1932

Abstract

Retinoblastoma is a pediatric tumor of the developing retina from which the genetic basis for cancer development was first described. Inactivation of both copies of the gene is the predominant initiating genetic lesion in retinoblastoma and is rate limiting for tumorigenesis. Recent whole-genome sequencing of retinoblastoma uncovered a tumor that had no coding-region mutations or focal chromosomal lesions other than in the gene, shifting the paradigm in the field. The retinoblastoma genome can be very stable; therefore, epigenetic deregulation of tumor-promoting pathways is required for tumorigenesis. This review highlights the genetic and epigenetic changes in retinoblastoma that have been reported, with special emphasis on recent whole-genome sequencing and epigenetic analyses that have identified novel candidate genes as potential therapeutic targets.

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2015-01-24
2024-06-17
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Literature Cited

  1. Knudson AG Jr. 1.  1971. Mutation and cancer: statistical study of retinoblastoma. PNAS 68:820–23 [Google Scholar]
  2. Friend SH, Bernards R, Rogelj S, Weinberg RA, Rapaport JM. 2.  et al. 1986. A human DNA segment with properties of the gene that predisposes to retinoblastoma and osteosarcoma. Nature 323:643–46 [Google Scholar]
  3. Dunn JM, Phillips RA, Becker AJ, Gallie BL. 3.  1988. Identification of germline and somatic mutations affecting the retinoblastoma gene. Science 241:1797–800 [Google Scholar]
  4. Hanahan D, Weinberg RA. 4.  2011. Hallmarks of cancer: the next generation. Cell 144:646–74 [Google Scholar]
  5. Manning AL, Longworth MS, Dyson NJ. 5.  2010. Loss of pRB causes centromere dysfunction and chromosomal instability. Genes Dev. 24:1364–76 [Google Scholar]
  6. Hernando E, Nahlé Z, Juan G, Diaz-Rodriguez E, Alaminos M. 6.  et al. 2004. Rb inactivation promotes genomic instability by uncoupling cell cycle progression from mitotic control. Nature 430:797–802 [Google Scholar]
  7. Dimaras H, Khetan V, Halliday W, Orlic M, Prigoda NL. 7.  et al. 2008. Loss of RB1 induces non-proliferative retinoma: Increasing genomic instability correlates with progression to retinoblastoma. Hum. Mol. Genet. 17:1363–72 [Google Scholar]
  8. Amato A, Lentini L, Schillaci T, Iovino F, Di Leonardo A. 8.  2009. RNAi mediated acute depletion of retinoblastoma protein (pRb) promotes aneuploidy in human primary cells via micronuclei formation. BMC Cell Biol. 10:79 [Google Scholar]
  9. Iovino F, Lentini L, Amato A, Di Leonardo A. 9.  2006. RB acute loss induces centrosome amplification and aneuploidy in murine primary fibroblasts. Mol. Cancer 5:38 [Google Scholar]
  10. Negrini S, Gorgoulis VG, Halazonetis TD. 10.  2010. Genomic instability—an evolving hallmark of cancer. Nat. Rev. Mol. Cell Biol. 11:220–28 [Google Scholar]
  11. Zhang J, Benavente CA, McEvoy J, Flores-Otero J, Ding L. 11.  et al. 2012. A novel retinoblastoma therapy from genomic and epigenetic analyses. Nature 481:329–34 [Google Scholar]
  12. Zielinski B, Gratias S, Toedt G, Mendrzyk F, Stange DE. 12.  et al. 2005. Detection of chromosomal imbalances in retinoblastoma by matrix-based comparative genomic hybridization. Genes Chromosomes Cancer 43:294–301 [Google Scholar]
  13. Yan Y, Dunkel IJ, Guan X, Abramson DH, Jhanwar SC, O'Reilly RJ. 13.  2000. Engraftment and growth of patient-derived retinoblastoma tumour in severe combined immunodeficiency mice. Eur. J. Cancer 36:221–28 [Google Scholar]
  14. Benavente CA, McEvoy JD, Finkelstein D, Wei L, Kang G. 14.  et al. 2013. Cross-species genomic and epigenomic landscape of retinoblastoma. Oncotarget 4:844–59 [Google Scholar]
  15. Squire J, Gallie BL, Phillips RA. 15.  1985. A detailed analysis of chromosomal changes in heritable and non-heritable retinoblastoma. Hum. Genet. 70:291–301 [Google Scholar]
  16. Squire J, Phillips RA, Boyce S, Godbout R, Rogers B, Gallie BL. 16.  1984. Isochromosome 6p, a unique chromosomal abnormality in retinoblastoma: verification by standard staining techniques, new densitometric methods, and somatic cell hybridization. Hum. Genet. 66:46–53 [Google Scholar]
  17. Potluri VR, Helson L, Ellsworth RM, Reid T, Gilbert F. 17.  1986. Chromosomal abnormalities in human retinoblastoma. A review. Cancer 58:663–71 [Google Scholar]
  18. Balaban-Malenbaum G, Gilbert F, Nichols WW, Hill R, Shields J, Meadows AT. 18.  1981. A deleted chromosome no. 13 in human retinoblastoma cells: relevance to tumorigenesis. Cancer Genet. Cytogenet. 3:243–50 [Google Scholar]
  19. Chaum E, Ellsworth RM, Abramson DH, Haik BG, Kitchin FD, Chaganti RS. 19.  1984. Cytogenetic analysis of retinoblastoma: evidence for multifocal origin and in vivo gene amplification. Cytogenet. Cell Genet. 38:82–91 [Google Scholar]
  20. Gilbert F, Balaban G, Breg WR, Gallie B, Reid T, Nichols W. 20.  1981. Homogeneously staining region in a retinoblastoma cell line: relevance to tumor initiation and progression. J. Natl. Cancer Inst. 67:301–6 [Google Scholar]
  21. Cowell JK, Hogg A. 21.  1992. Genetics and cytogenetics of retinoblastoma. Cancer Genet. Cytogenet. 64:1–11 [Google Scholar]
  22. Hogg A, Onadim Z, Baird PN, Cowell JK. 22.  1992. Detection of heterozygous mutations in the RB1 gene in retinoblastoma patients using single-strand conformation polymorphism analysis and polymerase chain reaction sequencing. Oncogene 7:1445–51 [Google Scholar]
  23. Oliveros O, Yunis E. 23.  1995. Chromosome evolution in retinoblastoma. Cancer Genet. Cytogenet. 82:155–60 [Google Scholar]
  24. Kadam PS, Ghule P, Jose J, Bamne M, Kurkure P. 24.  Amare et al. 2004. Constitutional genomic instability, chromosome aberrations in tumor cells and retinoblastoma. Cancer Genet. Cytogenet. 150:33–43 [Google Scholar]
  25. Corson TW, Gallie BL. 25.  2007. One hit, two hits, three hits, more? Genomic changes in the development of retinoblastoma. Genes Chromosomes Cancer 46:617–34 [Google Scholar]
  26. Grasemann C, Gratias S, Stephan H, Schüler A, Schramm A. 26.  et al. 2005. Gains and overexpression identify DEK and E2F3 as targets of chromosome 6p gains in retinoblastoma. Oncogene 24:6441–49 [Google Scholar]
  27. Orlic M, Spencer CE, Wang L, Gallie BL. 27.  2006. Expression analysis of 6p22 genomic gain in retinoblastoma. Genes Chromosomes Cancer 45:72–82 [Google Scholar]
  28. Feber A, Clark J, Goodwin G, Dodson AR, Smith PH. 28.  et al. 2004. Amplification and overexpression of E2F3 in human bladder cancer. Oncogene 23:1627–30 [Google Scholar]
  29. Oeggerli M, Schraml P, Ruiz C, Bloch M, Novotny H. 29.  et al. 2006. E2F3 is the main target gene of the 6p22 amplicon with high specificity for human bladder cancer. Oncogene 25:6538–43 [Google Scholar]
  30. Foster CS, Falconer A, Dodson AR, Norman AR, Dennis N. 30.  et al. 2004. Transcription factor E2F3 overexpressed in prostate cancer independently predicts clinical outcome. Oncogene 23:5871–79 [Google Scholar]
  31. Cooper CS, Nicholson AG, Foster C, Dodson A, Edwards S. 31.  et al. 2006. Nuclear overexpression of the E2F3 transcription factor in human lung cancer. Lung Cancer 54:155–62 [Google Scholar]
  32. Hu H-G, Scholten I, Gruss C, Knippers R. 32.  2007. The distribution of the DEK protein in mammalian chromatin. Biochem. Biophys. Res. Commun. 358:1008–14 [Google Scholar]
  33. Lindern M, Fornerod M, van Baal S, Jaegle M, de Wit T. 33.  Von et al. 1992. The translocation (6;9), associated with a specific subtype of acute myeloid leukemia, results in the fusion of two genes, dek and can, and the expression of a chimeric, leukemia-specific dek-can mRNA. Mol. Cell. Biol. 12:1687–97 [Google Scholar]
  34. Lin L, Piao J, Gao W, Piao Y, Jin G. 34.  et al. 2013. DEK over expression as an independent biomarker for poor prognosis in colorectal cancer. BMC Cancer 13:366 [Google Scholar]
  35. Lillington DM, Kingston JE, Coen PG, Price E, Hungerford J. 35.  et al. 2003. Comparative genomic hybridization of 49 primary retinoblastoma tumors identifies chromosomal regions associated with histopathology, progression, and patient outcome. Genes Chromosomes Cancer 36:121–28 [Google Scholar]
  36. Herzog S, Lohmann DR, Buiting K, Schüler A, Horsthemke B. 36.  et al. 2001. Marked differences in unilateral isolated retinoblastomas from young and older children studied by comparative genomic hybridization. Hum. Genet. 108:98–104 [Google Scholar]
  37. Nakagawa T, Tanaka Y, Matsuoka E, Kondo S, Okada Y. 37.  et al. 1997. Identification and classification of 16 new kinesin superfamily (KIF) proteins in mouse genome. PNAS 94:9654–59 [Google Scholar]
  38. Wang Q, Wang L, Li D, Deng J, Zhao Z. 38.  et al. 2013. Kinesin family member 14 is a candidate prognostic marker for outcome of glioma patients. Cancer Epidemiol. 37:79–84 [Google Scholar]
  39. Thériault BL, Pajovic S, Bernardini MQ, Shaw PA, Gallie BL. 39.  2012. Kinesin family member 14: an independent prognostic marker and potential therapeutic target for ovarian cancer. Int. J. Cancer 130:1844–54 [Google Scholar]
  40. Corson TW, Gallie BL. 40.  2006. KIF14 mRNA expression is a predictor of grade and outcome in breast cancer. Int. J. Cancer 119:1088–94 [Google Scholar]
  41. Corson TW, Zhu CQ, Lau SK, Shepherd FA, Tsao MS, Gallie BL. 41.  2007. KIF14 messenger RNA expression is independently prognostic for outcome in lung cancer. Clin. Cancer Res. 13:3229–34 [Google Scholar]
  42. Madhavan J, Coral K, Mallikarjuna K, Corson TW, Amit N. 42.  et al. 2007. High expression of KIF14 in retinoblastoma: association with older age at diagnosis. Investig. Ophthalmol. Vis. Sci. 48:4901–6 [Google Scholar]
  43. Laurie NA, Donovan SL, Shih CS, Zhang J, Mills N. 43.  et al. 2006. Inactivation of the p53 pathway in retinoblastoma. Nature 444:61–66 [Google Scholar]
  44. Roylance R, Gorman P, Papior T, Wan Y-L, Ives M. 44.  et al. 2006. A comprehensive study of chromosome 16q in invasive ductal and lobular breast carcinoma using array CGH. Oncogene 25:6544–53 [Google Scholar]
  45. Laurie N, Mohan A, McEvoy J, Reed D, Zhang J. 45.  et al. 2009. Changes in retinoblastoma cell adhesion associated with optic nerve invasion. Mol. Cell. Biol. 29:6268–82 [Google Scholar]
  46. Kato MV, Shimizu T, Ishizaki K, Kaneko A, Yandell DW. 46.  et al. 1996. Loss of heterozygosity on chromosome 17 and mutation of the p53 gene in retinoblastoma. Cancer Lett. 106:75–82 [Google Scholar]
  47. Horn HF, Vousden KH. 47.  2007. Coping with stress: multiple ways to activate p53. Oncogene 26:1306–16 [Google Scholar]
  48. Marine J-C, Francoz S, Maetens M, Wahl G, Toledo F, Lozano G. 48.  2006. Keeping p53 in check: essential and synergistic functions of Mdm2 and Mdm4. Cell Death Differ. 13:927–34 [Google Scholar]
  49. Marine J-C, Jochemsen AG. 49.  2004. Mdmx and Mdm2: brothers in arms?. Cell Cycle 3:900–4 [Google Scholar]
  50. Castéra L, Sabbagh A, Dehainault C, Michaux D, Mansuet-Lupo A. 50.  et al. 2010. MDM2 as a modifier gene in retinoblastoma. J. Natl. Cancer Inst. 102:1805–8 [Google Scholar]
  51. de Oliveira Reis AH, de Carvalho IN, de Sousa Damasceno PB, Ferman SE, Lucena E. 51.  et al. 2012. Influence of MDM2 and MDM4 on development and survival in hereditary retinoblastoma. Pediatr. Blood Cancer 59:39–43 [Google Scholar]
  52. McEvoy J, Flores-Otero J, Zhang J, Nemeth K, Brennan R. 52.  et al. 2011. Coexpression of normally incompatible developmental pathways in retinoblastoma genesis. Cancer Cell 20:260–75 [Google Scholar]
  53. McEvoy J, Ulyanov A, Brennan R, Wu G, Pounds S. 53.  et al. 2012. Analysis of MDM2 and MDM4 single nucleotide polymorphisms, mRNA splicing and protein expression in retinoblastoma. PLOS ONE 7:e42739 [Google Scholar]
  54. Chi P, Allis CD, Wang GG. 54.  2010. Covalent histone modifications—miswritten, misinterpreted and mis-erased in human cancers. Nat. Rev. Cancer 10:457–69 [Google Scholar]
  55. Lu J, Ruhf M-L, Perrimon N, Leder P. 55.  2007. A genome-wide RNA interference screen identifies putative chromatin regulators essential for E2F repression. PNAS 104:9381–86 [Google Scholar]
  56. Benetti R, Gonzalo S, Jaco I, Muñoz P, Gonzalez S. 56.  et al. 2008. A mammalian microRNA cluster controls DNA methylation and telomere recombination via Rbl2-dependent regulation of DNA methyltransferases. Nat. Struct. Mol. Biol. 15:998 [Google Scholar]
  57. Wen H, Andrejka L, Ashton J, Karess R, Lipsick JS. 57.  2008. Epigenetic regulation of gene expression by Drosophila Myb and E2F2-RBF via the Myb-MuvB/dREAM complex. Genes Dev. 22:601–14 [Google Scholar]
  58. Bourgo RJ, Siddiqui H, Fox S, Solomon D, Sansam CG. 58.  et al. 2009. SWI/SNF deficiency results in aberrant chromatin organization, mitotic failure, and diminished proliferative capacity. Mol. Biol. Cell 20:3192–99 [Google Scholar]
  59. Gonzalo S, Blasco MA. 59.  2005. Role of Rb family in the epigenetic definition of chromatin. Cell Cycle 4:752–55 [Google Scholar]
  60. Chen K, Rajewsky N. 60.  2007. The evolution of gene regulation by transcription factors and microRNAs. Nat. Rev. Genet. 8:93–103 [Google Scholar]
  61. Bartel DP. 61.  2009. MicroRNAs: target recognition and regulatory functions. Cell 136:215–33 [Google Scholar]
  62. Zhao JJ, Yang J, Lin J, Yao N, Zhu Y. 62.  et al. 2009. Identification of miRNAs associated with tumorigenesis of retinoblastoma by miRNA microarray analysis. Child's Nerv. Syst. 25:13–20 [Google Scholar]
  63. Conkrite K, Sundby M, Mukai S, Thomson JM, Mu D. 63.  et al. 2011. miR-17∼92 cooperates with RB pathway mutations to promote retinoblastoma. Genes Dev. 25:1734–45 [Google Scholar]
  64. Li BQ, Zhang J, Huang T, Zhang L, Cai YD. 64.  2012. Identification of retinoblastoma related genes with shortest path in a protein-protein interaction network. Biochimie 94:1910–17 [Google Scholar]
  65. Dalgard CL, Gonzalez M, deNiro JE, O'Brien JM. 65.  2009. Differential microRNA-34a expression and tumor suppressor function in retinoblastoma cells. Investig. Ophthalmol. Vis. Sci. 50:4542–51 [Google Scholar]
  66. Jo DH, Kim JH, Park WY, Kim KW, Yu YS. 66.  2011. Differential profiles of microRNAs in retinoblastoma cell lines of different proliferation and adherence patterns. J. Pediatr. Hematol. Oncol. 33:529–33 [Google Scholar]
  67. Johnson SM, Grosshans H, Shingara J, Byrom M, Jarvis R. 67.  et al. 2005. RAS is regulated by the let-7 microRNA family. Cell 120:635–47 [Google Scholar]
  68. Lee YS, Dutta A. 68.  2007. The tumor suppressor microRNA let-7 represses the HMGA2 oncogene. Genes Dev. 21:1025–30 [Google Scholar]
  69. Mayr C, Hemann MT, Bartel DP. 69.  2007. Disrupting the pairing between let-7 and Hmga2 enhances oncogenic transformation. Science 315:1576–79 [Google Scholar]
  70. Sampson VB, Rong NH, Han J, Yang Q, Aris V. 70.  et al. 2007. MicroRNA let-7a down-regulates MYC and reverts MYC-induced growth in Burkitt lymphoma cells. Cancer Res. 67:9762–70 [Google Scholar]
  71. Mu G, Liu H, Zhou F, Xu X, Jiang H. 71.  et al. 2010. Correlation of overexpression of HMGA1 and HMGA2 with poor tumor differentiation, invasion, and proliferation associated with let-7 down-regulation in retinoblastomas. Hum. Pathol. 41:493–502 [Google Scholar]
  72. Huang JC, Babak T, Corson TW, Chua G, Khan S. 72.  et al. 2007. Using expression profiling data to identify human microRNA targets. Nat. Methods 4:1045–49 [Google Scholar]
  73. Martin J, Bryar P, Mets M, Weinstein J, Jones A. 73.  et al. 2013. Differentially expressed miRNAs in retinoblastoma. Gene 512:294–99 [Google Scholar]
  74. Chang TC, Wentzel EA, Kent OA, Ramachandran K, Mullendore M. 74.  et al. 2007. Transactivation of miR-34a by p53 broadly influences gene expression and promotes apoptosis. Mol. Cell 26:745–52 [Google Scholar]
  75. He L, He X, Lim LP, de Stanchina E, Xuan Z. 75.  et al. 2007. A microRNA component of the p53 tumour suppressor network. Nature 447:1130–34 [Google Scholar]
  76. Raver-Shapira N, Marciano E, Meiri E, Spector Y, Rosenfeld N. 76.  et al. 2007. Transcriptional activation of miR-34a contributes to p53-mediated apoptosis. Mol. Cell 26:731–43 [Google Scholar]
  77. Tarasov V, Jung P, Verdoodt B, Lodygin D, Epanchintsev A. 77.  et al. 2007. Differential regulation of microRNAs by p53 revealed by massively parallel sequencing: miR-34a is a p53 target that induces apoptosis and G1-arrest. Cell Cycle 6:1586–93 [Google Scholar]
  78. Sage J, Ventura A. 78.  2011. miR than meets the eye. Genes Dev. 25:1663–67 [Google Scholar]
  79. Ventura A, Young AG, Winslow MM, Lintault L, Meissner A. 79.  et al. 2008. Targeted deletion reveals essential and overlapping functions of the miR-17∼92 family of miRNA clusters. Cell 132:875–86 [Google Scholar]
  80. He L, Thomson JM, Hemann MT, Hernando-Monge E, Mu D. 80.  et al. 2005. A microRNA polycistron as a potential human oncogene. Nature 435:828–33 [Google Scholar]
  81. Olive V, Jiang I, He L. 81.  2010. mir-17-92, a cluster of miRNAs in the midst of the cancer network. Int. J. Biochem. Cell Biol. 42:1348–54 [Google Scholar]
  82. Sylvestre Y, De Guire V, Querido E, Mukhopadhyay UK, Bourdeau V. 82.  et al. 2007. An E2F/miR-20a autoregulatory feedback loop. J. Biol. Chem. 282:2135–43 [Google Scholar]
  83. Woods K, Thomson JM, Hammond SM. 83.  2007. Direct regulation of an oncogenic micro-RNA cluster by E2F transcription factors. J. Biol. Chem. 282:2130–34 [Google Scholar]
  84. Nittner D, Lambertz I, Clermont F, Mestdagh P, Köhler C. 84.  et al. 2012. Synthetic lethality between Rb, p53 and Dicer or miR-17–92 in retinal progenitors suppresses retinoblastoma formation. Nat. Cell Biol. 14:958–65 [Google Scholar]
  85. Reis AH, Vargas FR, Lemos B. 85.  2012. More epigenetic hits than meets the eye: microRNAs and genes associated with the tumorigenesis of retinoblastoma. Front. Genet. 3:284 [Google Scholar]
  86. Greger V, Passarge E, Höpping W, Messmer E, Horsthemke B. 86.  1989. Epigenetic changes may contribute to the formation and spontaneous regression of retinoblastoma. Hum. Genet. 83:155–58 [Google Scholar]
  87. Sakai T, Toguchida J, Ohtani N, Yandell DW, Rapaport JM, Dryja TP. 87.  1991. Allele-specific hypermethylation of the retinoblastoma tumor-suppressor gene. Am. J. Hum. Genet. 48:880–88 [Google Scholar]
  88. Ohtani-Fujita N, Fujita T, Aoike A, Osifchin NE, Robbins PD, Sakai T. 88.  1993. CpG methylation inactivates the promoter activity of the human retinoblastoma tumor-suppressor gene. Oncogene 8:1063–67 [Google Scholar]
  89. Ohtani-Fujita N, Dryja TP, Rapaport JM, Fujita T, Matsumura S. 89.  et al. 1997. Hypermethylation in the retinoblastoma gene is associated with unilateral, sporadic retinoblastoma. Cancer Genet. Cytogenet. 98:43–49 [Google Scholar]
  90. Richter S, Vandezande K, Chen N, Zhang K, Sutherland J. 90.  et al. 2003. Sensitive and efficient detection of RB1 gene mutations enhances care for families with retinoblastoma. Am. J. Hum. Genet. 72:253–69 [Google Scholar]
  91. Livide G, Epistolato MC, Amenduni M, Disciglio V, Marozza A. 91.  et al. 2012. Epigenetic and copy number variation analysis in retinoblastoma by MS-MLPA. Pathol. Oncol. Res. 18:703–12 [Google Scholar]
  92. Harada K, Toyooka S, Maitra A, Maruyama R, Toyooka KO. 92.  et al. 2002. Aberrant promoter methylation and silencing of the RASSF1A gene in pediatric tumors and cell lines. Oncogene 21:4345–49 [Google Scholar]
  93. Choy KW, Lee TC, Cheung KF, Fan DS, Lo KW. 93.  et al. 2005. Clinical implications of promoter hypermethylation in RASSF1A and MGMT in retinoblastoma. Neoplasia 7:200–6 [Google Scholar]
  94. Indovina P, Acquaviva A, De Falco G, Rizzo V, Onnis A. 94.  et al. 2010. Downregulation and aberrant promoter methylation of p16INK4A: a possible novel heritable susceptibility marker to retinoblastoma. J. Cell. Physiol. 223:143–50 [Google Scholar]
  95. Rushlow DE, Mol BM, Kennett JY, Yee S, Pajovic S. 95.  et al. 2013. Characterisation of retinoblastomas without RB1 mutations: genomic, gene expression, and clinical studies. Lancet Oncol. 14:327–34 [Google Scholar]
  96. Sears R, Ohtani K, Nevins JR. 96.  1997. Identification of positively and negatively acting elements regulating expression of the E2F2 gene in response to cell growth signals. Mol. Cell. Biol. 17:5227–35 [Google Scholar]
  97. Adams MR, Sears R, Nuckolls F, Leone G, Nevins JR. 97.  2000. Complex transcriptional regulatory mechanisms control expression of the E2F3 locus. Mol. Cell. Biol. 20:3633–39 [Google Scholar]
  98. Leone G, Sears R, Huang E, Rempel R, Nuckolls F. 98.  et al. 2001. Myc requires distinct E2F activities to induce S phase and apoptosis. Mol. Cell 8:105–13 [Google Scholar]
  99. Stephens PJ, Greenman CD, Fu B, Yang F, Bignell GR. 99.  et al. 2011. Massive genomic rearrangement acquired in a single catastrophic event during cancer development. Cell 144:27–40 [Google Scholar]
  100. McEvoy J, Nagahawatte P, Finkelstein D, Richards-Yutz J, Valentine M. 100.  et al. 2014. RB1 gene inactivation by chromothripsis in human retinoblastoma. Oncotarget 5:2438–50 [Google Scholar]
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