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Fragile sites in cancer: more than meets the eye

Nature Reviews Cancer volume 17, pages 489–501 (2017)Cite this article

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Abstract

Ever since initial suggestions that instability at common fragile sites (CFSs) could be responsible for chromosome rearrangements in cancers, CFSs and associated genes have been the subject of numerous studies, leading to questions and controversies about their role and importance in cancer. It is now clear that CFSs are not frequently involved in translocations or other cancer-associated recurrent gross chromosome rearrangements. However, recent studies have provided new insights into the mechanisms of CFS instability, their effect on genome instability, and their role in generating focal copy number alterations that affect the genomic landscape of many cancers.

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Figure 1: Possible genomic outcomes of replication stress.
Figure 2: Model of genomic instability at active large transcription units.
Figure 3: Gene content of pan-cancer focal deletions showing strong associations with large genes.
Figure 4: Experimentally induced CNVs and focal deletions in cancer arise in the centres of large genes.

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References

  1. Glover, T. W., Berger, C., Coyle, J. & Echo, B. DNA polymerase alpha inhibition by aphidicolin induces gaps and breaks at common fragile sites in human chromosomes. Hum. Genet. 67, 136–142 (1984).

    CAS  PubMed  Google Scholar 

  2. Yunis, J. J. Fragile sites and predisposition to leukemia and lymphoma. Cancer Genet. Cytogenet. 12, 85–88 (1984).

    CAS  PubMed  Google Scholar 

  3. de Braekeleer, M. Fragile sites and chromosomal structural rearrangements in human leukemia and cancer. Anticancer Res. 7, 417–422 (1987).

    CAS  PubMed  Google Scholar 

  4. Yunis, J. J. Fragile sites, mutagens and genomic rearrangements in cancer. Basic Life Sci. 43, 11–21 (1988).

    CAS  PubMed  Google Scholar 

  5. Le Beau, M. M. Chromosomal fragile sites and cancer-specific rearrangements. Blood 67, 849–858 (1986).

    CAS  PubMed  Google Scholar 

  6. De Braekeleer, M., Smith, B. & Lin, C. C. Fragile sites and structural rearrangements in cancer. Hum. Genet. 69, 112–116 (1985).

    CAS  PubMed  Google Scholar 

  7. Barlow, J. H. et al. Identification of early replicating fragile sites that contribute to genome instability. Cell 152, 620–632 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Huebner, K., Hadaczek, P., Siprashvili, Z., Druck, T. & Croce, C. M. The FHIT gene, a multiple tumor suppressor gene encompassing the carcinogen sensitive chromosome fragile site, FRA3B. Biochim. Biophys. Acta 1332, M65–M70 (1997).

    CAS  PubMed  Google Scholar 

  9. Ohta, M. et al. The FHIT gene, spanning the chromosome 3p14.2 fragile site and renal carcinoma-associated t(3;8) breakpoint, is abnormal in digestive tract cancers. Cell 84, 587–597 (1996).

    CAS  PubMed  Google Scholar 

  10. Zack, T. I. et al. Pan-cancer patterns of somatic copy number alteration. Nat. Genet. 45, 1134–1140 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Yan, Z. A., Li, X. Z. & Zhou, X. T. The effect of hydroxyurea on the expression of the common fragile site at 3p14. J. Med. Genet. 24, 593–596 (1987).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. [No authors listed.] An international system for human cytogenetic nomenclature — high-resolution banding (1981). ISCN (1981). Report of the Standing Committee on Human Cytogenetic Nomenclature. Cytogenet. Cell Genet. 31, 5–23 (1981).

  13. Mariani, T. Fragile sites and statistics. Hum. Genet. 81, 319–322 (1989).

    CAS  PubMed  Google Scholar 

  14. Glover, T. W. & Stein, C. K. Induction of sister chromatid exchanges at common fragile sites. Am. J. Hum. Genet. 41, 882–890 (1987).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Wenger, S. L. Chemical induction of sister chromatid exchange at fragile sites. Cancer Genet. Cytogenet. 85, 72–74 (1995).

    CAS  PubMed  Google Scholar 

  16. Glover, T. W. & Stein, C. K. Chromosome breakage and recombination at fragile sites. Am. J. Hum. Genet. 43, 265–273 (1988).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Wang, N. D., Testa, J. R. & Smith, D. I. Determination of the specificity of aphidicolin-induced breakage of the human 3p14.2 fragile site. Genomics 17, 341–347 (1993).

    CAS  PubMed  Google Scholar 

  18. Rassool, F. V. et al. Preferential integration of marker DNA into the chromosomal fragile site at 3p14: an approach to cloning fragile sites. Proc. Natl Acad. Sci. USA 88, 6657–6661 (1991).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Durkin, S. G. & Glover, T. W. Chromosome fragile sites. Annu. Rev. Genet. 41, 169–192 (2007).

    CAS  PubMed  Google Scholar 

  20. Sarni, D. & Kerem, B. The complex nature of fragile site plasticity and its importance in cancer. Curr. Opin. Cell Biol. 40, 131–136 (2016).

    CAS  PubMed  Google Scholar 

  21. Arlt, M. F., Casper, A. M. & Glover, T. W. Common fragile sites. Cytogenet. Genome Res. 100, 92–100 (2003).

    CAS  PubMed  Google Scholar 

  22. Le Beau, M. M. et al. Replication of a common fragile site, FRA3B, occurs late in S phase and is delayed further upon induction: implications for the mechanism of fragile site induction. Hum. Mol. Genet. 7, 755–761 (1998).

    CAS  PubMed  Google Scholar 

  23. Wilke, C. M. et al. Multicolor FISH mapping of YAC clones in 3p14 and identification of a YAC spanning both FRA3B and the t(3;8) associated with hereditary renal cell carcinoma. Genomics 22, 319–326 (1994).

    CAS  PubMed  Google Scholar 

  24. Paradee, W. et al. Precise localization of aphidicolin-induced breakpoints on the short arm of human chromosome 3. Genomics 27, 358–361 (1995).

    CAS  PubMed  Google Scholar 

  25. Mangelsdorf, M. et al. Chromosomal fragile site FRA16D and DNA instability in cancer. Cancer Res. 60, 1683–1689 (2000).

    CAS  PubMed  Google Scholar 

  26. Bednarek, A. K. et al. WWOX, a novel WW domain-containing protein mapping to human chromosome 16q23.3-24.1, a region frequently affected in breast cancer. Cancer Res. 60, 2140–2145 (2000).

    CAS  PubMed  Google Scholar 

  27. Smith, D. I., Zhu, Y., McAvoy, S. & Kuhn, R. Common fragile sites, extremely large genes, neural development and cancer. Cancer Lett. 232, 48–57 (2006).

    CAS  PubMed  Google Scholar 

  28. Gao, G. & Smith, D. I. Very large common fragile site genes and their potential role in cancer development. Cell. Mol. Life Sci. 71, 4601–4615 (2014).

    CAS  PubMed  Google Scholar 

  29. Wilson, T. E. et al. Large transcription units unify copy number variants and common fragile sites arising under replication stress. Genome Res. 25, 189–200 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Murano, I., Kuwano, A. & Kajii, T. Cell type-dependent difference in the distribution and frequency of aphidicolin-induced fragile sites: T and B lymphocytes and bone marrow cells. Hum. Genet. 84, 71–74 (1989).

    CAS  PubMed  Google Scholar 

  31. Murano, I., Kuwano, A. & Kajii, T. Fibroblast-specific common fragile sites induced by aphidicolin. Hum. Genet. 83, 45–48 (1989).

    CAS  PubMed  Google Scholar 

  32. Kuwano, A., Murano, I. & Kajii, T. Cell type-dependent difference in the distribution and frequency of excess thymidine-induced common fragile sites: T lymphocytes and skin fibroblasts. Hum. Genet. 84, 527–531 (1990).

    CAS  PubMed  Google Scholar 

  33. Le Tallec, B. et al. Molecular profiling of common fragile sites in human fibroblasts. Nat. Struct. Mol. Biol. 18, 1421–1423 (2011).

    CAS  PubMed  Google Scholar 

  34. Le Tallec, B. et al. Common fragile site profiling in epithelial and erythroid cells reveals that most recurrent cancer deletions lie in fragile sites hosting large genes. Cell Rep. 4, 420–428 (2013).

    CAS  PubMed  Google Scholar 

  35. Hosseini, S. A. et al. Common chromosome fragile sites in human and murine epithelial cells and FHIT/FRA3B loss-induced global genome instability. Genes Chromosomes Cancer 52, 1017–1029 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Glover, T. W. in Genetic Instabilities and Neurological Diseases (eds Wells, R. D. & Warren, S. T.) 75–83 (Academic Press, 1998).

    Google Scholar 

  37. Palakodeti, A. et al. Impaired replication dynamics at the FRA3B common fragile site. Hum. Mol. Genet. 19, 99–110 (2010).

    CAS  PubMed  Google Scholar 

  38. Glover, T. W., Arlt, M. F., Casper, A. M. & Durkin, S. G. Mechanisms of common fragile site instability. Hum. Mol. Genet. 14 (Suppl. 2), R197–R205 (2005).

    CAS  PubMed  Google Scholar 

  39. Boldog, F. et al. Chromosome 3p14 homozygous deletions and sequence analysis of FRA3B. Hum. Mol. Genet. 6, 193–203 (1997).

    CAS  PubMed  Google Scholar 

  40. Ried, K. et al. Common chromosomal fragile site FRA16D sequence: identification of the FOR gene spanning FRA16D and homozygous deletions and translocation breakpoints in cancer cells. Hum. Mol. Genet. 9, 1651–1663 (2000).

    CAS  PubMed  Google Scholar 

  41. Arlt, M. F., Miller, D. E., Beer, D. G. & Glover, T. W. Molecular characterization of FRAXB and comparative common fragile site instability in cancer cells. Genes Chromosomes Cancer 33, 82–92 (2002).

    CAS  PubMed  Google Scholar 

  42. Zlotorynski, E. et al. Molecular basis for expression of common and rare fragile sites. Mol. Cell. Biol. 23, 7143–7151 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Mishmar, D. et al. Molecular characterization of a common fragile site (FRA7H) on human chromosome 7 by the cloning of a simian virus 40 integration site. Proc. Natl Acad. Sci. USA 95, 8141–8146 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Mirkin, E. V. & Mirkin, S. M. Replication fork stalling at natural impediments. Microbiol. Mol. Biol. Rev. 71, 13–35 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Zhang, H. & Freudenreich, C. H. An AT-rich sequence in human common fragile site FRA16D causes fork stalling and chromosome breakage in S. cerevisiae. Mol. Cell 27, 367–379 (2007).

    PubMed  PubMed Central  Google Scholar 

  46. Durkin, S. G. et al. Replication stress induces tumor-like microdeletions in FHIT/FRA3B. Proc. Natl Acad. Sci. USA 105, 246–251 (2008).

    CAS  PubMed  Google Scholar 

  47. Casper, A. M., Nghiem, P., Arlt, M. F. & Glover, T. W. ATR regulates fragile site stability. Cell 111, 779–789 (2002).

    CAS  PubMed  Google Scholar 

  48. Durkin, S. G., Arlt, M. F., Howlett, N. G. & Glover, T. W. Depletion of CHK1, but not CHK2, induces chromosomal instability and breaks at common fragile sites. Oncogene 25, 4381–4388 (2006).

    CAS  PubMed  Google Scholar 

  49. Zhu, M. & Weiss, R. S. Increased common fragile site expression, cell proliferation defects, and apoptosis following conditional inactivation of mouse Hus1 in primary cultured cells. Mol. Biol. Cell 18, 1044–1055 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Focarelli, M. L. et al. Claspin inhibition leads to fragile site expression. Genes Chromosomes Cancer 48, 1083–1090 (2009).

    CAS  PubMed  Google Scholar 

  51. Musio, A. et al. SMC1 involvement in fragile site expression. Hum. Mol. Genet. 14, 525–533 (2005).

    CAS  PubMed  Google Scholar 

  52. Bhat, A., Andersen, P. L., Qin, Z. & Xiao, W. Rev3, the catalytic subunit of Polzeta, is required for maintaining fragile site stability in human cells. Nucleic Acids Res. 41, 2328–2339 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Madireddy, A. et al. FANCD2 facilitates replication through common fragile sites. Mol. Cell 64, 388–404 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Bhowmick, R., Minocherhomji, S. & Hickson, I. D. RAD52 facilitates mitotic DNA synthesis following replication stress. Mol. Cell 64, 1117–1126 (2016).

    CAS  PubMed  Google Scholar 

  55. Mason, J. M. et al. The SNM1B/APOLLO DNA nuclease functions in resolution of replication stress and maintenance of common fragile site stability. Hum. Mol. Genet. 22, 4901–4913 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Ying, S. et al. MUS81 promotes common fragile site expression. Nat. Cell Biol. 15, 1001–1007 (2013).

    CAS  PubMed  Google Scholar 

  57. Naim, V., Wilhelm, T., Debatisse, M. & Rosselli, F. ERCC1 and MUS81-EME1 promote sister chromatid separation by processing late replication intermediates at common fragile sites during mitosis. Nat. Cell Biol. 15, 1008–1015 (2013).

    CAS  PubMed  Google Scholar 

  58. Minocherhomji, S. et al. Replication stress activates DNA repair synthesis in mitosis. Nature 528, 286–290 (2015).

    CAS  PubMed  Google Scholar 

  59. Bergoglio, V. et al. DNA synthesis by Pol eta promotes fragile site stability by preventing under-replicated DNA in mitosis. J. Cell Biol. 201, 395–408 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Walsh, E., Wang, X., Lee, M. Y. & Eckert, K. A. Mechanism of replicative DNA polymerase delta pausing and a potential role for DNA polymerase kappa in common fragile site replication. J. Mol. Biol. 425, 232–243 (2013).

    CAS  PubMed  Google Scholar 

  61. Pirzio, L. M., Pichierri, P., Bignami, M. & Franchitto, A. Werner syndrome helicase activity is essential in maintaining fragile site stability. J. Cell Biol. 180, 305–314 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Fundia, A., Gorla, N. & Larripa, I. Non-random distribution of spontaneous chromosome aberrations in two Bloom Syndrome patients. Hereditas 122, 239–243 (1995).

    CAS  PubMed  Google Scholar 

  63. Howlett, N. G., Taniguchi, T., Durkin, S. G., D'Andrea, A. D. & Glover, T. W. The Fanconi anemia pathway is required for the DNA replication stress response and for the regulation of common fragile site stability. Hum. Mol. Genet. 14, 693–701 (2005).

    CAS  PubMed  Google Scholar 

  64. Arlt, M. F. et al. BRCA1 is required for common-fragile-site stability via its G2/M checkpoint function. Mol. Cell. Biol. 24, 6701–6709 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  65. Schwartz, M. et al. Homologous recombination and nonhomologous end-joining repair pathways regulate fragile site stability. Genes Dev. 19, 2715–2726 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Letessier, A. et al. Cell-type-specific replication initiation programs set fragility of the FRA3B fragile site. Nature 470, 120–123 (2011).

    CAS  PubMed  Google Scholar 

  67. Miotto, B., Ji, Z. & Struhl, K. Selectivity of ORC binding sites and the relation to replication timing, fragile sites, and deletions in cancers. Proc. Natl Acad. Sci. USA 113, E4810–E4819 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  68. Sotiriou, S. K. et al. Mammalian RAD52 functions in break-induced replication repair of collapsed DNA replication forks. Mol. Cell 64, 1127–1134 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  69. Baumann, C., Korner, R., Hofmann, K. & Nigg, E. A. PICH, a centromere-associated SNF2 family ATPase, is regulated by Plk1 and required for the spindle checkpoint. Cell 128, 101–114 (2007).

    CAS  PubMed  Google Scholar 

  70. Chan, K. L. & Hickson, I. D. New insights into the formation and resolution of ultra-fine anaphase bridges. Semin. Cell Dev. Biol. 22, 906–912 (2011).

    CAS  PubMed  Google Scholar 

  71. Biebricher, A. et al. PICH: a DNA translocase specially adapted for processing anaphase bridge DNA. Mol. Cell 51, 691–701 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Sudmant, P. H. et al. An integrated map of structural variation in 2,504 human genomes. Nature 526, 75–81 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  73. Zhang, F., Gu, W., Hurles, M. E. & Lupski, J. R. Copy number variation in human health, disease, and evolution. Annu. Rev. Genomics Hum. Genet. 10, 451–481 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  74. Lee, C. & Scherer, S. W. The clinical context of copy number variation in the human genome. Expert Rev. Mol. Med. 12, e8 (2010).

    PubMed  Google Scholar 

  75. McConnell, M. J. et al. Mosaic copy number variation in human neurons. Science 342, 632–637 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  76. Campbell, I. M. et al. Parental somatic mosaicism is underrecognized and influences recurrence risk of genomic disorders. Am. J. Hum. Genet. 95, 173–182 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  77. Beroukhim, R. et al. The landscape of somatic copy-number alteration across human cancers. Nature 463, 899–905 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  78. Bignell, G. R. et al. Signatures of mutation and selection in the cancer genome. Nature 463, 893–898 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Arlt, M. F. et al. Replication stress induces genome-wide copy number changes in human cells that resemble polymorphic and pathogenic variants. Am. J. Hum. Genet. 84, 339–350 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  80. Arlt, M. F., Ozdemir, A. C., Birkeland, S. R., Wilson, T. E. & Glover, T. W. Hydroxyurea induces de novo copy number variants in human cells. Proc. Natl Acad. Sci. USA 108, 17360–17365 (2011).

    PubMed  PubMed Central  Google Scholar 

  81. Arlt, M. F., Rajendran, S., Birkeland, S. R., Wilson, T. E. & Glover, T. W. Copy number variants are produced in response to low-dose ionizing radiation in cultured cells. Environ. Mol. Mutagen. 55, 103–113 (2014).

    CAS  PubMed  Google Scholar 

  82. Arlt, M. F., Rajendran, S., Birkeland, S. R., Wilson, T. E. & Glover, T. W. De novo CNV formation in mouse embryonic stem cells occurs in the absence of Xrcc4-dependent nonhomologous end joining. PLoS Genet. 8, e1002981 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  83. Liu, P., Carvalho, C. M., Hastings, P. J. & Lupski, J. R. Mechanisms for recurrent and complex human genomic rearrangements. Curr. Opin. Genet. Dev. 22, 211–220 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  84. Helmrich, A., Ballarino, M. & Tora, L. Collisions between replication and transcription complexes cause common fragile site instability at the longest human genes. Mol. Cell 44, 966–977 (2011).

    CAS  PubMed  Google Scholar 

  85. Newman, T. J., Mamun, M. A., Nieduszynski, C. A. & Blow, J. J. Replisome stall events have shaped the distribution of replication origins in the genomes of yeasts. Nucleic Acids Res. 41, 9705–9718 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  86. Ozeri-Galai, E. et al. Failure of origin activation in response to fork stalling leads to chromosomal instability at fragile sites. Mol. Cell 43, 122–131 (2011).

    CAS  PubMed  Google Scholar 

  87. Snyder, M., Sapolsky, R. J. & Davis, R. W. Transcription interferes with elements important for chromosome maintenance in Saccharomyces cerevisiae. Mol. Cell. Biol. 8, 2184–2194 (1988).

    CAS  PubMed  PubMed Central  Google Scholar 

  88. Looke, M. et al. Relicensing of transcriptionally inactivated replication origins in budding yeast. J. Biol. Chem. 285, 40004–40011 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  89. Wei, P. C. et al. Long neural genes harbor recurrent DNA break clusters in neural stem/progenitor cells. Cell 164, 644–655 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  90. Wilke, C. M. et al. FRA3B extends over a broad region and contains a spontaneous HPV16 integration site: direct evidence for the coincidence of viral integration sites and fragile sites. Hum. Mol. Genet. 5, 187–195 (1996).

    CAS  PubMed  Google Scholar 

  91. Gao, G. et al. Common fragile sites (CFS) and extremely large CFS genes are targets for human papillomavirus integrations and chromosome rearrangements in oropharyngeal squamous cell carcinoma. Genes Chromosomes Cancer 56, 59–74 (2017).

    CAS  PubMed  Google Scholar 

  92. Kraus, I. et al. The majority of viral-cellular fusion transcripts in cervical carcinomas cotranscribe cellular sequences of known or predicted genes. Cancer Res. 68, 2514–2522 (2008).

    CAS  PubMed  Google Scholar 

  93. Thorland, E. C. et al. Human papillomavirus type 16 integrations in cervical tumors frequently occur in common fragile sites. Cancer Res. 60, 5916–5921 (2000).

    CAS  PubMed  Google Scholar 

  94. Wentzensen, N., Vinokurova, S. & von Knebel Doeberitz, M. Systematic review of genomic integration sites of human papillomavirus genomes in epithelial dysplasia and invasive cancer of the female lower genital tract. Cancer Res. 64, 3878–3884 (2004).

    CAS  PubMed  Google Scholar 

  95. Matovina, M., Sabol, I., Grubisic, G., Gasperov, N. M. & Grce, M. Identification of human papillomavirus type 16 integration sites in high-grade precancerous cervical lesions. Gynecol. Oncol. 113, 120–127 (2009).

    CAS  PubMed  Google Scholar 

  96. Walline, H. M. et al. Integration of high-risk human papillomavirus into cellular cancer-related genes in head and neck cancer cell lines. Head Neck 39, 840–852 (2017).

    PubMed  PubMed Central  Google Scholar 

  97. Jang, M. K., Shen, K. & McBride, A. A. Papillomavirus genomes associate with BRD4 to replicate at fragile sites in the host genome. PLoS Pathog. 10, e1004117 (2014).

    PubMed  PubMed Central  Google Scholar 

  98. Hu, Z. et al. Genome-wide profiling of HPV integration in cervical cancer identifies clustered genomic hot spots and a potential microhomology-mediated integration mechanism. Nat. Genet. 47, 158–163 (2015).

    CAS  PubMed  Google Scholar 

  99. Doolittle-Hall, J. M., Cunningham Glasspoole, D. L., Seaman, W. T. & Webster-Cyriaque, J. Meta-analysis of DNA tumor-viral integration site selection indicates a role for repeats, gene expression and epigenetics. Cancers (Basel) 7, 2217–2235 (2015).

    CAS  Google Scholar 

  100. Finnis, M. et al. Common chromosomal fragile site FRA16D mutation in cancer cells. Hum. Mol. Genet. 14, 1341–1349 (2005).

    CAS  PubMed  Google Scholar 

  101. Denison, S. R., Callahan, G., Becker, N. A., Phillips, L. A. & Smith, D. I. Characterization of FRA6E and its potential role in autosomal recessive juvenile parkinsonism and ovarian cancer. Genes Chromosomes Cancer 38, 40–52 (2003).

    CAS  PubMed  Google Scholar 

  102. Callahan, G., Denison, S. R., Phillips, L. A., Shridhar, V. & Smith, D. I. Characterization of the common fragile site FRA9E and its potential role in ovarian cancer. Oncogene 22, 590–601 (2003).

    CAS  PubMed  Google Scholar 

  103. Huang, H., Qian, C., Jenkins, R. B. & Smith, D. I. Fish mapping of YAC clones at human chromosomal band 7q31.2: identification of YACS spanning FRA7G within the common region of LOH in breast and prostate cancer. Genes Chromosomes Cancer 21, 152–159 (1998).

    CAS  PubMed  Google Scholar 

  104. Lai, L. A. et al. Deletion at fragile sites is a common and early event in Barrett's esophagus. Mol. Cancer Res. 8, 1084–1094 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  105. Michael, D., Beer, D. G., Wilke, C. W., Miller, D. E. & Glover, T. W. Frequent deletions of FHIT and FRA3B in Barrett's metaplasia and esophageal adenocarcinomas. Oncogene 15, 1653–1659 (1997).

    CAS  PubMed  Google Scholar 

  106. Gu, J. et al. Genome-wide catalogue of chromosomal aberrations in barrett's esophagus and esophageal adenocarcinoma: a high-density single nucleotide polymorphism array analysis. Cancer Prev. Res. (Phila.) 3, 1176–1186 (2010).

    CAS  Google Scholar 

  107. Bartkova, J. et al. DNA damage response as a candidate anti-cancer barrier in early human tumorigenesis. Nature 434, 864–870 (2005).

    CAS  PubMed  Google Scholar 

  108. Rajaram, M. et al. Two distinct categories of focal deletions in cancer genomes. PLoS ONE 8, e66264 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  109. Zhao, M., Kim, P., Mitra, R., Zhao, J. & Zhao, Z. TSGene 2.0: an updated literature-based knowledgebase for tumor suppressor genes. Nucleic Acids Res. 44, D1023–D1031 (2016).

    CAS  PubMed  Google Scholar 

  110. Romagosa, C. et al. p16(Ink4a) overexpression in cancer: a tumor suppressor gene associated with senescence and high-grade tumors. Oncogene 30, 2087–2097 (2011).

    CAS  PubMed  Google Scholar 

  111. Gorgoulis, V. G. et al. Activation of the DNA damage checkpoint and genomic instability in human precancerous lesions. Nature 434, 907–913 (2005).

    CAS  PubMed  Google Scholar 

  112. Halazonetis, T. D., Gorgoulis, V. G. & Bartek, J. An oncogene-induced DNA damage model for cancer development. Science 319, 1352–1355 (2008).

    CAS  PubMed  Google Scholar 

  113. Georgakilas, A. G. et al. Are common fragile sites merely structural domains or highly organized “functional” units susceptible to oncogenic stress? Cell. Mol. Life Sci. 71, 4519–4544 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  114. Dereli-Oz, A., Versini, G. & Halazonetis, T. D. Studies of genomic copy number changes in human cancers reveal signatures of DNA replication stress. Mol. Oncol. 5, 308–314 (2011).

    PubMed  PubMed Central  Google Scholar 

  115. Gaillard, H., Garcia-Muse, T. & Aguilera, A. Replication stress and cancer. Nat. Rev. Cancer 15, 276–289 (2015).

    CAS  PubMed  Google Scholar 

  116. Neelsen, K. J., Zanini, I. M., Herrador, R. & Lopes, M. Oncogenes induce genotoxic stress by mitotic processing of unusual replication intermediates. J. Cell Biol. 200, 699–708 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  117. Teixeira, L. K. et al. Cyclin E deregulation promotes loss of specific genomic regions. Curr. Biol. 25, 1327–1333 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  118. Kotsantis, P. et al. Increased global transcription activity as a mechanism of replication stress in cancer. Nat. Commun. 7, 13087 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  119. Tsantoulis, P. K. et al. Oncogene-induced replication stress preferentially targets common fragile sites in preneoplastic lesions. A genome-wide study. Oncogene 27, 3256–3264 (2008).

    CAS  PubMed  Google Scholar 

  120. Miron, K., Golan-Lev, T., Dvir, R., Ben-David, E. & Kerem, B. Oncogenes create a unique landscape of fragile sites. Nat. Commun. 6, 7094 (2015).

    CAS  PubMed  Google Scholar 

  121. Karras, J. R., Schrock, M. S., Batar, B. & Huebner, K. Fragile genes that are frequently altered in cancer: players not passengers. Cytogenet. Genome Res. 150, 208–216 (2017).

    CAS  Google Scholar 

  122. Schrock, M. S. & Huebner, K. WWOX: a fragile tumor suppressor. Exp. Biol. Med. (Maywood) 240, 296–304 (2015).

    CAS  Google Scholar 

  123. Guler, G. et al. Concordant loss of fragile gene expression early in breast cancer development. Pathol. Int. 55, 471–478 (2005).

    CAS  PubMed  Google Scholar 

  124. Sozzi, G. et al. Loss of FHIT function in lung cancer and preinvasive bronchial lesions. Cancer Res. 58, 5032–5037 (1998).

    CAS  PubMed  Google Scholar 

  125. Wu, X., Wu, G., Yao, X., Hou, G. & Jiang, F. The clinicopathological significance and ethnic difference of FHIT hypermethylation in non-small-cell lung carcinoma: a meta-analysis and literature review. Drug Des. Devel. Ther. 10, 699–709 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  126. Kandimalla, R., van Tilborg, A. A. & Zwarthoff, E. C. DNA methylation-based biomarkers in bladder cancer. Nat. Rev. Urol. 10, 327–335 (2013).

    CAS  PubMed  Google Scholar 

  127. Baryla, I., Styczen-Binkowska, E. & Bednarek, A. K. Alteration of WWOX in human cancer: a clinical view. Exp. Biol. Med. (Maywood) 240, 305–314 (2015).

    CAS  Google Scholar 

  128. Gao, G. & Smith, D. I. WWOX, large common fragile site genes, and cancer. Exp. Biol. Med. (Maywood) 240, 285–295 (2015).

    CAS  Google Scholar 

  129. Saldivar, J. C. et al. Initiation of genome instability and preneoplastic processes through loss of Fhit expression. PLoS Genet. 8, e1003077 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  130. Abu-Odeh, M., Hereema, N. A. & Aqeilan, R. I. WWOX modulates the ATR-mediated DNA damage checkpoint response. Oncotarget 7, 4344–4355 (2016).

    PubMed  Google Scholar 

  131. Drusco, A. et al. Common fragile site tumor suppressor genes and corresponding mouse models of cancer. J. Biomed. Biotechnol. 2011, 984505 (2011).

    PubMed  Google Scholar 

  132. Aqeilan, R. I. et al. Inactivation of the Wwox gene accelerates forestomach tumor progression in vivo. Cancer Res. 67, 5606–5610 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  133. Zanesi, N. et al. The tumor spectrum in FHIT-deficient mice. Proc. Natl Acad. Sci. USA 98, 10250–10255 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  134. Aqeilan, R. I. et al. Targeted deletion of Wwox reveals a tumor suppressor function. Proc. Natl Acad. Sci. USA 104, 3949–3954 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  135. Gong, Y. et al. Pan-cancer genetic analysis identifies PARK2 as a master regulator of G1/S cyclins. Nat. Genet. 46, 588–594 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  136. Le Beau, M. M. et al. An FHIT tumor suppressor gene? Genes Chromosomes Cancer 21, 281–289 (1998).

    CAS  PubMed  Google Scholar 

  137. Nagamani, S. C. et al. Detection of copy-number variation in AUTS2 gene by targeted exonic array CGH in patients with developmental delay and autistic spectrum disorders. Eur. J. Hum. Genet. 21, 343–346 (2013).

    CAS  PubMed  Google Scholar 

  138. Swaminathan, S. et al. Analysis of copy number variation in Alzheimer's disease: the NIALOAD/ NCRAD Family Study. Curr. Alzheimer Res. 9, 801–814 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  139. Gregor, A. et al. Expanding the clinical spectrum associated with defects in CNTNAP2 and NRXN1. BMC Med. Genet. 12, 106 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  140. Mikhail, F. M. et al. Clinically relevant single gene or intragenic deletions encompassing critical neurodevelopmental genes in patients with developmental delay, mental retardation, and/or autism spectrum disorders. Am. J. Med. Genet. A 155A, 2386–2396 (2011).

    PubMed  Google Scholar 

  141. Mermel, C. H. et al. GISTIC2.0 facilitates sensitive and confident localization of the targets of focal somatic copy-number alteration in human cancers. Genome Biol. 12, R41 (2011).

    PubMed  PubMed Central  Google Scholar 

  142. Broad Institute TCGA Genome Data Analysis Center. SNP6 copy number analysis (GISTIC2). Broad Institute https://doi.org/10.7908/C1P84B9Q (2016).

  143. Arlt, M. F. & Glover, T. W. Inhibition of topoisomerase I prevents chromosome breakage at common fragile sites. DNA Repair (Amst.) 9, 678–689 (2010).

    CAS  Google Scholar 

  144. Tuduri, S. et al. Topoisomerase I suppresses genomic instability by preventing interference between replication and transcription. Nat. Cell Biol. 11, 1315–1324 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  145. Casper, A. M., Durkin, S. G., Arlt, M. F. & Glover, T. W. Chromosomal instability at common fragile sites in Seckel syndrome. Am. J. Hum. Genet. 75, 654–660 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  146. Ozeri-Galai, E., Schwartz, M., Rahat, A. & Kerem, B. Interplay between ATM and ATR in the regulation of common fragile site stability. Oncogene 27, 2109–2117 (2008).

    CAS  PubMed  Google Scholar 

  147. Schwartz, M. et al. Impaired replication stress response in cells from immunodeficiency patients carrying Cernunnos/XLF mutations. PLoS ONE 4, e4516 (2009).

    PubMed  PubMed Central  Google Scholar 

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Acknowledgements

The authors would like to thank J. Moran for critical reading this manuscript and R. Beroukhim for sharing early versions of the The Cancer Genome Atlas (TCGA) copy number variant (CNV) data analyses. This work was supported in part by grants ES020875 from the US National Institute of Environmental Health Sciences and CA 200731 from the US National Cancer Institute.

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Authors and Affiliations

  1. Thomas W. Glover is at the Department of Human Genetics; the Department of Pathology; and the Department of Pediatrics and Communicable Diseases, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA,

    Thomas W. Glover

  2. the Department of Pathology,

    Thomas W. Glover

  3. Thomas E. Wilson is at the Department of Human Genetics; and the Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA.,

    Thomas E. Wilson

  4. and the Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA.,

    Thomas E. Wilson

  5. Martin F. Arlt is at the Department of Human Genetics, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA.,

    Martin F. Arlt

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Glover, T., Wilson, T. & Arlt, M. Fragile sites in cancer: more than meets the eye. Nat Rev Cancer 17, 489–501 (2017). https://doi.org/10.1038/nrc.2017.52

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