Molecular characterization of common fragile sites as a strategy to discover cancer susceptibility genes

Cellular and Molecular Life Sciences

Volumn 71, Issue 23, 2014, Pages 4561-4575

  Savelyeva, Larissa ^a   Brueckner, Lena M ^a  

^a GERMAN CANCER RESEARCH CENTER DKFZ   (Germany)

Author keywords

cFS genes; DPYD; Fragile sites; Fragilome; Molecular mapping; NBEA; SPIDR

Indexed keywords

DNA; DNA POLYMERASE;

ARTICLE; CANCER RESEARCH; CANCER SUSCEPTIBILITY; CARCINOGENESIS; CHROMOSOME FRAGILITY; CHROMOSOME STRUCTURE; CYTOGENETICS; DNA BASE COMPOSITION; DNA SEQUENCE; DNA STRUCTURE; EPIGENETICS; GENE MAPPING; GENETIC ANALYSIS; HETEROZYGOSITY LOSS; HUMAN; IN VITRO STUDY; METAPHASE CHROMOSOME; ANIMAL; CHEMISTRY; CHROMOSOME FRAGILE SITE; CHROMOSOME MAP; DNA REPLICATION; FLUORESCENCE IN SITU HYBRIDIZATION; GENETIC EPIGENESIS; GENETICS; NEOPLASM; PROCEDURES;

ANIMALS; CHROMOSOME FRAGILE SITES; CHROMOSOME MAPPING; DNA; DNA REPLICATION; EPIGENESIS, GENETIC; HUMANS; IN SITU HYBRIDIZATION, FLUORESCENCE; NEOPLASMS;

EID: 84911915086     PISSN: 1420682X     EISSN: 14209071     Source Type: Journal    
DOI: 10.1007/s00018-014-1723-z     Document Type: Article

References (113)

1. Lukusa T, Fryns JP (2008) Human chromosome fragility. Biochim Biophys Acta 1779(1):3-16
2. Gorgoulis VG, Vassiliou LV, Karakaidos P, Zacharatos P, Kotsinas A, Liloglou T, Venere M, Ditullio RA Jr, Kastrinakis NG, Levy B, Kletsas D, Yoneta A, Herlyn M, Kittas C, Halazonetis TD (2005) Activation of the DNA damage checkpoint and genomic instability in human precancerous lesions. Nature 434(7035):907-913
3. Halazonetis TD, Gorgoulis VG, Bartek J (2008) An oncogene-induced DNA damage model for cancer development. Science 319(5868):1352-1355
4. Durkin SG, Glover TW (2007) Chromosome fragile sites. Annu Rev Genet 41:169-192
5. Berger R, Bloomfield CD, Sutherland GR (1985) Report of the committee on chromosome rearrangements in neoplasia and on fragile sites. Cytogenet Cell Genet 40(1-4):490-535
6. Mrasek K, Schoder C, Teichmann AC, Behr K, Franze B, Wilhelm K, Blaurock N, Claussen U, Liehr T, Weise A (2010) Global screening and extended nomenclature for 230 aphidicolin-inducible fragile sites, including 61 yet unreported ones. Int J Oncol 36(4):929-940
7. Glover TW, Berger C, Coyle J, Echo B (1984) DNA polymerase alpha inhibition by aphidicolin induces gaps and breaks at common fragile sites in human chromosomes. Hum Genet 67(2):136-142
8. Glover TW, Stein CK (1988) Chromosome breakage and recombination at fragile sites. Am J Hum Genet 43(3):265-273
9. Wang ND, Testa JR, Smith DI (1993) Determination of the specificity of aphidicolin-induced breakage of the human 3p14.2 fragile site. Genomics 17(2):341-347. doi: 10.1006/geno.1993.1330
10. Wilke CM, Guo SW, Hall BK, Boldog F, Gemmill RM, Chandrasekharappa SC, Barcroft CL, Drabkin HA, Glover TW (1994) 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(2):319-326. doi: 10.1006/geno.1994.1390
11. Boldog FL, Waggoner B, Glover TW, Chumakov I, Le Paslier D, Cohen D, Gemmill RM, Drabkin HA (1994) Integrated YAC contig containing the 3p14.2 hereditary renal carcinoma 3;8 translocation breakpoint and the fragile site FRA3B. Genes Chromosomes Cancer 11(4):216-221
12. Paradee W, Wilke CM, Wang L, Shridhar R, Mullins CM, Hoge A, Glover TW, Smith DI (1996) A 350-kb cosmid contig in 3p14.2 that crosses the t(3;8) hereditary renal cell carcinoma translocation breakpoint and 17 aphidicolin-induced FRA3B breakpoints. Genomics 35(1):87-93. doi: 10.1006/geno.1996.0326
13. Rassool FV, McKeithan TW, Neilly ME, van Melle E, Espinosa R 3rd, Le Beau MM (1991) Preferential integration of marker DNA into the chromosomal fragile site at 3p14: an approach to cloning fragile sites. Proc Natl Acad Sci USA 88(15):6657-6661
14. Rassool FV, Le Beau MM, Shen ML, Neilly ME, Espinosa R 3rd, Ong ST, Boldog F, Drabkin H, McCarroll R, McKeithan TW (1996) Direct cloning of DNA sequences from the common fragile site region at chromosome band 3p14.2. Genomics 35(1):109-117
15. Fechter A, Buettel I, Kuehnel E, Savelyeva L, Schwab M (2007) Common fragile site FRA11G and rare fragile site FRA11B at 11q23.3 encompass distinct genomic regions. Genes Chromosomes Cancer 46(1):98-106
16. Fechter A, Buettel I, Kuehnel E, Schwab M, Savelyeva L (2007) Cloning of genetically tagged chromosome break sequences reveals new fragile sites at 6p21 and 13q22. Int J Cancer 120(11):2359-2367
17. Bester AC, Schwartz M, Schmidt M, Garrigue A, Hacein-Bey-Abina S, Cavazzana-Calvo M, Ben-Porat N, Von Kalle C, Fischer A, Kerem B (2006) Fragile sites are preferential targets for integrations of MLV vectors in gene therapy. Gene Ther 13(13):1057-1059. doi: 10.1038/sj.gt.3302752
18. Huang H, Qian J, Proffit J, Wilber K, Jenkins R, Smith DI (1998) FRA7G extends over a broad region: coincidence of human endogenous retroviral sequences (HERV-H) and small polydispersed circular DNAs (spcDNA) and fragile sites. Oncogene 16(18):2311-2319. doi: 10.1038/sj.onc.1200202
19. Callahan G, Denison SR, Phillips LA, Shridhar V, Smith DI (2003) Characterization of the common fragile site FRA9E and its potential role in ovarian cancer. Oncogene 22(4):590-601. doi: 10.1038/sj.onc.1206171
20. Denison SR, Becker NA, Ferber MJ, Phillips LA, Kalli KR, Lee J, Lillie J, Smith DI, Shridhar V (2002) Transcriptional profiling reveals that several common fragile-site genes are downregulated in ovarian cancer. Genes Chromosomes Cancer 34(4):406-415. doi: 10.1002/gcc.10084
21. Popescu NC, DiPaolo JA (1989) Preferential sites for viral integration on mammalian genome. Cancer Genet Cytogenet 42(2):157-171
22. Wilke CM, Hall BK, Hoge A, Paradee W, Smith DI, Glover TW (1996) 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(2):187-195
23. Thorland EC, Myers SL, Persing DH, Sarkar G, McGovern RM, Gostout BS, Smith DI (2000) Human papillomavirus type 16 integrations in cervical tumors frequently occur in common fragile sites. Cancer Res 60(21):5916-5921
24. Thorland EC, Myers SL, Gostout BS, Smith DI (2003) Common fragile sites are preferential targets for HPV16 integrations in cervical tumors. Oncogene 22(8):1225-1237. doi: 10.1038/sj.onc.1206170
25. Ferber MJ, Thorland EC, Brink AA, Rapp AK, Phillips LA, McGovern R, Gostout BS, Cheung TH, Chung TK, Fu WY, Smith DI (2003) Preferential integration of human papillomavirus type 18 near the c-myc locus in cervical carcinoma. Oncogene 22(46):7233-7242
26. Mishmar D, Rahat A, Scherer SW, Nyakatura G, Hinzmann B, Kohwi Y, Mandel-Gutfroind Y, Lee JR, Drescher B, Sas DE, Margalit H, Platzer M, Weiss A, Tsui LC, Rosenthal A, Kerem B (1998) 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(14):8141-8146
27. Gandhi M, Dillon LW, Pramanik S, Nikiforov YE, Wang YH (2010) DNA breaks at fragile sites generate oncogenic RET/PTC rearrangements in human thyroid cells. Oncogene 29(15):2272-2280
28. Ciullo M, Debily MA, Rozier L, Autiero M, Billault A, Mayau V, El Marhomy S, Guardiola J, Bernheim A, Coullin P, Piatier-Tonneau D, Debatisse M (2002) Initiation of the breakage-fusion-bridge mechanism through common fragile site activation in human breast cancer cells: the model of PIP gene duplication from a break at FRA7I. Hum Mol Genet 11(23):2887-2894
29. Zimonjic DB, Durkin ME, Keck-Waggoner CL, Park SW, Thorgeirsson SS, Popescu NC (2003) SMAD5 gene expression, rearrangements, copy number, and amplification at fragile site FRA5C in human hepatocellular carcinoma. Neoplasia 5(5):390-396
30. Reshmi SC, Huang X, Schoppy DW, Black RC, Saunders WS, Smith DI, Gollin SM (2007) Relationship between FRA11F and 11q13 gene amplification in oral cancer. Genes Chromosomes Cancer 46(2):143-154. doi: 10.1002/gcc.20394
31. Bester AC, Kafri M, Maoz K, Kerem B (2013) Infection with retroviral vectors leads to perturbed DNA replication increasing vector integrations into fragile sites. Sci Rep 3:2189. doi: 10.1038/srep02189
32. Smith DI, Zhu Y, McAvoy S, Kuhn R (2006) Common fragile sites, extremely large genes, neural development and cancer. Cancer Lett 232(1):48-57. doi: 10.1016/j.canlet.2005.06.049
33. Letessier A, Millot GA, Koundrioukoff S, Lachages AM, Vogt N, Hansen RS, Malfoy B, Brison O, Debatisse M (2011) Cell-type-specific replication initiation programs set fragility of the FRA3B fragile site. Nature 470(7332):120-123. doi: 10.1038/nature09745
34. Hansen RS, Thomas S, Sandstrom R, Canfield TK, Thurman RE, Weaver M, Dorschner MO, Gartler SM, Stamatoyannopoulos JA (2010) Sequencing newly replicated DNA reveals widespread plasticity in human replication timing. Proc Natl Acad Sci USA 107(1):139-144. doi: 10.1073/pnas.0912402107
35. Le Tallec B, Dutrillaux B, Lachages AM, Millot GA, Brison O, Debatisse M (2011) Molecular profiling of common fragile sites in human fibroblasts. Nat Struct Mol Biol 18(12):1421-1423. doi: 10.1038/nsmb.2155
36. Savelyeva L, Sagulenko E, Schmitt JG, Schwab M (2006) The neurobeachin gene spans the common fragile site FRA13A. Hum Genet 118(5):551-558
37. Blumrich A, Zapatka M, Brueckner LM, Zheglo D, Schwab M, Savelyeva L (2011) The FRA2C common fragile site maps to the borders of MYCN amplicons in neuroblastoma and is associated with gross chromosomal rearrangements in different cancers. Hum Mol Genet 20(8):1488-1501
38. Brueckner LM, Hess EM, Schwab M, Savelyeva L (2013) Instability at the FRA8I common fragile site disrupts the genomic integrity of the KIAA0146, CEBPD and PRKDC genes in colorectal cancer. Cancer Lett 336(1):85-95. doi: 10.1016/j.canlet.2013.04.007
39. Hormozian F, Schmitt JG, Sagulenko E, Schwab M, Savelyeva L (2007) FRA1E common fragile site breaks map within a 370kilobase pair region and disrupt the dihydropyrimidine dehydrogenase gene (DPYD). Cancer Lett 246(1-2):82-91
40. Limongi MZ, Pelliccia F, Rocchi A (2003) Characterization of the human common fragile site FRA2G. Genomics 81(2):93-97
41. Brueckner LM, Sagulenko E, Hess EM, Zheglo D, Blumrich A, Schwab M, Savelyeva L (2012) Genomic rearrangements at the FRA2H common fragile site frequently involve non-homologous recombination events across LTR and L1(LINE) repeats. Human genetics 131(8):1345-1359. doi: 10.1007/s00439-012-1165-3
42. Helmrich A, Stout-Weider K, Matthaei A, Hermann K, Heiden T, Schrock E (2007) Identification of the human/mouse syntenic common fragile site FRA7K/Fra12C1-relation of FRA7K and other human common fragile sites on chromosome 7 to evolutionary breakpoints. Int J Cancer 120(1):48-54
43. Sawinska M, Schmitt JG, Sagulenko E, Westermann F, Schwab M, Savelyeva L (2007) Novel aphidicolin-inducible common fragile site FRA9G maps to 9p22.2, within the C9orf39 gene. Genes Chromosomes Cancer 46(11):991-999
44. Arlt MF, Miller DE, Beer DG, Glover TW (2002) Molecular characterization of FRAXB and comparative common fragile site instability in cancer cells. Genes Chromosomes Cancer 33(1):82-92
45. Furey TS, Haussler D (2003) Integration of the cytogenetic map with the draft human genome sequence. Hum Mol Genet 12(9):1037-1044
46. Kent WJ, Sugnet CW, Furey TS, Roskin KM, Pringle TH, Zahler AM, Haussler D (2002) The human genome browser at UCSC. Genome Res 12(6):996-1006. doi: 10.1101/gr.229102
47. Flicek P, Amode MR, Barrell D, Beal K, Billis K, Brent S, Carvalho-Silva D, Clapham P, Coates G, Fitzgerald S, Gil L, Giron CG, Gordon L, Hourlier T, Hunt S, Johnson N, Juettemann T, Kahari AK, Keenan S, Kulesha E, Martin FJ, Maurel T, McLaren WM, Murphy DN, Nag R, Overduin B, Pignatelli M, Pritchard B, Pritchard E, Riat HS, Ruffier M, Sheppard D, Taylor K, Thormann A, Trevanion SJ, Vullo A, Wilder SP, Wilson M, Zadissa A, Aken BL, Birney E, Cunningham F, Harrow J, Herrero J, Hubbard TJ, Kinsella R, Muffato M, Parker A, Spudich G, Yates A, Zerbino DR, Searle SM (2014) Ensembl 2014. Nucleic Acids Res 42(Database issue):D749-D755. doi: 10.1093/nar/gkt1196
48. Hecht F (1988) Fragile sites, cancer chromosome breakpoints, and oncogenes all cluster in light G bands. Cancer Genet Cytogenet 31(1):17-24
49. Fungtammasan A, Walsh E, Chiaromonte F, Eckert KA, Makova KD (2012) A genome-wide analysis of common fragile sites: what features determine chromosomal instability in the human genome? Genome Res 22(6):993-1005. doi: 10.1101/gr.134395.111
50. Le Tallec B, Millot GA, Blin ME, Brison O, Dutrillaux B, Debatisse M (2013) Common fragile site profiling in epithelial and erythroid cells reveals that most recurrent cancer deletions lie in fragile sites hosting large genes. Cell reports 4(3):420-428. doi: 10.1016/j.celrep.2013.07.003
51. Zimonjic DB, Druck T, Ohta M, Kastury K, Croce CM, Popescu NC, Huebner K (1997) Positions of chromosome 3p14.2 fragile sites (FRA3B) within the FHIT gene. Cancer Res 57(6):1166-1170
52. Huang H, Qian C, Jenkins RB, Smith DI (1998) 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(2):152-159
53. Ried K, Finnis M, Hobson L, Mangelsdorf M, Dayan S, Nancarrow JK, Woollatt E, Kremmidiotis G, Gardner A, Venter D, Baker E, Richards RI (2000) 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(11):1651-1663
54. Mangelsdorf M, Ried K, Woollatt E, Dayan S, Eyre H, Finnis M, Hobson L, Nancarrow J, Venter D, Baker E, Richards RI (2000) Chromosomal fragile site FRA16D and DNA instability in cancer. Cancer Res 60(6):1683-1689
55. Morelli C, Karayianni E, Magnanini C, Mungall AJ, Thorland E, Negrini M, Smith DI, Barbanti-Brodano G (2002) Cloning and characterization of the common fragile site FRA6F harboring a replicative senescence gene and frequently deleted in human tumors. Oncogene 21(47):7266-7276. doi: 10.1038/sj.onc.1205573
56. Becker NA, Thorland EC, Denison SR, Phillips LA, Smith DI (2002) Evidence that instability within the FRA3B region extends four megabases. Oncogene 21(57):8713-8722. doi: 10.1038/sj.onc.1205950
57. Hellman A, Zlotorynski E, Scherer SW, Cheung J, Vincent JB, Smith DI, Trakhtenbrot L, Kerem B (2002) A role for common fragile site induction in amplification of human oncogenes. Cancer Cell 1(1):89-97
58. Krummel KA, Roberts LR, Kawakami M, Glover TW, Smith DI (2000) The characterization of the common fragile site FRA16D and its involvement in multiple myeloma translocations. Genomics 69(1):37-46. doi: 10.1006/geno.2000.6321
59. Rozier L, El-Achkar E, Apiou F, Debatisse M (2004) Characterization of a conserved aphidicolin-sensitive common fragile site at human 4q22 and mouse 6C1: possible association with an inherited disease and cancer. Oncogene 23(41):6872-6880. doi: 10.1038/sj.onc.1207809
60. Curatolo A, Limongi ZM, Pelliccia F, Rocchi A (2007) Molecular characterization of the human common fragile site FRA1H. Genes Chromosomes Cancer 46(5):487-493. doi: 10.1002/gcc.20432
61. Pelliccia F, Bosco N, Rocchi A (2010) Breakages at common fragile sites set boundaries of amplified regions in two leukemia cell lines K562 - Molecular characterization of FRA2H and localization of a new CFS FRA2S. Cancer Lett 299(1):37-44. doi: 10.1016/j.canlet.2010.08.001
62. Bosco N, Pelliccia F, Rocchi A (2010) Characterization of FRA7B, a human common fragile site mapped at the 7p chromosome terminal region. Cancer Genet Cytogenet 202(1):47-52. doi: 10.1016/j.cancergencyto.2010.06.008
63. Ma K, Qiu L, Mrasek K, Zhang J, Liehr T, Quintana LG, Li Z (2012) Common fragile sites: genomic hotspots of DNA damage and carcinogenesis. Int J Mol Sci 13(9):11974-11999. doi: 10.3390/ijms130911974
64. Rajaram M, Zhang J, Wang T, Li J, Kuscu C, Qi H, Kato M, Grubor V, Weil RJ, Helland A, Borrenson-Dale AL, Cho KR, Levine DA, Houghton AN, Wolchok JD, Myeroff L, Markowitz SD, Lowe SW, Zhang M, Krasnitz A, Lucito R, Mu D, Powers RS (2013) Two distinct categories of focal deletions in cancer genomes. PLoS One 8(6):e66264. doi: 10.1371/journal.pone.0066264
65. Zhu Y, McAvoy S, Kuhn R, Smith DI (2006) RORA, a large common fragile site gene, is involved in cellular stress response. Oncogene 25(20):2901-2908. doi: 10.1038/sj.onc.1209314
66. McAvoy S, Ganapathiraju S, Perez DS, James CD, Smith DI (2007) DMD and IL1RAPL1: two large adjacent genes localized within a common fragile site (FRAXC) have reduced expression in cultured brain tumors. Cytogenet Genome Res 119(3-4):196-203. doi: 10.1159/000112061
67. McAvoy S, Zhu Y, Perez DS, James CD, Smith DI (2008) Disabled-1 is a large common fragile site gene, inactivated in multiple cancers. Genes Chromosomes Cancer 47(2):165-174. doi: 10.1002/gcc.20519
68. Zlotorynski E, Rahat A, Skaug J, Ben-Porat N, Ozeri E, Hershberg R, Levi A, Scherer SW, Margalit H, Kerem B (2003) Molecular basis for expression of common and rare fragile sites. Mol Cell Biol 23(20):7143-7151
69. Debacker K, Winnepenninckx B, Ben-Porat N, FitzPatrick D, Van Luijk R, Scheers S, Kerem B, Frank Kooy R (2007) FRA18C: a new aphidicolin-inducible fragile site on chromosome 18q22, possibly associated with in vivo chromosome breakage. J Med Genet 44(5):347-352
70. Ragland RL, Glynn MW, Arlt MF, Glover TW (2008) Stably transfected common fragile site sequences exhibit instability at ectopic sites. Genes Chromosomes Cancer 47(10):860-872
71. Casper AM, Rosen DM, Rajula KD (2012) Sites of genetic instability in mitosis and cancer. Ann N Y Acad Sci 1267:24-30. doi: 10.1111/j.1749-6632.2012.06592.x
72. Lander ES, Linton LM, Birren B, Nusbaum C, Zody MC, Baldwin J, Devon K, Dewar K, Doyle M, FitzHugh W, Funke R, Gage D, Harris K, Heaford A, Howland J, Kann L, Lehoczky J, LeVine R, McEwan P, McKernan K, Meldrim J, Mesirov JP, Miranda C, Morris W, Naylor J, Raymond C, Rosetti M, Santos R, Sheridan A, Sougnez C, Stange-Thomann N, Stojanovic N, Subramanian A, Wyman D, Rogers J, Sulston J, Ainscough R, Beck S, Bentley D, Burton J, Clee C, Carter N, Coulson A, Deadman R, Deloukas P, Dunham A, Dunham I, Durbin R, French L, Grafham D, Gregory S, Hubbard T, Humphray S, Hunt A, Jones M, Lloyd C, McMurray A, Matthews L, Mercer S, Milne S, Mullikin JC, Mungall A, Plumb R, Ross M, Shownkeen R, Sims S, Waterston RH, Wilson RK, Hillier LW, McPherson JD, Marra MA, Mardis ER, Fulton LA, Chinwalla AT, Pepin KH, Gish WR, Chissoe SL, Wendl MC, Delehaunty KD, Miner TL, Delehaunty A, Kramer JB, Cook LL, Fulton RS, Johnson DL, Minx PJ, Clifton SW, Hawkins T, Branscomb E, Predki P, Richardson P, Wenning S, Slezak T, Doggett N, Cheng JF, Olsen A, Lucas S, Elkin C, Uberbacher E, Frazier M, Gibbs RA, Muzny DM, Scherer SE, Bouck JB, Sodergren EJ, Worley KC, Rives CM, Gorrell JH, Metzker ML, Naylor SL, Kucherlapati RS, Nelson DL, Weinstock GM, Sakaki Y, Fujiyama A, Hattori M, Yada T, Toyoda A, Itoh T, Kawagoe C, Watanabe H, Totoki Y, Taylor T, Weissenbach J, Heilig R, Saurin W, Artiguenave F, Brottier P, Bruls T, Pelletier E, Robert C, Wincker P, Smith DR, Doucette-Stamm L, Rubenfield M, Weinstock K, Lee HM, Dubois J, Rosenthal A, Platzer M, Nyakatura G, Taudien S, Rump A, Yang H, Yu J, Wang J, Huang G, Gu J, Hood L, Rowen L, Madan A, Qin S, Davis RW, Federspiel NA, Abola AP, Proctor MJ, Myers RM, Schmutz J, Dickson M, Grimwood J, Cox DR, Olson MV, Kaul R, Raymond C, Shimizu N, Kawasaki K, Minoshima S, Evans GA, Athanasiou M, Schultz R, Roe BA, Chen F, Pan H, Ramser J, Lehrach H, Reinhardt R, McCombie WR, De La Bastide M, Dedhia N, Blocker H, Hornischer K, Nordsiek G, Agarwala R, Aravind L, Bailey JA, Bateman A, Batzoglou S, Birney E, Bork P, Brown DG, Burge CB, Cerutti L, Chen HC, Church D, Clamp M, Copley RR, Doerks T, Eddy SR, Eichler EE, Furey TS, Galagan J, Gilbert JG, Harmon C, Hayashizaki Y, Haussler D, Hermjakob H, Hokamp K, Jang W, Johnson LS, Jones TA, Kasif S, Kaspryzk A, Kennedy S, Kent WJ, Kitts P, Koonin EV, Korf I, Kulp D, Lancet D, Lowe TM, McLysaght A, Mikkelsen T, Moran JV, Mulder N, Pollara VJ, Ponting CP, Schuler G, Schultz J, Slater G, Smit AF, Stupka E, Szustakowski J, Thierry-Mieg D, Thierry-Mieg J, Wagner L, Wallis J, Wheeler R, Williams A, Wolf YI, Wolfe KH, Yang SP, Yeh RF, Collins F, Guyer MS, Peterson J, Felsenfeld A, Wetterstrand KA, Patrinos A, Morgan MJ, de Jong P, Catanese JJ, Osoegawa K, Shizuya H, Choi S, Chen YJ, International human genome sequencing C (2001) Initial sequencing and analysis of the human genome. Nature 409(6822):860-921. doi: 10.1038/35057062
73. Tsantoulis PK, Kotsinas A, Sfikakis PP, Evangelou K, Sideridou M, Levy B, Mo L, Kittas C, Wu XR, Papavassiliou AG, Gorgoulis VG (2008) Oncogene-induced replication stress preferentially targets common fragile sites in preneoplastic lesions. A genome-wide study. Oncogene 27(23):3256-3264
74. Mimori K, Druck T, Inoue H, Alder H, Berk L, Mori M, Huebner K, Croce CM (1999) Cancer-specific chromosome alterations in the constitutive fragile region FRA3B. Proc Natl Acad Sci USA 96(13):7456-7461
75. Dillon LW, Burrow AA, Wang YH (2010) DNA instability at chromosomal fragile sites in cancer. Curr Genomics 11(5):326-337
76. Labib K, Hodgson B (2007) Replication fork barriers: pausing for a break or stalling for time? EMBO Rep 8(4):346-353
77. Shah SN, Opresko PL, Meng X, Lee MY, Eckert KA (2010) DNA structure and the Werner protein modulate human DNA polymerase delta-dependent replication dynamics within the common fragile site FRA16D. Nucleic Acids Res 38(4):1149-1162
78. Zhang H, Freudenreich CH (2007) An AT-rich sequence in human common fragile site FRA16D causes fork stalling and chromosome breakage in S. cerevisiae. Mol Cell 27(3):367-379
79. Helmrich A, Stout-Weider K, Hermann K, Schrock E, Heiden T (2006) Common fragile sites are conserved features of human and mouse chromosomes and relate to large active genes. Genome Res 16(10):1222-1230. doi: 10.1101/gr.5335506
80. Le Beau MM, Rassool FV, Neilly ME, Espinosa R 3rd, Glover TW, Smith DI, McKeithan TW (1998) 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(4):755-761
81. Wang L, Darling J, Zhang JS, Huang H, Liu W, Smith DI (1999) Allele-specific late replication and fragility of the most active common fragile site, FRA3B. Hum Mol Genet 8(3):431-437
82. Palakodeti A, Han Y, Jiang Y, Le Beau MM (2004) The role of late/slow replication of the FRA16D in common fragile site induction. Genes Chromosomes Cancer 39(1):71-76. doi: 10.1002/gcc.10290
83. Hellman A, Rahat A, Scherer SW, Darvasi A, Tsui LC, Kerem B (2000) Replication delay along FRA7H, a common fragile site on human chromosome 7, leads to chromosomal instability. Mol Cell Biol 20(12):4420-4427
84. Handt O, Baker E, Dayan S, Gartler SM, Woollatt E, Richards RI, Hansen RS (2000) Analysis of replication timing at the FRA10B and FRA16B fragile site loci. Chromosome Res 8(8):677-688
85. Palumbo E, Matricardi L, Tosoni E, Bensimon A, Russo A (2010) Replication dynamics at common fragile site FRA6E. Chromosoma 119(6):575-587. doi: 10.1007/s00412-010-0279-4
86. Palakodeti A, Lucas I, Jiang Y, Young DJ, Fernald AA, Karrison T, Le Beau MM (2010) Impaired replication dynamics at the FRA3B common fragile site. Hum Mol Genet 19(1):99-110. doi: 10.1093/hmg/ddp470
87. Ozeri-Galai E, Lebofsky R, Rahat A, Bester AC, Bensimon A, Kerem B (2011) Failure of origin activation in response to fork stalling leads to chromosomal instability at fragile sites. Mol Cell 43(1):122-131. doi: 10.1016/j.molcel.2011.05.019
88. Jiang Y, Lucas I, Young DJ, Davis EM, Karrison T, Rest JS, Le Beau MM (2009) Common fragile sites are characterized by histone hypoacetylation. Hum Mol Genet 18(23):4501-4512. doi: 10.1093/hmg/ddp410
89. Koch CM, Andrews RM, Flicek P, Dillon SC, Karaoz U, Clelland GK, Wilcox S, Beare DM, Fowler JC, Couttet P, James KD, Lefebvre GC, Bruce AW, Dovey OM, Ellis PD, Dhami P, Langford CF, Weng ZP, Birney E, Carter NP, Vetrie D, Dunham I (2007) The landscape of histone modifications across 1% of the human genome in five human cell lines. Genome Res 17(6):691-707. doi: 10.1101/Gr.5704207
90. Helmrich A, Ballarino M, Tora L (2011) Collisions between replication and transcription complexes cause common fragile site instability at the longest human genes. Mol Cell 44(6):966-977. doi: 10.1016/j.molcel.2011.10.013
91. Yunis JJ, Soreng AL, Bowe AE (1987) Fragile sites are targets of diverse mutagens and carcinogens. Oncogene 1(1):59-69
92. Bignell GR, Greenman CD, Davies H, Butler AP, Edkins S, Andrews JM, Buck G, Chen L, Beare D, Latimer C, Widaa S, Hinton J, Fahey C, Fu B, Swamy S, Dalgliesh GL, Teh BT, Deloukas P, Yang F, Campbell PJ, Futreal PA, Stratton MR (2010) Signatures of mutation and selection in the cancer genome. Nature 463(7283):893-898
93. Beroukhim R, Mermel CH, Porter D, Wei G, Raychaudhuri S, Donovan J, Barretina J, Boehm JS, Dobson J, Urashima M, Mc Henry KT, Pinchback RM, Ligon AH, Cho YJ, Haery L, Greulich H, Reich M, Winckler W, Lawrence MS, Weir BA, Tanaka KE, Chiang DY, Bass AJ, Loo A, Hoffman C, Prensner J, Liefeld T, Gao Q, Yecies D, Signoretti S, Maher E, Kaye FJ, Sasaki H, Tepper JE, Fletcher JA, Tabernero J, Baselga J, Tsao MS, Demichelis F, Rubin MA, Janne PA, Daly MJ, Nucera C, Levine RL, Ebert BL, Gabriel S, Rustgi AK, Antonescu CR, Ladanyi M, Letai A, Garraway LA, Loda M, Beer DG, True LD, Okamoto A, Pomeroy SL, Singer S, Golub TR, Lander ES, Getz G, Sellers WR, Meyerson M (2010) The landscape of somatic copy-number alteration across human cancers. Nature 463(7283):899-905
94. Dereli-Oz A, Versini G, Halazonetis TD (2011) Studies of genomic copy number changes in human cancers reveal signatures of DNA replication stress. Mol Oncol 5(4):308-314. doi: 10.1016/j.molonc.2011.05.002
95. Saldivar JC, Shibata H, Huebner K (2010) Pathology and biology associated with the fragile FHIT gene and gene product. J Cell Biochem 109(5):858-865
96. Lewandowska U, Zelazowski M, Seta K, Byczewska M, Pluciennik E, Bednarek AK (2009) WWOX, the tumour suppressor gene affected in multiple cancers. J Physiol Pharmacol 60(Suppl 1):47-56
97. Poulogiannis G, McIntyre RE, Dimitriadi M, Apps JR, Wilson CH, Ichimura K, Luo F, Cantley LC, Wyllie AH, Adams DJ, Arends MJ (2010) PARK2 deletions occur frequently in sporadic colorectal cancer and accelerate adenoma development in Apc mutant mice. Proc Natl Acad Sci USA 107(34):15145-15150. doi: 10.1073/pnas.1009941107
98. Zhu J, Li X, Kong X, Moran MS, Su P, Haffty BG, Yang Q (2012) Testin is a tumor suppressor and prognostic marker in breast cancer. Cancer Sci 103(12):2092-2101. doi: 10.1111/cas.12020
99. Lee S, Kwon H, Jeong K, Pak Y (2011) Regulation of cancer cell proliferation by caveolin-2 down-regulation and re-expression. Int J Oncol 38(5):1395-1402. doi: 10.3892/ijo.2011.958
100. Nair R, Lauks J, Jung S, Cooke NE, de Wit H, Brose N, Kilimann MW, Verhage M, Rhee J (2013) Neurobeachin regulates neurotransmitter receptor trafficking to synapses. J Cell Biol 200(1):61-80. doi: 10.1083/jcb.201207113
101. Savelyeva L, Sagulenko E, Schmitt JG, Schwab M (2006) Low-frequency common fragile sites: link to neuropsychiatric disorders? Cancer Lett 232(1):58-69
102. Volders K, Nuytens K, Creemers JW (2011) The autism candidate gene Neurobeachin encodes a scaffolding protein implicated in membrane trafficking and signaling. Curr Mol Med 11(3):204-217
103. McAvoy S, Ganapathiraju SC, Ducharme-Smith AL, Pritchett JR, Kosari F, Perez DS, Zhu Y, James CD, Smith DI (2007) Non-random inactivation of large common fragile site genes in different cancers. Cytogenet Genome Res 118(2-4):260-269. doi: 10.1159/000108309
104. Gao G, Kasperbauer JL, Tombers NM, Wang V, Mayer K, Smith DI (2014) A selected group of large common fragile site genes have decreased expression in oropharyngeal squamous cell carcinomas. Genes Chromosomes Cancer 53(5):392-401. doi: 10.1002/gcc.22150
105. O'Neal J, Gao F, Hassan A, Monahan R, Barrios S, Kilimann MW, Lee I, Chng WJ, Vij R, Tomasson MH (2009) Neurobeachin (NBEA) is a target of recurrent interstitial deletions at 13q13 in patients with MGUS and multiple myeloma. Exp Hematol 37(2):234-244. doi: 10.1016/j.exphem.2008.10.014
106. Nagoshi H, Taki T, Hanamura I, Nitta M, Otsuki T, Nishida K, Okuda K, Sakamoto N, Kobayashi S, Yamamoto-Sugitani M, Tsutsumi Y, Kobayashi T, Matsumoto Y, Horiike S, Kuroda J, Taniwaki M (2012) Frequent PVT1 rearrangement and novel chimeric genes PVT1-NBEA and PVT1-WWOX occur in multiple myeloma with 8q24 abnormality. Cancer Res 72(19):4954-4962
107. Wan L, Han J, Liu T, Dong S, Xie F, Chen H, Huang J (2013) Scaffolding protein SPIDR/KIAA0146 connects the Bloom syndrome helicase with homologous recombination repair. Proc Natl Acad Sci USA 110(26):10646-10651. doi: 10.1073/pnas.1220921110
108. Akasaka T, Balasas T, Russell LJ, Sugimoto KJ, Majid A, Walewska R, Karran EL, Brown DG, Cain K, Harder L, Gesk S, Martin-Subero JI, Atherton MG, Bruggemann M, Calasanz MJ, Davies T, Haas OA, Hagemeijer A, Kempski H, Lessard M, Lillington DM, Moore S, Nguyen-Khac F, Radford-Weiss I, Schoch C, Struski S, Talley P, Welham MJ, Worley H, Strefford JC, Harrison CJ, Siebert R, Dyer MJ (2007) Five members of the CEBP transcription factor family are targeted by recurrent IGH translocations in B-cell precursor acute lymphoblastic leukemia (BCP-ALL). Blood 109(8):3451-3461
109. Gross E, Meul C, Raab S, Propping C, Avril S, Aubele M, Gkazepis A, Schuster T, Grebenchtchikov N, Schmitt M, Kiechle M, Meijer J, Vijzelaar R, Meindl A, van Kuilenburg AB (2013) Somatic copy number changes in DPYD are associated with lower risk of recurrence in triple-negative breast cancers. Br J Cancer 109(9):2347-2355. doi: 10.1038/bjc.2013.621
110. van Kuilenburg AB, Meijer J, Mul AN, Hennekam RC, Hoovers JM, de Die-Smulders CE, Weber P, Mori AC, Bierau J, Fowler B, Macke K, Sass JO, Meinsma R, Hennermann JB, Miny P, Zoetekouw L, Vijzelaar R, Nicolai J, Ylstra B, Rubio-Gozalbo ME (2009) Analysis of severely affected patients with dihydropyrimidine dehydrogenase deficiency reveals large intragenic rearrangements of DPYD and a de novo interstitial deletion del(1)(p13.3p21.3). Hum Genet 125(5-6):581-590. doi: 10.1007/s00439-009-0653-6
111. Kobunai T, Ooyama A, Sasaki S, Wierzba K, Takechi T, Fukushima M, Watanabe T, Nagawa H (2007) Changes to the dihydropyrimidine dehydrogenase gene copy number influence the susceptibility of cancers to 5-FU-based drugs: data mining of the NCI-DTP data sets and validation with human tumour xenografts. Eur J Cancer 43(4):791-798. doi: 10.1016/j.ejca.2006.09.026
112. Miller CT, Lin L, Casper AM, Lim J, Thomas DG, Orringer MB, Chang AC, Chambers AF, Giordano TJ, Glover TW, Beer DG (2006) Genomic amplification of MET with boundaries within fragile site FRA7G and upregulation of MET pathways in esophageal adenocarcinoma. Oncogene 25(3):409-418. doi: 10.1038/sj.onc.1209057
113. Dekaban A (1965) Persisting clone of cells with an abnormal chromosome in a woman previously irradiated. J Nucl Med 6(10):740-746