, No. 12, 2008, pp. 2253-2258. doi:10.1016/j.ophtha.2008.07.003
E. Y. Cho, Y. L. Suh and H. J. Shin, “Trilateral Retinoblastoma: A Case Report,” Journal of Korean Medical Science, Vol. 17, 2002, pp. 137-140.
J. M. Provenzale, S. Gururangan and G. Klintworth, “Trilateral Retinoblastoma: Clinical and Radiologic Progression,” American Journal of Roentgenology, Vol. 183, No. 2, 2004, pp. 505-511.
K. C. Sippel, R. E. Fraioli, G. D. Smith, M. E. Schalkoff, J. Sutherland, B. L. Gallie, et al., “Frequency of Somatic and Germ-Line Mosaicism in Retinoblastoma: Implications for Genetic Counseling,” American Journal of Human Genetics, Vol. 62, No. 3, 1998, pp. 610-619. doi:10.1086/301766
D. Rushlow, B. Piovesan, K. Zhang, N. L. Prigoda-Lee, M. N. Marchong, R. D. Clark, et al., “Detection of Mosaic RB1 Mutations in Families with Retinoblastoma,” Vol. 30, No. 5, 2009, pp. 842-851.
R. H. Barbosa, F. R. Vargas, F. C. Aguiar, S. Ferman, E. Lucena, C. R. Bonvicino, et al., “Hereditary Retinoblastoma Transmitted by Maternal Germline Mosaicism,” Pediatric Blood Cancer, Vol. 51, No. 5, 2008, pp. 598-602. doi:10.1002/pbc.21687
S. K. Murphy, R. L. Jirtle, “Imprinting Evolution and the Price of Silence,” Bioessays, Vol. 25, No. 6, 2003, pp. 577-588. doi:10.1002/bies.10277
A. P. Feinberg, B. Tycko, “The History of Cancer Epigenetics,” Nature Review Cancer, Vol. 4, 2004, pp. 143-153. doi:10.1038/nrc1279
A. P. Feinberg, “The Epigenetics of Cancer Etiology,” Seminars in Cancer Biology, Vol. 14, No. 6, 2004, pp. 427-432. doi:10.1016/j.semcancer.2004.06.005
S. S. Palii, K. D. Robertson, “Epigenetic Control of Tumour Suppression,” Critical Reviews in Eukaryotic Gene Expression, Vol. 17, No. 4, 2007, pp. 295-316.
K. Buiting, D. Kanber, D. Lohmann, “Imprinting of RB1 (the New Kid on the Block),” Briefings in Functional Genomics, Vol. 9, No. 4, 2010, 347-353. doi:10.1093/bfgp/elq014
V. Greger, E. Passarge, W. H?pping, M. Messmer and B. Horsthemke, “Epigenetic Changes may Contribute to the Formation and Spontaneous Regression of Retinoblastoma,” Human Genetics, Vol. 83, No. 2, 1989, pp. 155-158. doi:10.1007/BF00286709
M. D. Anway, A. S. Cupp, M. Uzumcu and M. K. Skinner, “Epigenetic Transgenerational Actions of Endocrine Disruptors and Male Fertility,” Science, Vol. 308, No. 5727, 2005, pp. 1466-1469. doi:10.1126/science.1108190
V. S. Turusov, T. V. Nikonova and Y. Parfenov, “Increased Multiplicity of Lung Adenomas in Five Generations of Mice Treated with Benz(a)Pyrene When Pregnant,” Cancer Letters, Vol. 55, No. 3, 1990, pp. 227-231. doi:10.1016/0304-3835(90)90123-F
M. D. Anway, C. Leathers and M. K. Skinner, “Endocrine Disruptor Vinclozolin Induced Epigenetic Transgenerational Adult-Onset Disease,” Endocrinology, Vol. 147, No. 12, 2006, pp. 5515-5523. doi:10.1210/en.2006-0640
H. S. Chang, M. D. Anway, S. S. Rekow and M .K. Skinner, “Transgenerational Epigenetic Imprinting of the Male Germline by Endocrine Disruptor Exposure during Gonadal Sex Determination,” Endocrinology, Vol. 147, No. 12, 2006, pp. 5524-5541. doi:10.1210/en.2006-0987
G. Durcova-Hills, P. Hajkova, S. Sullivan, S. Barton, M. Azim Surani and A. McLaren, “Influence of Sex Chromosome Constitution on the Genomic Imprinting of Germ Cells,” Proceedings of the National Academy Sciences USA, Vol. 103, No. 30, 2006, pp. 1184-1188. doi:10.1073/pnas.0602621103
D. Brugge and R. Goble, “The History of Uranium Mining and the Navajo People,” American Journal of Public Health, Vol. 92, No. 9, 2002, pp. 1410-1419.
R. L. Berkow and J. K. Fleshman, “Retinoblastoma in Navajo Indian Children,” American Journal of Diseases in Children, Vol. 137, No. 2, 1983, 137-138.
C. A. Stiller, “Retinoblastoma and Low Level of Radiation,” British Medical Journal, Vol. 307, 1993, pp. 461-462. doi:10.1136/bmj.307.6902.461
B. Lewin, “Genes VIII,” Pearson Prentice Hall, Upper Saddle River, 2004.
A. P. Feinberg and B. Vogelstein, “Hypomethylation Distinguishes Genes of Some Human Cancers from Their Normal Counterparts,” Nature, Vol. 301, 1983, pp. 89-92. doi:10.1038/301089a0
J. Peedicayil, “Epigenetic Therapy: A New Development in Pharmacology,” Indian Journal of Medical Research, Vol. 123, No. 1, 2006, pp. 17-24.
E. N. Gal-Yam, Y. Saito, G. Egger and P. A. Jones, “Cancer Epigenetics: Modifications, Screening and Therapy,” Annual Review of Medicine, Vol. 59, 2008, pp. 267-280. doi:10.1146/annurev.med.59.061606.095816
M. Nakao, “Epigenetics: Interaction of DNA Methylation and Chromatin,” Gene, Vol. 278, No. 1-2, 2001, pp. 25-31. doi:10.1016/S0378-1119(01)00721-1
M. Esteller, “Epigenetics in Cancer,” New England Journal of Medicine, Vol. 358, 2008, pp. 1148-1159. doi:10.1056/NEJMra072067
A. C. Schefler, D. H. Abramson, “Retinoblastoma: What is New in 2007-2008,” Current Opinions in Ophthalmology, Vol. 19, No. 6, 2008, pp. 526-534. doi:10.1097/ICU.0b013e328312975b
P. W. Laird, “Cencer Epigenetics,” Human Molecular Genetics, Vol. 14, No. 1, 2005, pp. R65-R76. doi:10.1093/hmg/ddi113
R. W. Johnstone, “Histone-Deacetylase Inhibitors: Novel Drugs for the Treatment of Cancer,” Nature Review Drug Discovery, Vol. 1, 2002, pp. 287-299. doi:10.1038/nrd772
G. Egger, G. Liang, A. Aparicio and P. A. Jones, “Epigenetics in Human Disease and Prospects for Epigenetic Therapy,” Nature, Vol. 429, 2004, pp. 457-463. doi:10.1038/nature02625
M. Esteller, “DNA Methylation and Cancer Therapy: New Developments and Expectations,” Current Opinion Oncology, Vol. 17, No. 1, 2005, pp. 55-60. doi:10.1097/01.cco.0000147383.04709.10
A. Zelent, S. Waxman, M. Carducci, J. Wright, J. Zweibel and S. D. Gore, “State of the Translational Science: Summary of Baltimore Workshop on Gene Re-expression as a Therapeutic Target in Cancer,” Clinical Cancer Research, Vol. 10, 2004, pp. 4622-4629. doi:10.1158/1078-0432.CCR-1219-03
P. W. Laird, “The Power and the Promise of DNA Methylation Markers,” Nature, Vol. 3, No. 4, 2003, pp. 253-266.
J. P. Issa, “Cancer Prevention: Epigenetics Steps up to the Plate,” Cancer Prevention Research, Vol. 1, No. 4, 2008, pp. 219-222. doi:10.1158/1940-6207.CAPR-08-0029
D. Crews, “Epigenetics and Its Implications for Behavioural Neuroendocrinology,” Neuroendocrinology, Vol. 29, No. 3, 2008, pp. 344-357. doi:10.1016/j.yfrne.2008.01.003