1932

Abstract

During tumor evolution, cancer cells can accumulate numerous genetic alterations, ranging from single nucleotide mutations to whole-chromosomal changes. Although a great deal of progress has been made in the past decades in characterizing genomic alterations, recent cancer genome sequencing studies have provided a wealth of information on the detailed molecular profiles of such alterations in various types of cancers. Here, we review our current understanding of the mechanisms and consequences of cancer genome instability, focusing on the findings uncovered through analysis of exome and whole-genome sequencing data. These analyses have shown that most cancers have evidence of genome instability, and the degree of instability is variable within and between cancer types. Importantly, we describe some recent evidence supporting the idea that chromosomal instability could be a major driving force in tumorigenesis and cancer evolution, actively shaping the genomes of cancer cells to maximize their survival advantage.

Loading

Article metrics loading...

/content/journals/10.1146/annurev-pathol-012615-044446
2016-05-23
2024-03-28
Loading full text...

Full text loading...

/deliver/fulltext/pathol/11/1/annurev-pathol-012615-044446.html?itemId=/content/journals/10.1146/annurev-pathol-012615-044446&mimeType=html&fmt=ahah

Literature Cited

  1. Boveri T. 1.  1914. Zur frage der entstehung maligner tumoren Jena, Ger.: Gustav Fischer
  2. Sieber OM, Heinimann K, Tomlinson IPM. 2.  2003. Genomic instability—the engine of tumorigenesis?. Nat. Rev. Cancer 3:9701–8 [Google Scholar]
  3. Holland AJ, Cleveland DW. 3.  2009. Boveri revisited: chromosomal instability, aneuploidy and tumorigenesis. Nat. Rev. Mol. Cell Biol. 10:7478–87 [Google Scholar]
  4. Negrini S, Gorgoulis VG, Halazonetis TD. 4.  2010. Genomic instability—an evolving hallmark of cancer. Nat. Rev. Mol. Cell Biol. 11:3220–28 [Google Scholar]
  5. Hanahan D, Weinberg RA. 5.  2011. Hallmarks of cancer: the next generation. Cell 144:5646–74 [Google Scholar]
  6. Cooper GM. 6.  1982. Cellular transforming genes. Science 217:4562801–6 [Google Scholar]
  7. Vogelstein B, Papadopoulos N, Velculescu VE, Zhou S, Diaz LA, Kinzler KW. 7.  2013. Cancer genome landscapes. Science 339:61271546–58 [Google Scholar]
  8. Lawrence MS, Stojanov P, Mermel CH, Robinson JT, Garraway LA. 8.  et al. 2014. Discovery and saturation analysis of cancer genes across 21 tumour types. Nature 505:7484495–501 [Google Scholar]
  9. Lengauer C, Kinzler KW, Vogelstein B. 9.  1998. Genetic instabilities in human cancers. Nature 396:6712643–49 [Google Scholar]
  10. Gerlinger M, Rowan AJ, Horswell S, Larkin J, Endesfelder D. 10.  et al. 2012. Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. N. Engl. J. Med. 366:10883–92 [Google Scholar]
  11. de Bruin EC, McGranahan N, Mitter R, Salm M, Wedge DC. 11.  et al. 2014. Spatial and temporal diversity in genomic instability processes defines lung cancer evolution. Science 346:6206251–56 [Google Scholar]
  12. Zhang J, Fujimoto J, Zhang J, Zhang J, Wedge DC. 12.  et al. 2014. Intratumor heterogeneity in localized lung adenocarcinomas delineated by multiregion sequencing. Science 346:6206256–59 [Google Scholar]
  13. Sjöblom T, Jones S, Wood LD, Parsons DW, Lin J. 13.  et al. 2006. The consensus coding sequences of human breast and colorectal cancers. Science 314:5797268–74 [Google Scholar]
  14. Wood LD, Parsons DW, Jones S, Lin J, Sjöblom T. 14.  et al. 2007. The genomic landscapes of human breast and colorectal cancers. Science 318:58531108–13 [Google Scholar]
  15. Lawrence MS, Stojanov P, Polak P, Kryukov GV, Cibulskis K. 15.  et al. 2013. Mutational heterogeneity in cancer and the search for new cancer-associated genes. Nature 499:7457214–18 [Google Scholar]
  16. Alexandrov LB, Nik-Zainal S, Wedge DC, Aparicio SAJR, Behjati S. 16.  et al. 2013. Signatures of mutational processes in human cancer. Nature 500:7463415–21 [Google Scholar]
  17. Mack S, Witt H, Piro R, Gu L, Zuyderduyn S. 17.  et al. 2014. Epigenomic alterations define lethal CIMP-positive ependymomas of infancy. Nature 506:7489445–50 [Google Scholar]
  18. 18. Cancer Genome Atlas Network 2012. Comprehensive molecular characterization of human colon and rectal cancer. Nature 487:7407330–37 [Google Scholar]
  19. Shaffer LG, McGowan-Jordan J, Schmid M. 19.  2013. ISCN 2013: An International System for Human Cytogenetic Nomenclature (2013) Basel, Switz.: Karger [Google Scholar]
  20. Kallioniemi A, Kallioniemi O-P, Sudar D, Rutovitz D, Gray JW. 20.  et al. 1992. Comparative genomic hybridization for molecular cytogenetic analysis of solid tumors. Science 258:5083818–21 [Google Scholar]
  21. Mei R, Galipeau PC, Prass C, Berno A, Ghandour G. 21.  et al. 2000. Genome-wide detection of allelic imbalance using human SNPs and high-density DNA arrays. Genome Res. 10:81126–37 [Google Scholar]
  22. Nowell PC, Hungerford DA. 22.  1960. Chromosome studies on normal and leukemic human leukocytes. J. Natl. Cancer Inst. 25:185–109 [Google Scholar]
  23. Rowley JD. 23.  2001. Chromosome translocations: dangerous liaisons revisited. Nat. Rev. Cancer 1:3245–50 [Google Scholar]
  24. Yang L, Luquette LJ, Gehlenborg N, Xi R, Haseley PS. 24.  et al. 2013. Diverse mechanisms of somatic structural variations in human cancer genomes. Cell 153:4919–29 [Google Scholar]
  25. Stephens PJ, McBride DJ, Lin M-L, Varela I, Pleasance ED. 25.  et al. 2009. Complex landscapes of somatic rearrangement in human breast cancer genomes. Nature 462:72761005–10 [Google Scholar]
  26. Stephens PJ, Greenman CD, Fu B, Yang F, Bignell GR. 26.  et al. 2011. Massive genomic rearrangement acquired in a single catastrophic event during cancer development. Cell 144:127–40 [Google Scholar]
  27. Gordon DJ, Resio B, Pellman D. 27.  2012. Causes and consequences of aneuploidy in cancer. Nat. Rev. Genet. 13:3189–203 [Google Scholar]
  28. Beroukhim R, Mermel CH, Porter D, Wei G, Raychaudhuri S. 28.  et al. 2010. The landscape of somatic copy-number alteration across human cancers. Nature 463:7283899–905 [Google Scholar]
  29. Bignell GR, Greenman CD, Davies H, Butler AP, Edkins S. 29.  et al. 2010. Signatures of mutation and selection in the cancer genome. Nature 463:7283893–98 [Google Scholar]
  30. Kim TM, Xi R, Luquette LJ, Park RW, Johnson MD, Park PJ. 30.  2013. Functional genomic analysis of chromosomal aberrations in a compendium of 8000 cancer genomes. Genome Res. 23:2217–27 [Google Scholar]
  31. Kops GJ, Weaver BA, Cleveland DW. 31.  2005. On the road to cancer: aneuploidy and the mitotic checkpoint. Nat. Rev. Cancer 5:10773–85 [Google Scholar]
  32. Michel LS, Liberal V, Chatterjee A, Kirchwegger R, Pasche B. 32.  et al. 2001. MAD2 haplo-insufficiency causes premature anaphase and chromosome instability in mammalian cells. Nature 409:6818355–59 [Google Scholar]
  33. Jeganathan K, Malureanu L, Baker DJ, Abraham SC, van Deursen JM. 33.  2007. Bub1 mediates cell death in response to chromosome missegregation and acts to suppress spontaneous tumorigenesis. J. Cell Biol. 179:2255–67 [Google Scholar]
  34. Rao CV, Yang YM, Swamy MV, Liu T, Fang Y. 34.  et al. 2005. Colonic tumorigenesis in BubR1+/−ApcMin/+ compound mutant mice is linked to premature separation of sister chromatids and enhanced genomic instability. PNAS 102:124365–70 [Google Scholar]
  35. Babu JR, Jeganathan KB, Baker DJ, Wu X, Kang-Decker N, van Deursen JM. 35.  2003. Rae1 is an essential mitotic checkpoint regulator that cooperates with Bub3 to prevent chromosome missegregation. J. Cell Biol. 160:3341–53 [Google Scholar]
  36. Dai W, Wang Q, Liu T, Swamy M, Fang Y. 36.  et al. 2004. Slippage of mitotic arrest and enhanced tumor development in mice with BUBR1 haploinsufficiency. Cancer Res. 64:2440–45 [Google Scholar]
  37. Weaver BA, Silk AD, Montagna C, Verdier-Pinard P, Cleveland DW. 37.  2007. Aneuploidy acts both oncogenically and as a tumor suppressor. Cancer Cell 11:125–36 [Google Scholar]
  38. Chesnokova V, Kovacs K, Castro AV, Zonis S, Melmed S. 38.  2005. Pituitary hypoplasia in Pttg−/− mice is protective for Rb+/− pituitary tumorigenesis. Mol. Endocrinol. 19:92371–79 [Google Scholar]
  39. Torres EM, Sokolsky T, Tucker CM, Chan LY, Boselli M. 39.  et al. 2007. Effects of aneuploidy on cellular physiology and cell division in haploid yeast. Science 317:5840916–24 [Google Scholar]
  40. Williams BR, Prabhu VR, Hunter KE, Glazier CM, Whittaker CA. 40.  et al. 2008. Aneuploidy affects proliferation and spontaneous immortalization in mammalian cells. Science 322:5902703–9 [Google Scholar]
  41. Thompson SL, Compton DA. 41.  2010. Proliferation of aneuploid human cells is limited by a p53-dependent mechanism. J. Cell Biol. 188:3369–81 [Google Scholar]
  42. Torres EM, Dephoure N, Panneerselvam A, Tucker CM, Whittaker CA. 42.  et al. 2010. Identification of aneuploidy-tolerating mutations. Cell 143:171–83 [Google Scholar]
  43. Solimini NL, Xu Q, Mermel CH, Liang AC, Schlabach MR. 43.  et al. 2012. Recurrent hemizygous deletions in cancers may optimize proliferative potential. Science 337:6090104–9 [Google Scholar]
  44. Davoli T, Xu AW, Mengwasser KE, Sack LM, Yoon JC. 44.  et al. 2013. Cumulative haploinsufficiency and triplosensitivity drive aneuploidy patterns and shape the cancer genome. Cell 155:4948–62 [Google Scholar]
  45. Macheret M, Halazonetis TD. 45.  2015. DNA replication stress as a hallmark of cancer. Annu. Rev. Pathol. 10:425–48 [Google Scholar]
  46. Zeman MK, Cimprich KA. 46.  2013. Causes and consequences of replication stress. Nat. Cell Biol. 16:12–9 [Google Scholar]
  47. Petermann E, Orta ML, Issaeva N, Schultz N, Helleday T. 47.  2010. Hydroxyurea-stalled replication forks become progressively inactivated and require two different RAD51-mediated pathways for restart and repair. Mol. Cell 37:4492–502 [Google Scholar]
  48. Bartkova J, Rezaei N, Liontos M, Karakaidos P, Kletsas D. 48.  et al. 2006. Oncogene-induced senescence is part of the tumorigenesis barrier imposed by DNA damage checkpoints. Nature 444:7119633–37 [Google Scholar]
  49. Di Micco R, Fumagalli M, Cicalese A, Piccinin S, Gasparini P. 49.  et al. 2006. Oncogene-induced senescence is a DNA damage response triggered by DNA hyper-replication. Nature 444:7119638–42 [Google Scholar]
  50. Halazonetis TD, Gorgoulis VG, Bartek J. 50.  2008. An oncogene-induced DNA damage model for cancer development. Science 319:58681352–55 [Google Scholar]
  51. Durkin SG, Glover TW. 51.  2007. Chromosome fragile sites. Annu. Rev. Genet. 41:169–92 [Google Scholar]
  52. Gorgoulis VG, Vassiliou L-VF, Karakaidos P, Zacharatos P, Kotsinas A. 52.  et al. 2005. Activation of the DNA damage checkpoint and genomic instability in human precancerous lesions. Nature 434:7035907–13 [Google Scholar]
  53. Costantino L, Sotiriou SK, Rantala JK, Magin S, Mladenov E. 53.  et al. 2014. Break-induced replication repair of damaged forks induces genomic duplications in human cells. Science 343:616688–91 [Google Scholar]
  54. McBride DJ, Etemadmoghadam D, Cooke SL, Alsop K, George J. 54.  et al. 2012. Tandem duplication of chromosomal segments is common in ovarian and breast cancer genomes. J. Pathol. 227:4446–55 [Google Scholar]
  55. Burrell RA, McClelland SE, Endesfelder D, Groth P, Weller M-C. 55.  et al. 2013. Replication stress links structural and numerical cancer chromosomal instability. Nature 494:7438492–96 [Google Scholar]
  56. Coschi CH, Ishak CA, Gallo D, Marshall A, Talluri S. 56.  et al. 2014. Haploinsufficiency of an RB-E2F1-Condensin II complex leads to aberrant replication and aneuploidy. Cancer Discov. 4:7840–53 [Google Scholar]
  57. Fearon ER, Vogelstein B. 57.  1990. A genetic model for colorectal tumorigenesis. Cell 61:5759–67 [Google Scholar]
  58. Weaver JMJ, Ross-Innes CS, Shannon N, Lynch AG, Forshew T. 58.  et al. 2014. Ordering of mutations in preinvasive disease stages of esophageal carcinogenesis. Nat. Genet. 46:8837–43 [Google Scholar]
  59. Nordentoft I, Lamy P, Birkenkamp-Demtroder K, Shumansky K, Vang S. 59.  et al. 2014. Mutational context and diverse clonal development in early and late bladder cancer. Cell Rep. 7:51649–63 [Google Scholar]
  60. Tighe A, Johnson VL, Albertella M, Taylor SS. 60.  2001. Aneuploid colon cancer cells have a robust spindle checkpoint. EMBO Rep. 2:7609–14 [Google Scholar]
  61. Gascoigne KE, Taylor SS. 61.  2008. Cancer cells display profound intra- and interline variation following prolonged exposure to antimitotic drugs. Cancer Cell 14:2111–22 [Google Scholar]
  62. Cahill DP, Lengauer C, Yu J, Riggins GJ, Willson JKV. 62.  et al. 1998. Mutations of mitotic checkpoint genes in human cancers. Nature 392:6673300–3 [Google Scholar]
  63. Barber TD, McManus K, Yuen KW, Reis M, Parmigiani G. 63.  et al. 2008. Chromatid cohesion defects may underlie chromosome instability in human colorectal cancers. PNAS 105:93443–48 [Google Scholar]
  64. Manning AL, Yazinski SA, Nicolay B, Bryll A, Zou L, Dyson NJ. 64.  2014. Suppression of genome instability in pRB-deficient cells by enhancement of chromosome cohesion. Mol. Cell 53:6993–1004 [Google Scholar]
  65. Solomon DA, Kim T, Diaz-Martinez LA, Fair J, Elkahloun AG. 65.  et al. 2011. Mutational inactivation of STAG2 causes aneuploidy in human cancer. Science 333:60451039–43 [Google Scholar]
  66. Balbás-Martínez C, Sagrera A, Carrillo-de-Santa-Pau E, Earl J, Márquez M. 66.  et al. 2013. Recurrent inactivation of STAG2 in bladder cancer is not associated with aneuploidy. Nat. Genet. 45:121464–69 [Google Scholar]
  67. Thompson SL, Compton DA. 67.  2008. Examining the link between chromosomal instability and aneuploidy in human cells. J. Cell Biol. 180:4665–72 [Google Scholar]
  68. Holland AJ, Cleveland DW. 68.  2012. Losing balance: the origin and impact of aneuploidy in cancer. EMBO Rep. 13:6501–14 [Google Scholar]
  69. Bakhoum SF, Thompson SL, Manning AL, Compton DA. 69.  2009. Genome stability is ensured by temporal control of kinetochore-microtubule dynamics. Nat. Cell Biol. 11:127–35 [Google Scholar]
  70. Bakhoum SF, Genovese G, Compton DA. 70.  2009. Deviant kinetochore microtubule dynamics underlie chromosomal instability. Curr. Biol. 19:221937–42 [Google Scholar]
  71. Ganem NJ, Godinho SA, Pellman D. 71.  2009. A mechanism linking extra centrosomes to chromosomal instability. Nature 460:7252278–82 [Google Scholar]
  72. Quintyne NJ, Reing JE, Hoffelder DR, Gollin SM, Saunders WS. 72.  2005. Spindle multipolarity is prevented by centrosomal clustering. Science 307:5706127–29 [Google Scholar]
  73. Storchova Z, Kuffer C. 73.  2008. The consequences of tetraploidy and aneuploidy. J. Cell Sci. 121:Pt. 233859–66 [Google Scholar]
  74. Levine DS, Rabinovitch PS, Haggitt RC, Blount PL, Dean PJ. 74.  et al. 1991. Distribution of aneuploid cell populations in ulcerative colitis with dysplasia or cancer. Gastroenterology 101:51198–210 [Google Scholar]
  75. Galipeau PC, Cowan DS, Sanchez CA, Barrett MT, Emond MJ. 75.  et al. 1996. 17p (p53) allelic losses, 4N (G2/tetraploid) populations, and progression to aneuploidy in Barrett's esophagus. PNAS 93:147081–84 [Google Scholar]
  76. Olaharski AJ, Sotelo R, Solorza-Luna G, Gonsebatt ME, Guzman P. 76.  et al. 2006. Tetraploidy and chromosomal instability are early events during cervical carcinogenesis. Carcinogenesis 27:2337–43 [Google Scholar]
  77. Fodde R, Kuipers J, Rosenberg C, Smits R, Kielman M. 77.  et al. 2001. Mutations in the APC tumour suppressor gene cause chromosomal instability. Nat. Cell Biol. 3:4433–38 [Google Scholar]
  78. Wang X, Zhou YX, Qiao W, Tominaga Y, Ouchi M. 78.  et al. 2006. Overexpression of aurora kinase A in mouse mammary epithelium induces genetic instability preceding mammary tumor formation. Oncogene 25:547148–58 [Google Scholar]
  79. Dewhurst SM, McGranahan N, Burrell RA, Rowan AJ, Gronroos E. 79.  et al. 2014. Tolerance of whole-genome doubling propagates chromosomal instability and accelerates cancer genome evolution. Cancer Discov. 4:2175–85 [Google Scholar]
  80. Selmecki AM, Maruvka YE, Richmond PA, Guillet M, Shoresh N. 80.  et al. 2015. Polyploidy can drive rapid adaptation in yeast. Nature 519:7543349–52 [Google Scholar]
  81. Fujiwara T, Bandi M, Nitta M, Ivanova EV, Bronson RT, Pellman D. 81.  2005. Cytokinesis failure generating tetraploids promotes tumorigenesis in p53-null cells. Nature 437:70611043–47 [Google Scholar]
  82. Maser RS, DePinho RA. 82.  2002. Connecting chromosomes, crisis, and cancer. Science 297:5581565–69 [Google Scholar]
  83. Artandi SE, DePinho RA. 83.  2010. Telomeres and telomerase in cancer. Carcinogenesis 31:19–18 [Google Scholar]
  84. Engelhardt M, Drullinsky P, Guillem J, Moore MA. 84.  1997. Telomerase and telomere length in the development and progression of premalignant lesions to colorectal cancer. Clin. Cancer Res. 3:111931–41 [Google Scholar]
  85. Roger L, Jones RE, Heppel NH, Williams GT, Sampson JR, Baird DM. 85.  2013. Extensive telomere erosion in the initiation of colorectal adenomas and its association with chromosomal instability. J. Natl. Cancer Inst. 105:161202–11 [Google Scholar]
  86. Chin K, de Solorzano CO, Knowles D, Jones A, Chou W. 86.  et al. 2004. In situ analyses of genome instability in breast cancer. Nat. Genet. 36:9984–88 [Google Scholar]
  87. McClintock B. 87.  1938. The production of homozygous deficient tissues with mutant characteristics by means of the aberrant mitotic behavior of ring-shaped chromosomes. Genetics 23:4315–76 [Google Scholar]
  88. De Lange T. 88.  2005. Telomere-related genome instability in cancer. Cold Spring Harb. Symp. Quant. Biol. 70:197–204 [Google Scholar]
  89. Artandi SE, Chang S, Lee SL, Alson S, Gottlieb GJ. 89.  et al. 2000. Telomere dysfunction promotes non-reciprocal translocations and epithelial cancers in mice. Nature 406:6796641–45 [Google Scholar]
  90. O'Hagan RC, Chang S, Maser RS, Mohan R, Artandi SE. 90.  et al. 2002. Telomere dysfunction provokes regional amplification and deletion in cancer genomes. Cancer Cell 2:2149–55 [Google Scholar]
  91. Else T, Trovato A, Kim AC, Wu Y, Ferguson DO. 91.  et al. 2009. Genetic p53 deficiency partially rescues the adrenocortical dysplasia phenotype at the expense of increased tumorigenesis. Cancer Cell 15:6465–76 [Google Scholar]
  92. Davoli T, Denchi EL, de Lange T. 92.  2010. Persistent telomere damage induces bypass of mitosis and tetraploidy. Cell 141:181–93 [Google Scholar]
  93. Carter SL, Cibulskis K, Helman E, McKenna A, Shen H. 93.  et al. 2012. Absolute quantification of somatic DNA alterations in human cancer. Nat. Biotechnol. 30:5413–21 [Google Scholar]
  94. Lovejoy CA, Li W, Reisenweber S, Thongthip S, Bruno J. 94.  et al. 2012. Loss of ATRX, genome instability, and an altered DNA damage response are hallmarks of the alternative lengthening of telomeres pathway. PLOS Genet. 8:7e1002772 [Google Scholar]
  95. Zack TI, Schumacher SE, Carter SL, Cherniack AD, Saksena G. 95.  et al. 2013. Pan-cancer patterns of somatic copy number alteration. Nat. Genet. 45:101134–40 [Google Scholar]
  96. Xi R, Hadjipanayis AG, Luquette LJ, Kim TM, Lee E. 96.  et al. 2011. Copy number variation detection in whole-genome sequencing data using the Bayesian information criterion. PNAS 108:46E1128–36 [Google Scholar]
  97. Gong Y, Zack TI, Morris LG, Lin K, Hukkelhoven E. 97.  et al. 2014. Pan-cancer genetic analysis identifies PARK2 as a master regulator of G1/S cyclins. Nat. Genet. 46:6588–94 [Google Scholar]
  98. Brennan CW, Verhaak RGW, McKenna A, Campos B, Noushmehr H. 98.  et al. 2013. The somatic genomic landscape of glioblastoma. Cell 155:2462–77 [Google Scholar]
  99. Myllykangas S, Himberg J, Bohling T, Nagy B, Hollmen J, Knuutila S. 99.  2006. DNA copy number amplification profiling of human neoplasms. Oncogene 25:557324–32 [Google Scholar]
  100. Tomlins SA, Rhodes DR, Perner S, Dhanasekaran SM, Mehra R. 100.  et al. 2005. Recurrent fusion of TMPRSS2 and ETS transcription factor genes in prostate cancer. Science 310:5748644–48 [Google Scholar]
  101. Soda M, Choi YL, Enomoto M, Takada S, Yamashita Y. 101.  et al. 2007. Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer. Nature 448:7153561–66 [Google Scholar]
  102. Takeuchi K, Soda M, Togashi Y, Suzuki R, Sakata S. 102.  et al. 2012. RET, ROS1 and ALK fusions in lung cancer. Nat. Med. 18:3378–81 [Google Scholar]
  103. Druker BJ, Talpaz M, Resta DJ, Peng B, Buchdunger E. 103.  et al. 2001. Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. N. Engl. J. Med. 344:141031–37 [Google Scholar]
  104. Kwak EL, Bang YJ, Camidge DR, Shaw AT, Solomon B. 104.  et al. 2010. Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer. N. Engl. J. Med. 363:181693–703 [Google Scholar]
  105. Maher CA, Kumar-Sinha C, Cao X, Kalyana-Sundaram S, Han B. 105.  et al. 2009. Transcriptome sequencing to detect gene fusions in cancer. Nature 458:723497–101 [Google Scholar]
  106. Ju YS, Lee WC, Shin JY, Lee S, Bleazard T. 106.  et al. 2012. A transforming KIF5B and RET gene fusion in lung adenocarcinoma revealed from whole-genome and transcriptome sequencing. Genome Res. 22:3436–45 [Google Scholar]
  107. Singh D, Chan JM, Zoppoli P, Niola F, Sullivan R. 107.  et al. 2012. Transforming fusions of FGFR and TACC genes in human glioblastoma. Science 337:60991231–35 [Google Scholar]
  108. Korbel JO, Urban AE, Affourtit JP, Godwin B, Grubert F. 108.  et al. 2007. Paired-end mapping reveals extensive structural variation in the human genome. Science 318:5849420–26 [Google Scholar]
  109. Campbell PJ, Stephens PJ, Pleasance ED, O'Meara S, Li H. 109.  et al. 2008. Identification of somatically acquired rearrangements in cancer using genome-wide massively parallel paired-end sequencing. Nat. Genet. 40:6722–29 [Google Scholar]
  110. Drier Y, Lawrence MS, Carter SL, Stewart C, Gabriel SB. 110.  et al. 2013. Somatic rearrangements across cancer reveal classes of samples with distinct patterns of DNA breakage and rearrangement-induced hypermutability. Genome Res. 23:2228–35 [Google Scholar]
  111. Hastings PJ, Lupski JR, Rosenberg SM, Ira G. 111.  2009. Mechanisms of change in gene copy number. Nat. Rev. Genet. 10:8551–64 [Google Scholar]
  112. Lee E, Iskow R, Yang L, Gokcumen O, Haseley P. 112.  et al. 2012. Landscape of somatic retrotransposition in human cancers. Science 337:6097967–71 [Google Scholar]
  113. Solyom S, Ewing AD, Rahrmann EP, Doucet T, Nelson HH. 113.  et al. 2012. Extensive somatic L1 retrotransposition in colorectal tumors. Genome Res. 22:122328–38 [Google Scholar]
  114. Helman E, Lawrence MS, Stewart C, Sougnez C, Getz G, Meyerson M. 114.  2014. Somatic retrotransposition in human cancer revealed by whole-genome and exome sequencing. Genome Res. 24:71053–63 [Google Scholar]
  115. Tubio JMC, Li Y, Ju YS, Martincorena I, Cooke SL. 115.  et al. 2014. Extensive transduction of nonrepetitive DNA mediated by L1 retrotransposition in cancer genomes. Science 345:61961251343 [Google Scholar]
  116. Miki Y, Nishisho I, Horii A, Miyoshi Y, Utsunomiya J. 116.  et al. 1992. Disruption of the APC gene by a retrotransposal insertion of L1 sequence in a colon cancer. Cancer Res. 52:3643–45 [Google Scholar]
  117. Iskow RC, McCabe MT, Mills RE, Torene S, Pittard WS. 117.  et al. 2010. Natural mutagenesis of human genomes by endogenous retrotransposons. Cell 141:71253–61 [Google Scholar]
  118. Korbel JO, Campbell PJ. 118.  2013. Criteria for inference of chromothripsis in cancer genomes. Cell 152:61226–36 [Google Scholar]
  119. Forment JV, Kaidi A, Jackson SP. 119.  2012. Chromothripsis and cancer: causes and consequences of chromosome shattering. Nat. Rev. Cancer 12:10663–70 [Google Scholar]
  120. Holland AJ, Cleveland DW. 120.  2012. Chromoanagenesis and cancer: mechanisms and consequences of localized, complex chromosomal rearrangements. Nat. Med. 18:111630–38 [Google Scholar]
  121. Crasta K, Ganem NJ, Dagher R, Lantermann AB, Ivanova EV. 121.  et al. 2013. DNA breaks and chromosome pulverization from errors in mitosis. Nature 482:738353–58 [Google Scholar]
  122. Hatch EM, Fischer AH, Deerinck TJ, Hetzer MW. 122.  2013. Catastrophic nuclear envelope collapse in cancer cell micronuclei. Cell 154:147–60 [Google Scholar]
  123. Zhang CZ, Spektor A, Cornils H, Francis JM, Jackson EK. 123.  et al. 2015. Chromothripsis from DNA damage in micronuclei. Nature 522:7555179–84 [Google Scholar]
  124. Liu P, Erez A, Nagamani SCS, Dhar SU, Kołodziejska KE. 124.  et al. 2011. Chromosome catastrophes involve replication mechanisms generating complex genomic rearrangements. Cell 146:6889–903 [Google Scholar]
  125. Rausch T, Jones DTW, Zapatka M, Stütz AM, Zichner T. 125.  et al. 2012. Genome sequencing of pediatric medulloblastoma links catastrophic DNA rearrangements with TP53 mutations. Cell 148:1–259–71 [Google Scholar]
  126. Belton JM, McCord RP, Gibcus JH, Naumova N, Zhan Y, Dekker J. 126.  2012. Hi-C: a comprehensive technique to capture the conformation of genomes. Methods 58:3268–76 [Google Scholar]
  127. Zhang J, Poh HM, Peh SQ, Sia YY, Li G. 127.  et al. 2012. ChIA-PET analysis of transcriptional chromatin interactions. Methods 58:3289–99 [Google Scholar]
  128. Fudenberg G, Getz G, Meyerson M, Mirny LA. 128.  2011. High order chromatin architecture shapes the landscape of chromosomal alterations in cancer. Nat. Biotechnol. 29:121109–13 [Google Scholar]
  129. Wijchers PJ, de Laat W. 129.  2011. Genome organization influences partner selection for chromosomal rearrangements. Trends Genet. 27:263–71 [Google Scholar]
  130. Zhang Y, McCord RP, Ho YJ, Lajoie BR, Hildebrand DG. 130.  et al. 2012. Spatial organization of the mouse genome and its role in recurrent chromosomal translocations. Cell 148:5908–21 [Google Scholar]
  131. Lieberman-Aiden E, van Berkum NL, Williams L, Imakaev M, Ragoczy T. 131.  et al. 2009. Comprehensive mapping of long-range interactions reveals folding principles of the human genome. Science 326:5950289–93 [Google Scholar]
  132. Schleiermacher G, Janoueix-Lerosey I, Combaret V, Derre J, Couturier J. 132.  et al. 2003. Combined 24-color karyotyping and comparative genomic hybridization analysis indicates predominant rearrangements of early replicating chromosome regions in neuroblastoma. Cancer Genet. Cytogenet. 141:132–42 [Google Scholar]
  133. Barlow JH, Faryabi RB, Callen E, Wong N, Malhowski A. 133.  et al. 2013. Identification of early replicating fragile sites that contribute to genome instability. Cell 152:3620–32 [Google Scholar]
  134. Pedersen BS, De S. 134.  2013. Loss of heterozygosity preferentially occurs in early replicating regions in cancer genomes. Nucleic Acids Res. 41:167615–24 [Google Scholar]
  135. Kitamura E, Blow JJ, Tanaka TU. 135.  2006. Live-cell imaging reveals replication of individual replicons in eukaryotic replication factories. Cell 125:71297–308 [Google Scholar]
  136. Preston BD, Albertson TM, Herr AJ. 136.  2010. DNA replication fidelity and cancer. Semin. Cancer Biol. 20:5281–93 [Google Scholar]
  137. Kim T-M, Laird PW, Park PJ. 137.  2013. The landscape of microsatellite instability in colorectal and endometrial cancer genomes. Cell 155:4858–68 [Google Scholar]
  138. Tomlinson IPM, Novelli MR, Bodmer WF. 138.  1996. The mutation rate and cancer. PNAS 93:2514800–3 [Google Scholar]
  139. Fox EJ, Prindle MJ, Loeb LA. 139.  2013. Do mutator mutations fuel tumorigenesis?. Cancer Metastasis Rev. 32:3–4353–61 [Google Scholar]
  140. Ciriello G, Miller ML, Aksoy BA, Senbabaoglu Y, Schultz N, Sander C. 140.  2013. Emerging landscape of oncogenic signatures across human cancers. Nat. Genet. 45:101127–33 [Google Scholar]
  141. Westcott PMK, Halliwill KD, To MD, Rashid M, Rust AG. 141.  et al. 2014. The mutational landscapes of genetic and chemical models of Kras-driven lung cancer. Nature 517:7535489–92 [Google Scholar]
  142. Shinbrot E, Henninger EE, Weinhold N, Covington KR, Goksenin AY. 142.  et al. 2014. Exonuclease mutations in DNA polymerase epsilon reveal replication strand specific mutation patterns and human origins of replication. Genome Res. 24:111740–50 [Google Scholar]
  143. Henderson S, Chakravarthy A, Su X, Boshoff C, Fenton TR. 143.  2014. APOBEC-mediated cytosine deamination links PIK3CA helical domain mutations to human papillomavirus-driven tumor development. Cell Rep. 7:61833–41 [Google Scholar]
  144. Shlien A, Campbell BB, de Borja R, Alexandrov LB, Merico D. 144.  et al. 2015. Combined hereditary and somatic mutations of replication error repair genes result in rapid onset of ultra-hypermutated cancers. Nat. Genet. 47:3257–62 [Google Scholar]
  145. Llosa NJ, Cruise M, Tam A, Wicks EC, Hechenbleikner EM. 145.  et al. 2015. The vigorous immune microenvironment of microsatellite instable colon cancer is balanced by multiple counter-inhibitory checkpoints. Cancer Discov. 5:143–51 [Google Scholar]
  146. Le DT, Uram JN, Wang H, Bartlett BR, Kemberling H. 146.  et al. 2015. PD-1 blockade in tumors with mismatch-repair deficiency. N. Engl. J. Med. 372:262509–20 [Google Scholar]
  147. Peltomaki P. 147.  2003. Role of DNA mismatch repair defects in the pathogenesis of human cancer. J. Clin. Oncol. 21:61174–79 [Google Scholar]
  148. Aaltonen LA, Peltomaki P, Leach FS, Sistonen P, Pylkkanen L. 148.  et al. 1993. Clues to the pathogenesis of familial colorectal cancer. Science 260:5109812–16 [Google Scholar]
  149. Thibodeau SN, Bren G, Schaid D. 149.  1993. Microsatellite instability in cancer of the proximal colon. Science 260:5109816–19 [Google Scholar]
  150. Ionov Y, Peinado MA, Malkhosyan S, Shibata D, Perucho M. 150.  1993. Ubiquitous somatic mutations in simple repeated sequences reveal a new mechanism for colonic carcinogenesis. Nature 363:6429558–61 [Google Scholar]
  151. de la Chapelle A, Hampel H. 151.  2010. Clinical relevance of microsatellite instability in colorectal cancer. J. Clin. Oncol. 28:203380–87 [Google Scholar]
  152. Lynch HT, de la Chapelle A. 152.  2003. Hereditary colorectal cancer. N. Engl. J. Med. 348:10919–32 [Google Scholar]
  153. 153. Cancer Genome Atlas Research Network 2013. Integrated genomic characterization of endometrial carcinoma. Nature 497:744767–73 [Google Scholar]
  154. 154. Cancer Genome Atlas Research Network 2014. Comprehensive molecular characterization of gastric adenocarcinoma. Nature 513:7517202–9 [Google Scholar]
  155. Popat S, Hubner R, Houlston R. 155.  2005. Systematic review of microsatellite instability and colorectal cancer prognosis. J. Clin. Oncol. 23:3609–18 [Google Scholar]
  156. Ribic CM, Sargent DJ, Moore MJ, Thibodeau SN, French AJ. 156.  et al. 2003. Tumor microsatellite-instability status as a predictor of benefit from fluorouracil-based adjuvant chemotherapy for colon cancer. N. Engl. J. Med. 349:3247–57 [Google Scholar]
  157. Tajima A, Hess MT, Cabrera BL, Kolodner RD, Carethers JM. 157.  2004. The mismatch repair complex hMutSα recognizes 5-fluorouracil-modified DNA: implications for chemosensitivity and resistance. Gastroenterology 127:61678–84 [Google Scholar]
  158. Boland CR, Thibodeau SN, Hamilton SR, Sidransky D, Eshleman JR. 158.  et al. 1998. A national cancer institute workshop on microsatellite instability for cancer detection and familial predisposition: development of international criteria for the determination of microsatellite instability in colorectal cancer. Cancer Res. 58:225248–57 [Google Scholar]
  159. Kim TM, Park PJ. 159.  2014. A genome-wide view of microsatellite instability: old stories of cancer mutations revisited with new sequencing technologies. Cancer Res. 74:226377–82 [Google Scholar]
  160. Herman JG, Umar A, Polyak K, Graff JR, Ahuja N. 160.  et al. 1998. Incidence and functional consequences of hMLH1 promoter hypermethylation in colorectal carcinoma. PNAS 95:126870–75 [Google Scholar]
  161. Laiho P, Launonen V, Lahermo P, Esteller M, Guo M. 161.  et al. 2002. Low-level microsatellite instability in most colorectal carcinomas. Cancer Res. 62:41166–70 [Google Scholar]
  162. Kuismanen SA, Moisio AL, Schweizer P, Truninger K, Salovaara R. 162.  et al. 2002. Endometrial and colorectal tumors from patients with hereditary nonpolyposis colon cancer display different patterns of microsatellite instability. Am. J. Pathol. 160:61953–58 [Google Scholar]
  163. Umar A, Boland CR, Terdiman JP, Syngal S, de la Chapelle A. 163.  et al. 2004. Revised Bethesda Guidelines for hereditary nonpolyposis colorectal cancer (Lynch syndrome) and microsatellite instability. J. Natl. Cancer Inst. 96:4261–68 [Google Scholar]
  164. Schuster-Bockler B, Lehner B. 164.  2012. Chromatin organization is a major influence on regional mutation rates in human cancer cells. Nature 488:7412504–7 [Google Scholar]
  165. Supek F, Lehner B. 165.  2015. Differential DNA mismatch repair underlies mutation rate variation across the human genome. Nature 521:81–84 [Google Scholar]
  166. Heitzer E, Tomlinson I. 166.  2014. Replicative DNA polymerase mutations in cancer. Curr. Opin. Genet. Dev. 24:107–13 [Google Scholar]
  167. da Costa LT, Liu B, el-Deiry W, Hamilton SR, Kinzler KW. 167.  et al. 1995. Polymerase delta variants in RER colorectal tumours. Nat. Genet. 9:110–11 [Google Scholar]
  168. Flohr T, Dai JC, Buttner J, Popanda O, Hagmuller E, Thielmann HW. 168.  1999. Detection of mutations in the DNA polymerase δ gene of human sporadic colorectal cancers and colon cancer cell lines. Int. J. Cancer 80:6919–29 [Google Scholar]
  169. Palles C, Cazier J-B, Howarth KM, Domingo E, Jones AM. 169.  et al. 2013. Germline mutations affecting the proofreading domains of POLE and POLD1 predispose to colorectal adenomas and carcinomas. Nat. Genet. 45:2136–44 [Google Scholar]
  170. Church DN, Stelloo E, Nout RA, Valtcheva N, Depreeuw J. 170.  et al. 2015. Prognostic significance of POLE proofreading mutations in endometrial cancer. J. Natl. Cancer Inst. 107:1402 [Google Scholar]
  171. Pursell ZF, Isoz I, Lundström E-B, Johansson E, Kunkel TA. 171.  2007. Yeast DNA polymerase ε participates in leading-strand DNA replication. Science 317:5834127–30 [Google Scholar]
  172. McElhinny SAN, Gordenin DA, Stith CM, Burgers PM, Kunkel TA. 172.  2008. Division of labor at the eukaryotic replication fork. Mol. Cell 30:2137–44 [Google Scholar]
  173. Krokan HE, Bjørås M. 173.  2013. Base excision repair. Cold Spring Harb. Perspect. Biol. 5:4a012583 [Google Scholar]
  174. Hecht SS. 174.  1999. Tobacco smoke carcinogens and lung cancer. J. Natl. Cancer Inst. 91:141194–210 [Google Scholar]
  175. David SS, O'Shea VL, Kundu S. 175.  2007. Base-excision repair of oxidative DNA damage. Nature 447:7147941–50 [Google Scholar]
  176. Topal MD, Baker MS. 176.  1982. DNA precursor pool: a significant target for N-methyl-N-nitrosourea in C3H/10T½ clone 8 cells. PNAS 79:72211–15 [Google Scholar]
  177. Huycke MM, Gaskins HR. 177.  2004. Commensal bacteria, redox stress, and colorectal cancer: mechanisms and models. Exp. Biol. Med. 229:7586–97 [Google Scholar]
  178. Al-Tassan N, Chmiel NH, Maynard J, Fleming N, Livingston AL. 178.  et al. 2002. Inherited variants of MYH associated with somatic G:C→T:A mutations in colorectal tumors. Nat. Genet. 30:2227–32 [Google Scholar]
  179. Lipton L, Halford SE, Johnson V, Novelli MR, Jones A. 179.  et al. 2003. Carcinogenesis in MYH-associated polyposis follows a distinct genetic pathway. Cancer Res. 63:227595–99 [Google Scholar]
  180. Smith CG, West H, Harris R, Idziaszczyk S, Maughan TS. 180.  et al. 2013. Role of the oxidative DNA damage repair gene OGG1 in colorectal tumorigenesis. J. Natl. Cancer Inst. 105:161249–53 [Google Scholar]
  181. Kinnersley B, Buch S, Castellvi-Bel S, Farrington SM, Forsti A. 181.  et al. 2014. Re: Role of the oxidative DNA damage repair gene OGG1 in colorectal tumorigenesis. J. Natl. Cancer Inst. 106:5dju086 [Google Scholar]
  182. Speina E, Arczewska KD, Gackowski D, Zielińska M, Siomek A. 182.  et al. 2005. Contribution of hMTH1 to the maintenance of 8-oxoguanine levels in lung DNA of non-small-cell lung cancer patients. J. Natl. Cancer Inst. 97:5384–95 [Google Scholar]
  183. Gad H, Koolmeister T, Jemth A-S, Eshtad S, Jacques SA. 183.  et al. 2014. MTH1 inhibition eradicates cancer by preventing sanitation of the dNTP pool. Nature 508:7495215–21 [Google Scholar]
  184. Huber KVM, Salah E, Radic B, Gridling M, Elkins JM. 184.  et al. 2014. Stereospecific targeting of MTH1 by (S)-crizotinib as an anticancer strategy. Nature 508:7495222–27 [Google Scholar]
  185. Helleday T. 185.  2014. Cancer phenotypic lethality, exemplified by the non-essential MTH1 enzyme being required for cancer survival. Ann. Oncol. 25:71253–55 [Google Scholar]
  186. de Laat WL, Jaspers NG, Hoeijmakers JH. 186.  1999. Molecular mechanism of nucleotide excision repair. Genes Dev. 13:7768–85 [Google Scholar]
  187. DiGiovanna JJ, Kraemer KH. 187.  2012. Shining a light on xeroderma pigmentosum. J. Investig. Dermatol. 132:3 Pt. 2785–96 [Google Scholar]
  188. Cleaver JE. 188.  1968. Defective repair replication of DNA in xeroderma pigmentosum. Nature 218:5142652–56 [Google Scholar]
  189. Dumaz N, Drougard C, Sarasin A, Daya-Grosjean L. 189.  1993. Specific UV-induced mutation spectrum in the p53 gene of skin tumors from DNA-repair-deficient xeroderma pigmentosum patients. PNAS 90:2210529–33 [Google Scholar]
  190. Bodak N, Queille S, Avril MF, Bouadjar B, Drougard C. 190.  et al. 1999. High levels of patched gene mutations in basal-cell carcinomas from patients with xeroderma pigmentosum. PNAS 96:95117–22 [Google Scholar]
  191. Lee W, Jiang Z, Liu J, Haverty PM, Guan Y. 191.  et al. 2010. The mutation spectrum revealed by paired genome sequences from a lung cancer patient. Nature 465:7297473–77 [Google Scholar]
  192. Pleasance ED, Stephens PJ, O'Meara S, McBride DJ, Meynert A. 192.  et al. 2010. A small-cell lung cancer genome with complex signatures of tobacco exposure. Nature 463:7278184–90 [Google Scholar]
  193. Polak P, Lawrence MS, Haugen E, Stoletzki N, Stojanov P. 193.  et al. 2014. Reduced local mutation density in regulatory DNA of cancer genomes is linked to DNA repair. Nat. Biotechnol. 32:171–75 [Google Scholar]
  194. Yasuda T, Sugasawa K, Shimizu Y, Iwai S, Shiomi T, Hanaoka F. 194.  2005. Nucleosomal structure of undamaged DNA regions suppresses the non-specific DNA binding of the XPC complex. DNA Repair 4:3389–95 [Google Scholar]
  195. Nik-Zainal S, Alexandrov LB, Wedge DC, Van Loo P, Greenman CD. 195.  et al. 2012. Mutational processes molding the genomes of 21 breast cancers. Cell 149:5979–93 [Google Scholar]
  196. Roberts SA, Sterling J, Thompson C, Harris S, Mav D. 196.  et al. 2012. Clustered mutations in yeast and in human cancers can arise from damaged long single-strand DNA regions. Mol. Cell 46:4424–35 [Google Scholar]
  197. Sakofsky CJ, Roberts SA, Malc E, Mieczkowski PA, Resnick MA. 197.  et al. 2014. Break-induced replication is a source of mutation clusters underlying kataegis. Cell Rep. 7:51640–48 [Google Scholar]
  198. Conticello SG. 198.  2008. The AID/APOBEC family of nucleic acid mutators. Genome Biol. 9:6229 [Google Scholar]
  199. Harris RS, Petersen-Mahrt SK, Neuberger MS. 199.  2002. RNA editing enzyme APOBEC1 and some of its homologs can act as DNA mutators. Mol. Cell 10:51247–53 [Google Scholar]
  200. Roberts SA, Lawrence MS, Klimczak LJ, Grimm SA, Fargo D. 200.  et al. 2013. An APOBEC cytidine deaminase mutagenesis pattern is widespread in human cancers. Nat. Genet. 45:9970–76 [Google Scholar]
  201. Burns MB, Temiz NA, Harris RS. 201.  2013. Evidence for APOBEC3B mutagenesis in multiple human cancers. Nat. Genet. 45:9977–83 [Google Scholar]
  202. Burns MB, Lackey L, Carpenter MA, Rathore A, Land AM. 202.  et al. 2013. APOBEC3B is an enzymatic source of mutation in breast cancer. Nature 494:7437366–70 [Google Scholar]
  203. Taylor BJ, Nik-Zainal S, Wu YL, Stebbings LA, Raine K. 203.  et al. 2013. DNA deaminases induce break-associated mutation showers with implication of APOBEC3B and 3A in breast cancer kataegis. eLife 2:e00534 [Google Scholar]
  204. Nik-Zainal S, Wedge DC, Petljak M, Butler AP, Bolli N. 204.  et al. 2014. Association of a germline copy number polymorphism of APOBEC3A and APOBEC3B with burden of putative APOBEC-dependent mutations in breast cancer. Nat. Genet. 46:5487–91 [Google Scholar]
  205. Long J, Delahanty RJ, Li G, Gao Y-T, Lu W. 205.  et al. 2013. A common deletion in the APOBEC3 genes and breast cancer risk. J. Natl. Cancer Inst. 105:8573–79 [Google Scholar]
  206. Qian J, Wang Q, Dose M, Pruett N, Kieffer-Kwon KR. 206.  et al. 2014. B cell super-enhancers and regulatory clusters recruit AID tumorigenic activity. Cell 159:71524–37 [Google Scholar]
  207. Bolli N, Avet-Loiseau H, Wedge DC, Van Loo P, Alexandrov LB. 207.  et al. 2014. Heterogeneity of genomic evolution and mutational profiles in multiple myeloma. Nat. Commun. 5:2997 [Google Scholar]
  208. Meng FL, Du Z, Federation A, Hu J, Wang Q. 208.  et al. 2014. Convergent transcription at intragenic super-enhancers targets AID-initiated genomic instability. Cell 159:71538–48 [Google Scholar]
  209. Patel AP, Tirosh I, Trombetta JJ, Shalek AK, Gillespie SM. 209.  et al. 2014. Single-cell RNA-seq highlights intratumoral heterogeneity in primary glioblastoma. Science 344:61901396–401 [Google Scholar]
  210. Bedard PL, Hansen AR, Ratain MJ, Siu LL. 210.  2013. Tumour heterogeneity in the clinic. Nature 501:7467355–64 [Google Scholar]
  211. Campbell PJ, Yachida S, Mudie LJ, Stephens PJ, Pleasance ED. 211.  et al. 2010. The patterns and dynamics of genomic instability in metastatic pancreatic cancer. Nature 467:73191109–13 [Google Scholar]
  212. Johnson BE, Mazor T, Hong C, Barnes M, Aihara K. 212.  et al. 2013. Mutational analysis reveals the origin and therapy-driven evolution of recurrent glioma. Science 343:6167189–93 [Google Scholar]
  213. Hunter C, Smith R, Cahill DP, Stephens P, Stevens C. 213.  et al. 2006. A hypermutation phenotype and somatic MSH6 mutations in recurrent human malignant gliomas after alkylator chemotherapy. Cancer Res. 66:83987–91 [Google Scholar]
/content/journals/10.1146/annurev-pathol-012615-044446
Loading
/content/journals/10.1146/annurev-pathol-012615-044446
Loading

Data & Media loading...

  • Article Type: Review Article
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error