食管癌组织中基因断裂及基因重排的鉴定
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摘要
基因断裂及基因重排是人类恶性肿瘤发生发展的重要机制之一,目前只在少数几种实体肿瘤中明确了一些有意义的染色体断裂及易位,尚无食管癌组织中的相关报道。本研究通过筛选和鉴定食管癌组织中发生于基因内部的断裂以及由染色体易位引起的基因重排,旨在进一步探索其在食管癌发生发展过程中的作用和意义。
本课题采用SNP芯片技术在六例食管鳞癌(ESCC)组织标本中鉴定出了发生于MTAP、CDKN2B-AS1、NRP2、PPP3CA等基因内部的断裂,同时采用实时定量PCR以及双色荧光原位杂交技术(FISH)技术在较大标本中验证了MTAP、NRP2、ODZ2等基因的断裂。运用RACE实验检测了可能存在的基因重排。运用Western技术分析了MTAP以及NRP2断裂后蛋白表达水平的改变。通过功能实验,进一步研究了MTAP对食管癌细胞的作用。
Real-time PCR结果显示,在40例ESCC标本中发现了9例含有MTAP的断裂(发生频率为22.5%)。FISH结果揭示了ODZ2、CADM2及NRP2在ESCC中的断裂频率分别为12.5%、8.3%及16.7%。我们通过3'-RACE技术在一例ESCC标本中鉴定出三种MTAP-CDKN2B-AS1融合转录产物,分别为MTAP基因的1至5号外显子与CDKN2B-AS1的13、14以及19号外显子之间发生的融合。运用3'-RACE技术在另一例ESCC标本中鉴定出NRP2与ANXA13形成融合转录产物,为NRP2基因的前14个外显子部分与ANXA13的1号外显子之间发生的反向融合。RACE技术同时在另外两例ESCC标本中分别鉴定出PPP3CA及LPHN3的自身拼接。
对59例ESCC的SNP结果进行的深入分析表明,MTAP在ESCC中存在高频率断裂及缺失。Western blot结果显示：发生MTAP断裂的9例标本中有5例MTAP表达下调。在KYSE150和KYSE170中敲降MTAP后细胞发生EMT样改变,细胞运动侵袭能力显著上调。表明MTAP基因的断裂和表达下调可能有促进食管鳞癌的发生发展的重要功能。
本研究首次在ESCC中鉴定出两种基因重排方式MTAP-CDKN2B-AS1以及NRP2-ANXA13。功能研究结果显示敲降MTAP可诱导食管癌细胞发生EMT,为研究MTAP在ESCC中的功能打下基础。我们的工作为深入探索MTAP和NRP2在食管鳞癌中的意义提供了重要线索。
Genetic disruptions and gene rearrangements are the most common genetic alterations in human malignant tumors. So far, a few functional genetic disruptions and gene rearrangements have been identified in several solid tumors, but no such evidence was found in esophageal carcinoma. The purpose of the present study was to clarify the genetic alterations in esophageal squamous cell carcinoma (ESCC).
Six ESCC samples were collected for SNP micro-array and a few disruptions were found including MTAP, CDKN2B-AS1, NRP2, ANXA13and PPP3CA. Frequency of MTAP, NRP2, ODZ2and CADM2disruptions were identified by real-time PCR and dual-color fluorescence in situ hybridization (FISH). Alterations of MTAP and NRP2expression in tumors were detected by western blotting. RACE technique is applied to detect the possible fusion transcripts. Cell proliferation assays and transwell assays were carried out to investigate the effect of MTAP alteration on malignant phenotype of ESCC cells.
Real-time PCR results showed that MTAP disruptions were present in22.5%(9/40) of ESCCs and the frequency of ODZ2, CADM2and NRP2disruptions was found to be12.5%,8.3%and16.7%. Three fusion transcripts were detected in one ESCC sample which were1-5exons of MTAP fused with13,14and19exons of CDKN2B-AS1respectively. In another sample, NRP2and ANXA13formed the fusion transcript which was the first exon of ANXA13fused with the1-14exons of NRP2. PPP3CA and LPHN3self-rearrangements were identified in the other two ESCC samples.
Further analysis of earlier59ESCC SNP micro-array confirmed high frequency deletion and disruption of MTAP. Down-regulation of MTAP was detected in5out of the9ESCC samples with MTAP disruptions by western blotting. Functional studies indicated that silencing MTAP by small interfering RNA induced epithelial-mesenchymal transition (EMT), accompanied by a decrease of E-cadherin and an increase of N-cadherin and Slug. Also, MTAP knockdown promoted cell migration and invasion in ESCC KYSE150and KYSE170cells. Our results indicate that MTAP disruptions and reduced expression exist in ESCCs and that MTAP plays a part in mediating cell migration, invasion and EMT of ESCC cells.
In conclusion, two new fusion transcripts:MTAP-CDKN2B-AS1and NRP2-ANXA13are identified for the first time. Functional study show that MTAP knocking down induces EMT in esophageal cancer cells. Our work provides important clues in exploring the significance of MTAP and NRP2in esophageal squamous carcinoma.
本课题采用SNP芯片技术在六例食管鳞癌(ESCC)组织标本中鉴定出了发生于MTAP、CDKN2B-AS1、NRP2、PPP3CA等基因内部的断裂,同时采用实时定量PCR以及双色荧光原位杂交技术(FISH)技术在较大标本中验证了MTAP、NRP2、ODZ2等基因的断裂。运用RACE实验检测了可能存在的基因重排。运用Western技术分析了MTAP以及NRP2断裂后蛋白表达水平的改变。通过功能实验,进一步研究了MTAP对食管癌细胞的作用。
Real-time PCR结果显示,在40例ESCC标本中发现了9例含有MTAP的断裂(发生频率为22.5%)。FISH结果揭示了ODZ2、CADM2及NRP2在ESCC中的断裂频率分别为12.5%、8.3%及16.7%。我们通过3'-RACE技术在一例ESCC标本中鉴定出三种MTAP-CDKN2B-AS1融合转录产物,分别为MTAP基因的1至5号外显子与CDKN2B-AS1的13、14以及19号外显子之间发生的融合。运用3'-RACE技术在另一例ESCC标本中鉴定出NRP2与ANXA13形成融合转录产物,为NRP2基因的前14个外显子部分与ANXA13的1号外显子之间发生的反向融合。RACE技术同时在另外两例ESCC标本中分别鉴定出PPP3CA及LPHN3的自身拼接。
对59例ESCC的SNP结果进行的深入分析表明,MTAP在ESCC中存在高频率断裂及缺失。Western blot结果显示：发生MTAP断裂的9例标本中有5例MTAP表达下调。在KYSE150和KYSE170中敲降MTAP后细胞发生EMT样改变,细胞运动侵袭能力显著上调。表明MTAP基因的断裂和表达下调可能有促进食管鳞癌的发生发展的重要功能。
本研究首次在ESCC中鉴定出两种基因重排方式MTAP-CDKN2B-AS1以及NRP2-ANXA13。功能研究结果显示敲降MTAP可诱导食管癌细胞发生EMT,为研究MTAP在ESCC中的功能打下基础。我们的工作为深入探索MTAP和NRP2在食管鳞癌中的意义提供了重要线索。
Genetic disruptions and gene rearrangements are the most common genetic alterations in human malignant tumors. So far, a few functional genetic disruptions and gene rearrangements have been identified in several solid tumors, but no such evidence was found in esophageal carcinoma. The purpose of the present study was to clarify the genetic alterations in esophageal squamous cell carcinoma (ESCC).
Six ESCC samples were collected for SNP micro-array and a few disruptions were found including MTAP, CDKN2B-AS1, NRP2, ANXA13and PPP3CA. Frequency of MTAP, NRP2, ODZ2and CADM2disruptions were identified by real-time PCR and dual-color fluorescence in situ hybridization (FISH). Alterations of MTAP and NRP2expression in tumors were detected by western blotting. RACE technique is applied to detect the possible fusion transcripts. Cell proliferation assays and transwell assays were carried out to investigate the effect of MTAP alteration on malignant phenotype of ESCC cells.
Real-time PCR results showed that MTAP disruptions were present in22.5%(9/40) of ESCCs and the frequency of ODZ2, CADM2and NRP2disruptions was found to be12.5%,8.3%and16.7%. Three fusion transcripts were detected in one ESCC sample which were1-5exons of MTAP fused with13,14and19exons of CDKN2B-AS1respectively. In another sample, NRP2and ANXA13formed the fusion transcript which was the first exon of ANXA13fused with the1-14exons of NRP2. PPP3CA and LPHN3self-rearrangements were identified in the other two ESCC samples.
Further analysis of earlier59ESCC SNP micro-array confirmed high frequency deletion and disruption of MTAP. Down-regulation of MTAP was detected in5out of the9ESCC samples with MTAP disruptions by western blotting. Functional studies indicated that silencing MTAP by small interfering RNA induced epithelial-mesenchymal transition (EMT), accompanied by a decrease of E-cadherin and an increase of N-cadherin and Slug. Also, MTAP knockdown promoted cell migration and invasion in ESCC KYSE150and KYSE170cells. Our results indicate that MTAP disruptions and reduced expression exist in ESCCs and that MTAP plays a part in mediating cell migration, invasion and EMT of ESCC cells.
In conclusion, two new fusion transcripts:MTAP-CDKN2B-AS1and NRP2-ANXA13are identified for the first time. Functional study show that MTAP knocking down induces EMT in esophageal cancer cells. Our work provides important clues in exploring the significance of MTAP and NRP2in esophageal squamous carcinoma.
引文
1. Robinson DR, Kalyana-Sundaram S, Wu YM, Shankar S, Cao X, et al. (2011) Functionally recurrent rearrangements of the MAST kinase and Notch gene families in breast cancer. Nat Med 17:1646-1651.
2. Cazes A, Louis-Brennetot C, Mazot P, Dingli F, Lombard B, et al. (2013) Characterization of rearrangements involving the ALK gene reveals a novel truncated form associated with tumor aggressiveness in neuroblastoma. Cancer Res 73:195-204.
3. Maus MK, Stephens C, Zeger G, Grimminger PP, Huang E (2012) Identification of Novel Variant of EML4-ALK Fusion Gene in NSCLC:Potential Benefits of the RT-PCR Method. Int J Biomed Sci 8:1-6.
4. Gopalan A, Leversha MA, Dudas ME, Maschino AC, Chang J, et al. (2013) TMPRSS2-ERG rearrangement in dominant anterior prostatic tumours:incidence and correlation with ERG immunohistochemistry. Histopathology 63:279-286.
5. Gridelli C, Peters S, Sgambato A, Casaluce F, Adjei AA, et al. (2014) ALK inhibitors in the treatment of advanced NSCLC. Cancer Treat Rev 40:300-306.
6. Bass AJ, Lawrence MS, Brace LE, Ramos AH, Drier Y, et al. (2011) Genomic sequencing of colorectal adenocarcinomas identifies a recurrent VTI1A-TCF7L2 fusion. Nat Genet 43:964-968.
7. Rickman DS, Soong TD, Moss B, Mosquera JM, Dlabal J, et al. (2012) Oncogene-mediated alterations in chromatin conformation. Proc Natl Acad Sci U S A 109:9083-9088.
8. Attard G, Ang JE, Olmos D, de Bono JS (2008) Dissecting prostate carcinogenesis through ETS gene rearrangement studies:implications for anticancer drug development. J Clin Pathol 61:891-896.
9. Minuti G, D'Incecco A, Cappuzzo F (2013) Targeted therapy for NSCLC with driver mutations. Expert Opin Biol Ther 13:1401-1412.
10. Shaw AT, Yeap BY, Mino-Kenudson M, Digumarthy SR, Costa DB, et al. (2009) Clinical features and outcome of patients with non-small-cell lung cancer who harbor EML4-ALK. J Clin Oncol 27:4247-4253.
11. Kuwano H, Sadanaga N, Watanabe M, Ikebe M, Mori M, et al. (1993) [Multidisciplinary treatment of esophageal cancer]. Gan To Kagaku Ryoho 20: 1167-1172.
12. Best SR, Ha PK, Blanco RG, Saunders JR, Jr., Zinreich ES, et al. (2011) Factors associated with pharyngoesophageal stricture in patients treated with concurrent chemotherapy and radiation therapy for oropharyngeal squamous cell carcinoma. Head Neck 33:1727-1734.
13. Leal M, Lima E, Silva P, Assumpcao P, Calcagno D, et al. (2007) Promoter hypermethylation of CDH1, FHIT, MTAP and PLAGL1 in gastric adenocarcinoma in individuals from Northern Brazil. World J Gastroenterol 13:2568-2574.
14. Pretto G, Gurski RR, Binato M, Navarini D, Aguiar WW, et al. (2013) Increase of epidermal growth factor receptor expression in progression of GERD, Barrett, and adenocarcinoma of esophagus. Dig Dis Sci 58:115-122.
15. Yamazaki M, Yamashita Y, Kubo N, Yashiro M, Ohira M, et al. (2012) Concurrent biological targeting therapy of squamous cell carcinoma of the esophagus with cetuximab and trastuzumab. Oncol Rep 28:49-54.
16. Lai LA, Kostadinov R, Barrett MT, Peiffer DA, Pokholok D, et al. (2010) Deletion at fragile sites is a common and early event in Barrett's esophagus. Mol Cancer Res 8:1084-1094.
17. Fang JM, Arlt MF, Burgess AC, Dagenais SL, Beer DG, et al. (2001) Translocation breakpoints in FHIT and FRA3B in both homologs of chromosome 3 in an esophageal adenocarcinoma. Genes Chromosomes Cancer 30:292-298.
18. Esan OA, Senft JR, Wenger SL (2012) Patterns of BCR/ABL Gene Rearrangements in Chronic Myeloid Leukemia with Complex t(9;22) Using Fluorescence In Situ Hybridization (FISH). J Assoc Genet Technol 38:5-7.
19. Landegent JE, Jansen in de Wal N, Dirks RW, Baao F, van der Ploeg M (1987) Use of whole cosmid cloned genomic sequences for chromosomal localization by non-radioactive in situ hybridization. Hum Genet 77:366-370.
20. Li J, Lin D, Cao H, Wang YP (2013) An improved sparse representation model with structural information for Multicolour Fluorescence In-Situ Hybridization (M-FISH) image classification. BMC Syst Biol 7 Suppl 4:S5.
21. Chyhrai A, Sanjmyatav J, Gajda M, Reichelt O, Wunderlich H, et al. (2010) Multi-colour FISH on preoperative renal tumour biopsies to confirm the diagnosis of uncertain renal masses. World J Urol 28:269-274.
22. Betts DR, Stanchescu R, Niggli FK, Cohen N, Rechavi G, et al. (2008) SKY reveals a high frequency of unbalanced translocations involving chromosome 6 in t(12;21)-positive acute lymphoblastic leukemia. Leuk Res 32:39-43.
23. Badawy T, El-Abd S, Zahra M, Eid M, Abdou S, et al. (2008) Quantitative measurement of telomerase reverse transcriptase mRNA and chromosomal analysis of urine by M-FISH in the diagnosis and follow-up of bladder cancer. Mol Med Rep 1:325-333.
24. Grigorova M, Lyman RC, Caldas C, Edwards PA (2005) Chromosome abnormalities in 10 lung cancer cell lines of the NCI-H series analyzed with spectral karyotyping. Cancer Genet Cytogenet 162:1-9.
25. Micci F, Teixeira MR, Heim S (2001) Complete cytogenetic characterization of the human breast cancer cell line MA11 combining G-banding, comparative genomic hybridization, multicolor fluorescence in situ hybridization, RxFISH, and chromosome-specific painting. Cancer Genet Cytogenet 131:25-30.
26. Yang Y, Chu J, Wu Y, Luo M, Xu X, et al. (2008) Chromosome analysis of esophageal squamous cell carcinoma cell line KYSE 410-4 by repetitive multicolor fluorescence in situ hybridization. J Genet Genomics 35:11-16.
27. Oikawa M, Kuniba H, Kondoh T, Kinoshita A, Nagayasu T, et al. (2010) Familial brain arteriovenous malformation maps to 5p13-q14,15q11-q13 or 18p11:linkage analysis with clipped fingernail DNA on high-density SNP array. Eur J Med Genet 53:244-249.
28. Tuefferd M, de Bondt A, Van den Wyngaert I, Talloen W, Gohlmann H (2011) Microarray profiling of DNA extracted from FFPE tissues using SNP 6.0 Affymetrix platform. Methods Mol Biol 724:147-160.
29. Serizawa M, Takahashi T, Yamamoto N, Koh Y (2013) Genomic aberrations associated with erlotinib resistance in non-small cell lung cancer cells. Anticancer Res 33:5223-5233.
30. Monroy-Jaramillo N, Guerrero-Camacho JL, Rodriguez-Violante M, Boll-Woehrlen MC, Yescas-Gomez P, et al. (2014) Genetic mutations in early-onset Parkinson's disease Mexican patients:Molecular testing implications. Am J Med Genet B Neuropsychiatr Genet.
31. Wang R, Pan Y, Li C, Hu H, Zhang Y, et al. (2012) The use of quantitative real-time reverse transcriptase PCR for 5'and 3'portions of ALK transcripts to detect ALK rearrangements in lung cancers. Clin Cancer Res 18:4725-4732.
32. Hu N, Wang C, Ng D, Clifford R, Yang HH, et al. (2009) Genomic characterization of esophageal squamous cell carcinoma from a high-risk population in China. Cancer Res 69:5908-5917.
33. Lin X, Finkelstein SD, Zhu B, Ujevich BJ, Silverman JF (2009) Loss of heterozygosities in Barrett esophagus, dysplasia, and adenocarcinoma detected by esophageal brushing cytology and gastroesophageal biopsy. Cancer 117:57-66.
34. Howarth KD, Blood KA, Ng BL, Beavis JC, Chua Y, et al. (2008) Array painting reveals a high frequency of balanced translocations in breast cancer cell lines that break in cancer-relevant genes. Oncogene 27:3345-3359.
35. Saracoglu K, Brown J, Kearney L, Uhrig S, Azofeifa J, et al. (2001) New concepts to improve resolution and sensitivity of molecular cytogenetic diagnostics by multicolor fluorescence in situ hybridization. Cytometry 44:7-15.
36. Ying J, Shan L, Li J, Zhong L, Xue L, et al. (2012) Genome-wide screening for genetic alterations in esophageal cancer by aCGH identifies 11q13 amplification oncogenes associated with nodal metastasis. PLoS One 7:e39797.
37. Ruan Y, Ooi HS, Choo SW, Chiu KP, Zhao XD, et al. (2007) Fusion transcripts and transcribed retrotransposed loci discovered through comprehensive transcriptome analysis using Paired-End diTags (PETs). Genome Res 17:828-838.
38. Iacobucci I, Storlazzi CT, Cilloni D, Lonetti A, Ottaviani E, et al. (2009) Identification and molecular characterization of recurrent genomic deletions on 7p12 in the IKZF1 gene in a large cohort of BCR-ABL1-positive acute lymphoblastic leukemia patients:on behalf of Gruppo Italiano Malattie Ematologiche dell'Adulto Acute Leukemia Working Party (GIMEMA AL WP). Blood 114:2159-2167.
39. Lai Y, Zhao H (2005) A statistical method to detect chromosomal regions with DNA copy number alterations using SNP-array-based CGH data. Comput Biol Chem 29:47-54.
40. Pani AM, Hobart HH, Morris CA, Mervis CB, Bray-Ward P, et al. (2010) Genome rearrangements detected by SNP microarrays in individuals with intellectual disability referred with possible Williams syndrome. PLoS One 5:e12349.
41. Pei J, Feder MM, Al-Saleem T, Liu Z, Liu A, et al. (2010) Combined classical cytogenetics and microarray-based genomic copy number analysis reveal frequent 3;5 rearrangements in clear cell renal cell carcinoma. Genes Chromosomes Cancer 49:610-619.
42. Shinozuka H, Cogan NO, Smith KF, Spangenberg GC, Forster JW (2010) Fine-scale comparative genetic and physical mapping supports map-based cloning strategies for the self-incompatibility loci of perennial ryegrass (Lolium perenne L.). Plant Mol Biol 72:343-355.
43. Howard TP,3rd, Hayward AP, Tordillos A, Fragoso C, Moreno MA, et al. (2014) Identification of the maize gravitropism gene lazy plant 1 by a transposon-tagging genome resequencing strategy. PLoS One 9:e87053.
44. Chen W, Song LJ, Zeng YQ, Yang Y, Wang H (2013) Analysis on differential expressed genes of ovarian tissue between high-and low-yield laying hen. Anim Biotechnol 24:278-287.
45. Argimon S, Konganti K, Chen H, Alekseyenko AV, Brown S, et al. (2014) Comparative genomics of oral isolates of Streptococcus mutans by in silico genome subtraction does not reveal accessory DNA associated with severe early childhood caries. Infect Genet Evol 21:269-278.
46. Frohman MA, Downs TR, Chomczynski P, Frohman LA (1989) Cloning and characterization of mouse growth hormone-releasing hormone (GRH) complementary DNA:increased GRH messenger RNA levels in the growth hormone-deficient lit/lit mouse. Mol Endocrinol 3:1529-1536.
47. Bespalova IN, Adkins S, Burmeister M (1998) 3'RACE:skewed ratio of specific to general PCR primers improves yield and specificity. Biotechniques 24:575-577.
48. Mosquera JM, Sboner A, Zhang L, Kitabayashi N, Chen CL, et al. (2013) Recurrent NCOA2 gene rearrangements in congenital/infantile spindle cell rhabdomyosarcoma. Genes Chromosomes Cancer 52:538-550.
49. Kralik JM, Kranewitter W, Boesmueller H, Marschon R, Tschurtschenthaler G, et al. (2011) Characterization of a newly identified ETV6-NTRK3 fusion transcript in acute myeloid leukemia. Diagn Pathol 6:19.
50. Antonescu CR, Zhang L, Shao SY, Mosquera JM, Weinreb I, et al. (2013) Frequent PLAG1 gene rearrangements in skin and soft tissue myoepithelioma with ductal differentiation. Genes Chromosomes Cancer 52:675-682.
51. Burrow AA, Williams LE, Pierce LC, Wang YH (2009) Over half of breakpoints in gene pairs involved in cancer-specific recurrent translocations are mapped to human chromosomal fragile sites. BMC Genomics 10:59.
52. Glover TW, Arlt MF, Casper AM, Durkin SG (2005) Mechanisms of common fragile site instability. Hum Mol Genet 14 Spec No.2:R197-205.
53. Boldog FL, Waggoner B, Glover TW, Chumakov I, Le Paslier D, et al. (1994) Integrated YAC contig containing the 3pl4.2 hereditary renal carcinoma 3;8 translocation breakpoint and the fragile site FRA3B. Genes Chromosomes Cancer 11:216-221.
54. Ritchie RJ, Chakrabarti L, Knight SJ, Harding RM, Davies KE (1997) Population genetics of the FRAXE and FRAXF GCC repeats, and a novel CGG repeat, in Xq28. Am J Med Genet 73:463-469.
55. Casper AM, Nghiem P, Arlt MF, Glover TW (2002) ATR regulates fragile site stability. Cell 111:779-789.
56. Bartkova J, Horejsi Z, Koed K, Kramer A, Tort F, et al. (2005) DNA damage response as a candidate anti-cancer barrier in early human tumorigenesis. Nature 434:864-870.
57. Gorgoulis VG, Vassiliou LV, Karakaidos P, Zacharatos P, Kotsinas A, et al. (2005) Activation of the DNA damage checkpoint and genomic instability in human precancerous lesions. Nature 434:907-913.
58. Debacker K, Kooy RF (2007) Fragile sites and human disease. Hum Mol Genet 16 Spec No.2:R150-158.
59. Coquelle A, Pipiras E, Toledo F, Buttin G, Debatisse M (1997) Expression of fragile sites triggers intrachromosomal mammalian gene amplification and sets boundaries to early amplicons. Cell 89:215-225.
60. Durkin SG, Glover TW (2007) Chromosome fragile sites. Annu Rev Genet 41: 169-192.
61. Aguilera A, Gomez-Gonzalez B (2008) Genome instability:a mechanistic view of its causes and consequences. Nat Rev Genet 9:204-217.
62. Weerkamp F, Dekking E, Ng YY, van der Velden VH, Wai H, et al. (2009) Flow cytometric immunobead assay for the detection of BCR-ABL fusion proteins in leukemia patients. Leukemia 23:1106-1117.
63. Hao JJ, Gong T, Zhang Y, Shi ZZ, Xu X, et al. (2013) Characterization of gene rearrangements resulted from genomic structural aberrations in human esophageal squamous cell carcinoma KYSE150 cells. Gene 513:196-201.
64. Kirovski G, Stevens AP, Czech B, Dettmer K, Weiss TS, et al. (2011) Down-regulation of methylthioadenosine phosphorylase (MTAP) induces progression of hepatocellular carcinoma via accumulation of 5'-deoxy-5'-methylthioadenosine (MTA). Am J Pathol 178:1145-1152.
65. Horvath A, Pakala SB, Mudvari P, Reddy SD, Ohshiro K, et al. (2013) Novel insights into breast cancer genetic variance through RNA sequencing. Sci Rep 3: 2256.
66. Dou JX, Zhang WD, Li WT, Li HL, Cai XS, et al. (2009) [Expression of methylthioadenosine phosphorylase (MTAP) gene and demethylation of its promoter in human colorectal cancer]. Ai Zheng 28:390-394.
67. Hellerbrand C, Muhlbauer M, Wallner S, Schuierer M, Behrmann I, et al. (2006) Promoter-hypermethylation is causing functional relevant downregulation of methylthioadenosine phosphorylase (MTAP) expression in hepatocellular carcinoma. Carcinogenesis 27:64-72.
68. Matsuyama H, Ikemoto K, Eguchi S, Oga A, Kawauchi S, et al. (2013) Copy number aberrations using multicolour fluorescence in situ hybridization (FISH) for prognostication in non-muscle-invasive bladder cancer (NIMBC). BJU Int.
69. Girgis AH, Iakovlev VV, Beheshti B, Bayani J, Squire JA, et al. (2012) Multilevel whole-genome analysis reveals candidate biomarkers in clear cell renal cell carcinoma. Cancer Res 72:5273-5284.
70. Shi ZZ, Shang L, Jiang YY, Hao JJ, Zhang Y, et al. (2013) Consistent and differential genetic aberrations between esophageal dysplasia and squamous cell carcinoma detected by array comparative genomic hybridization. Clin Cancer Res 19:5867-5878.
71. Caunt M, Mak J, Liang WC, Stawicki S, Pan Q, et al. (2008) Blocking neuropilin-2 function inhibits tumor cell metastasis. Cancer Cell 13:331-342.
72. Handa A, Tokunaga T, Tsuchida T, Lee YH, Kijima H, et al. (2000) Neuropilin-2 expression affects the increased vascularization and is a prognostic factor in osteosarcoma. Int J Oncol 17:291-295.
73. Yasuoka H, Kodama R, Hirokawa M, Takamura Y, Miyauchi A, et al. (2011) Neuropilin-2 expression in papillary thyroid carcinoma:correlation with VEGF-D expression, lymph node metastasis, and VEGF-D-induced aggressive cancer cell phenotype. J Clin Endocrinol Metab 96:E1857-1861.
74. Goel HL, Pursell B, Chang C, Shaw LM, Mao J, et al. (2013) GLI1 regulates a novel neuropilin-2/alpha6betal integrin based autocrine pathway that contributes to breast cancer initiation. EMBO Mol Med 5:488-508.
75. Druliner BR, Fincher JA, Sexton BS, Vera DL, Roche M, et al. (2013) Chromatin patterns associated with lung adenocarcinoma progression. Cell Cycle 12: 1536-1543.
76. Yang C, Lu W, Lin T, You P, Ye M, et al. (2013) Activation of Liver FGF21 in hepatocarcinogenesis and during hepatic stress. BMC Gastroenterol 13:67.
77. Hu X, Sui X, Li L, Huang X, Rong R, et al. (2013) Protocadherin 17 acts as a tumour suppressor inducing tumour cell apoptosis and autophagy, and is frequently methylated in gastric and colorectal cancers. J Pathol 229:62-73.
78. Cao W, Chen X, Dai H, Wang H, Shen B, et al. (2004) Mutational spectra of p53 in geographically localized esophageal squamous cell carcinoma groups in China. Cancer 101:834-844.
79. Dar NA, Islami F, Bhat GA, Shah IA, Makhdoomi MA, et al. (2013) Poor oral hygiene and risk of esophageal squamous cell carcinoma in Kashmir. Br J Cancer 109:1367-1372.
80. Hao JJ, Shi ZZ, Zhao ZX, Zhang Y, Gong T, et al. (2012) Characterization of gene rearrangements in esophageal squamous carcinoma cell lines by a combination of M-FISH and array-CGH:further confirmation of some split genomic regions in primary tumors. BMC Cancer 12:367.
81. Das RK, Anura A, Pal M, Bag S, Majumdar S, et al. (2013) Epithelio-mesenchymal transitional attributes in oral sub-mucous fibrosis. Exp Mol Pathol 95:259-269.
82. Mallini P, Lennard T, Kirby J, Meeson A (2013) Epithelial-to-mesenchymal transition:What is the impact on breast cancer stem cells and drug resistance. Cancer Treat Rev.
83. Yamada S, Fuchs BC, Fujii T, Shimoyama Y, Sugimoto H, et al. (2013) Epithelial-to-mesenchymal transition predicts prognosis of pancreatic cancer. Surgery 154:946-954.
84. Yan YR, Xie Q, Li F, Zhang Y, Ma JW, et al. (2013) Epithelial-to-mesenchymal transition is involved in BCNU resistance in human glioma cells. Neuropathology.
85. Zhu XL, Wang YL, Chen JP, Duan LL, Cong PF, et al. (2013) Alternol inhibits migration and invasion of human hepatocellular carcinoma cells by targeting epithelial-to-mesenchymal transition. Tumour Biol.
86. Hwang-Verslues WW, Chang PH, Jeng YM, Kuo WH, Chiang PH, et al. (2013) Loss of corepressor PER2 under hypoxia up-regulates OCT1-mediated EMT gene expression and enhances tumor malignancy. Proc Natl Acad Sci U S A 110: 12331-12336.
87. Hugo H, Ackland ML, Blick T, Lawrence MG, Clements JA, et al. (2007) Epithelial-mesenchymal and mesenchymal-epithelial transitions in carcinoma progression. J Cell Physiol 213:374-383.
88. Radisky DC, Levy DD, Littlepage LE, Liu H, Nelson CM, et al. (2005) Raclb and reactive oxygen species mediate MMP-3-induced EMT and genomic instability. Nature 436:123-127.
89. Illman SA, Lehti K, Keski-Oja J, Lohi J (2006) Epilysin (MMP-28) induces TGF-beta mediated epithelial to mesenchymal transition in lung carcinoma cells. J Cell Sci 119:3856-3865.
90. Chaffer CL, Brennan JP, Slavin JL, Blick T, Thompson EW, et al. (2006) Mesenchymal-to-epithelial transition facilitates bladder cancer metastasis:role of fibroblast growth factor receptor-2. Cancer Res 66:11271-11278.
91. Lee TK, Poon RT, Yuen AP, Ling MT, Kwok WK, et al. (2006) Twist overexpression correlates with hepatocellular carcinoma metastasis through induction of epithelial-mesenchymal transition. Clin Cancer Res 12:5369-5376.
92. Alonso SR, Tracey L, Ortiz P, Perez-Gomez B, Palacios J, et al. (2007) A high-throughput study in melanoma identifies epithelial-mesenchymal transition as a major determinant of metastasis. Cancer Res 67:3450-3460.
1. Burrow AA, Williams LE, Pierce LC, Wang YH (2009) Over half of breakpoints in gene pairs involved in cancer-specific recurrent translocations are mapped to human chromosomal fragile sites. BMC Genomics 10:59.
2. Fehr A, Roser K, Heidorn K, Hallas C, Loning T, et al. (2008) A new type of MAML2 fusion in mucoepidermoid carcinoma. Genes Chromosomes Cancer 47: 203-206.
3. Tonon G, Modi S, Wu L, Kubo A, Coxon AB, et al. (2003) t(11;19)(q21;p13) translocation in mucoepidermoid carcinoma creates a novel fusion product that disrupts a Notch signaling pathway. Nat Genet 33:208-213.
4. Alberti L, Carniti C, Miranda C, Roccato E, Pierotti MA (2003) RET and NTRK1 proto-oncogenes in human diseases. J Cell Physiol 195:168-186.
5. Ciampi R, Knauf JA, Kerler R, Gandhi M, Zhu Z, et al. (2005) Oncogenic AKAP9-BRAF fusion is a novel mechanism of MAPK pathway activation in thyroid cancer. J Clin Invest 115:94-101.
6. Lee JH, Lee ES, Kim YS, Won NH, Chae YS (2006) BRAF mutation and AKAP9 expression in sporadic papillary thyroid carcinomas. Pathology 38:201-204.
7. Petrini P, French CA, Rajan A, Cameron MJ, Jaffe ES, et al. (2012) NUT rearrangement is uncommon in human thymic epithelial tumors. J Thorac Oncol 7: 744-750.
8. Soda M, Choi YL, Enomoto M, Takada S, Yamashita Y, et al. (2007) Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer. Nature 448:561-566.
9. Rikova K, Guo A, Zeng Q, Possemato A, Yu J, et al. (2007) Global survey of phosphotyrosine signaling identifies oncogenic kinases in lung cancer. Cell 131: 1190-1203.
10. Takeuchi K, Choi YL, Togashi Y, Soda M, Hatano S, et al. (2009) KIF5B-ALK, a novel fusion oncokinase identified by an immunohistochemistry-based diagnostic system for ALK-positive lung cancer. Clin Cancer Res 15:3143-3149.
11. Wong DW, Leung EL, Wong SK, Tin VP, Sihoe AD, et al. (2011) A novel KIF5B-ALK variant in nonsmall cell lung cancer. Cancer 117:2709-2718.
12. Du XL, Hu H, Lin DC, Xia SH, Shen XM, et al. (2007) Proteomic profiling of proteins dysregulted in Chinese esophageal squamous cell carcinoma. J Mol Med (Berl) 85:863-875.
13. Teixeira MR (2006) Recurrent fusion oncogenes in carcinomas. Crit Rev Oncog 12: 257-271.
14. Tao J, Deng NT, Ramnarayanan K, Huang B, Oh HK, et al. (2011) CD44-SLC1A2 gene fusions in gastric cancer. Sci Transl Med 3:77ra30.
15. Bass AJ, Lawrence MS, Brace LE, Ramos AH, Drier Y, et al. (2011) Genomic sequencing of colorectal adenocarcinomas identifies a recurrent VTI1A-TCF7L2 fusion. Nat Genet 43:964-968.
16. Tognon C, Knezevich SR, Huntsman D, Roskelley CD, Melnyk N, et al. (2002) Expression of the ETV6-NTRK3 gene fusion as a primary event in human secretory breast carcinoma. Cancer Cell 2:367-376.
17. Lae M, Freneaux P, Sastre-Garau X, Chouchane O, Sigal-Zafrani B, et al. (2009) Secretory breast carcinomas with ETV6-NTRK3 fusion gene belong to the basal-like carcinoma spectrum. Mod Pathol 22:291-298.
18. Stephens PJ, McBride DJ, Lin ML, Varela I, Pleasance ED, et al. (2009) Complex landscapes of somatic rearrangement in human breast cancer genomes. Nature 462: 1005-1010.
19. Ha KC, Lalonde E, Li L, Cavallone L, Natrajan R, et al. (2011) Identification of gene fusion transcripts by transcriptome sequencing in BRCA1-mutated breast cancers and cell lines. BMC Med Genomics 4:75.
20. Chua YL, Ito Y, Pole JC, Newman S, Chin SF, et al. (2009) The NRG1 gene is frequently silenced by methylation in breast cancers and is a strong candidate for the 8p tumour suppressor gene. Oncogene 28:4041-4052.
21. Prentice LM, Shadeo A, Lestou VS, Miller MA, deLeeuw RJ, et al. (2005) NRG1 gene rearrangements in clinical breast cancer:identification of an adjacent novel amplicon associated with poor prognosis. Oncogene 24:7281-7289.
22. Salzman J, Marinelli RJ, Wang PL, Green AE, Nielsen JS, et al. (2011) ESRRA-C11orf20 is a recurrent gene fusion in serous ovarian carcinoma. PLoS Bio19:e1001156.
23. Skalsky YM, Ajuh PM, Parker C, Lamond AI, Goodwin G, et al. (2001) PRCC, the commonest TFE3 fusion partner in papillary renal carcinoma is associated with pre-mRNA splicing factors. Oncogene 20:178-187.
24. Martignoni G, Pea M, Gobbo S, Brunelli M, Bonetti F, et al. (2009) Cathepsin-K immunoreactivity distinguishes MiTF/TFE family renal translocation carcinomas from other renal carcinomas. Mod Pathol 22:1016-1022.
25. Debelenko LV, Raimondi SC, Daw N, Shivakumar BR, Huang D, et al. (2011) Renal cell carcinoma with novel VCL-ALK fusion:new representative of ALK-associated tumor spectrum. Mod Pathol 24:430-442.
26. Marino-Enriquez A, Ou WB, Weldon CB, Fletcher JA, Perez-Atayde AR (2011) ALK rearrangement in sickle cell trait-associated renal medullary carcinoma. Genes Chromosomes Cancer 50:146-153.
27. Tomlins SA, Rhodes DR, Perner S, Dhanasekaran SM, Mehra R, et al. (2005) Recurrent fusion of TMPRSS2 and ETS transcription factor genes in prostate cancer. Science 310:644-648.
28. Shah RB, Chinnaiyan AM (2009) The discovery of common recurrent transmembrane protease serine 2 (TMPRSS2)-erythroblastosis virus E26 transforming sequence (ETS) gene fusions in prostate cancer:significance and clinical implications. Adv Anat Pathol 16:145-153.
29. Morris DS, Tomlins SA, Montie JE, Chinnaiyan AM (2008) The discovery and application of gene fusions in prostate cancer. BJU Int 102:276-282.
30. Han B, Mehra R, Dhanasekaran SM, Yu J, Menon A, et al. (2008) A fluorescence in situ hybridization screen for E26 transformation-specific aberrations:identification of DDX5-ETV4 fusion protein in prostate cancer. Cancer Res 68:7629-7637.
31. French CA, Ramirez CL, Kolmakova J, Hickman TT, Cameron MJ, et al. (2008) BRD-NUT oncoproteins:a family of closely related nuclear proteins that block epithelial differentiation and maintain the growth of carcinoma cells. Oncogene 27: 2237-2242.
32. Greenman CD, Bignell G, Butler A, Edkins S, Hinton J, et al. (2010) PICNIC:an algorithm to predict absolute allelic copy number variation with microarray cancer data. Biostatistics 11:164-175.
33. Sonoki T, Willis TG, Oscier DG, Karran EL, Siebert R, et al. (2004) Rapid amplification of immunoglobulin heavy chain switch (IGHS) translocation breakpoints using long-distance inverse PCR. Leukemia 18:2026-2031.
34. Campbell PJ, Stephens PJ, Pleasance ED, O'Meara S, Li H, et al. (2008) Identification of somatically acquired rearrangements in cancer using genome-wide massively parallel paired-end sequencing. Nat Genet 40:722-729.
35. Hampton OA, Den Hollander P, Miller CA, Delgado DA, Li J, et al. (2009) A sequence-level map of chromosomal breakpoints in the MCF-7 breast cancer cell line yields insights into the evolution of a cancer genome. Genome Res 19:167-177.
36. Volik S, Zhao S, Chin K, Brebner JH, Herndon DR, et al. (2003) End-sequence profiling:sequence-based analysis of aberrant genomes. Proc Natl Acad Sci U S A 100:7696-7701.
37. Vinatzer U, Gollinger M, Mullauer L, Raderer M, Chott A, et al. (2008) Mucosa-associated lymphoid tissue lymphoma:novel translocations including rearrangements of ODZ2, JMJD2C, and CNN3. Clin Cancer Res 14:6426-6431.
38. Adeyinka A, Kytola S, Mertens F, Pandis N, Larsson C (2000) Spectral karyotyping and chromosome banding studies of primary breast carcinomas and their lymph node metastases. Int J Mol Med 5:235-240.
39. Macville M, Schrock E, Padilla-Nash H, Keck C, Ghadimi BM, et al. (1999) Comprehensive and definitive molecular cytogenetic characterization of HeLa cells by spectral karyotyping. Cancer Res 59:141-150.
40. Konig JJ, van Dongen JW, Schroder FH (1993) Preferential loss of abnormal prostate carcinoma cells by collagenase treatment. Cytometry 14:805-810.
2. Cazes A, Louis-Brennetot C, Mazot P, Dingli F, Lombard B, et al. (2013) Characterization of rearrangements involving the ALK gene reveals a novel truncated form associated with tumor aggressiveness in neuroblastoma. Cancer Res 73:195-204.
3. Maus MK, Stephens C, Zeger G, Grimminger PP, Huang E (2012) Identification of Novel Variant of EML4-ALK Fusion Gene in NSCLC:Potential Benefits of the RT-PCR Method. Int J Biomed Sci 8:1-6.
4. Gopalan A, Leversha MA, Dudas ME, Maschino AC, Chang J, et al. (2013) TMPRSS2-ERG rearrangement in dominant anterior prostatic tumours:incidence and correlation with ERG immunohistochemistry. Histopathology 63:279-286.
5. Gridelli C, Peters S, Sgambato A, Casaluce F, Adjei AA, et al. (2014) ALK inhibitors in the treatment of advanced NSCLC. Cancer Treat Rev 40:300-306.
6. Bass AJ, Lawrence MS, Brace LE, Ramos AH, Drier Y, et al. (2011) Genomic sequencing of colorectal adenocarcinomas identifies a recurrent VTI1A-TCF7L2 fusion. Nat Genet 43:964-968.
7. Rickman DS, Soong TD, Moss B, Mosquera JM, Dlabal J, et al. (2012) Oncogene-mediated alterations in chromatin conformation. Proc Natl Acad Sci U S A 109:9083-9088.
8. Attard G, Ang JE, Olmos D, de Bono JS (2008) Dissecting prostate carcinogenesis through ETS gene rearrangement studies:implications for anticancer drug development. J Clin Pathol 61:891-896.
9. Minuti G, D'Incecco A, Cappuzzo F (2013) Targeted therapy for NSCLC with driver mutations. Expert Opin Biol Ther 13:1401-1412.
10. Shaw AT, Yeap BY, Mino-Kenudson M, Digumarthy SR, Costa DB, et al. (2009) Clinical features and outcome of patients with non-small-cell lung cancer who harbor EML4-ALK. J Clin Oncol 27:4247-4253.
11. Kuwano H, Sadanaga N, Watanabe M, Ikebe M, Mori M, et al. (1993) [Multidisciplinary treatment of esophageal cancer]. Gan To Kagaku Ryoho 20: 1167-1172.
12. Best SR, Ha PK, Blanco RG, Saunders JR, Jr., Zinreich ES, et al. (2011) Factors associated with pharyngoesophageal stricture in patients treated with concurrent chemotherapy and radiation therapy for oropharyngeal squamous cell carcinoma. Head Neck 33:1727-1734.
13. Leal M, Lima E, Silva P, Assumpcao P, Calcagno D, et al. (2007) Promoter hypermethylation of CDH1, FHIT, MTAP and PLAGL1 in gastric adenocarcinoma in individuals from Northern Brazil. World J Gastroenterol 13:2568-2574.
14. Pretto G, Gurski RR, Binato M, Navarini D, Aguiar WW, et al. (2013) Increase of epidermal growth factor receptor expression in progression of GERD, Barrett, and adenocarcinoma of esophagus. Dig Dis Sci 58:115-122.
15. Yamazaki M, Yamashita Y, Kubo N, Yashiro M, Ohira M, et al. (2012) Concurrent biological targeting therapy of squamous cell carcinoma of the esophagus with cetuximab and trastuzumab. Oncol Rep 28:49-54.
16. Lai LA, Kostadinov R, Barrett MT, Peiffer DA, Pokholok D, et al. (2010) Deletion at fragile sites is a common and early event in Barrett's esophagus. Mol Cancer Res 8:1084-1094.
17. Fang JM, Arlt MF, Burgess AC, Dagenais SL, Beer DG, et al. (2001) Translocation breakpoints in FHIT and FRA3B in both homologs of chromosome 3 in an esophageal adenocarcinoma. Genes Chromosomes Cancer 30:292-298.
18. Esan OA, Senft JR, Wenger SL (2012) Patterns of BCR/ABL Gene Rearrangements in Chronic Myeloid Leukemia with Complex t(9;22) Using Fluorescence In Situ Hybridization (FISH). J Assoc Genet Technol 38:5-7.
19. Landegent JE, Jansen in de Wal N, Dirks RW, Baao F, van der Ploeg M (1987) Use of whole cosmid cloned genomic sequences for chromosomal localization by non-radioactive in situ hybridization. Hum Genet 77:366-370.
20. Li J, Lin D, Cao H, Wang YP (2013) An improved sparse representation model with structural information for Multicolour Fluorescence In-Situ Hybridization (M-FISH) image classification. BMC Syst Biol 7 Suppl 4:S5.
21. Chyhrai A, Sanjmyatav J, Gajda M, Reichelt O, Wunderlich H, et al. (2010) Multi-colour FISH on preoperative renal tumour biopsies to confirm the diagnosis of uncertain renal masses. World J Urol 28:269-274.
22. Betts DR, Stanchescu R, Niggli FK, Cohen N, Rechavi G, et al. (2008) SKY reveals a high frequency of unbalanced translocations involving chromosome 6 in t(12;21)-positive acute lymphoblastic leukemia. Leuk Res 32:39-43.
23. Badawy T, El-Abd S, Zahra M, Eid M, Abdou S, et al. (2008) Quantitative measurement of telomerase reverse transcriptase mRNA and chromosomal analysis of urine by M-FISH in the diagnosis and follow-up of bladder cancer. Mol Med Rep 1:325-333.
24. Grigorova M, Lyman RC, Caldas C, Edwards PA (2005) Chromosome abnormalities in 10 lung cancer cell lines of the NCI-H series analyzed with spectral karyotyping. Cancer Genet Cytogenet 162:1-9.
25. Micci F, Teixeira MR, Heim S (2001) Complete cytogenetic characterization of the human breast cancer cell line MA11 combining G-banding, comparative genomic hybridization, multicolor fluorescence in situ hybridization, RxFISH, and chromosome-specific painting. Cancer Genet Cytogenet 131:25-30.
26. Yang Y, Chu J, Wu Y, Luo M, Xu X, et al. (2008) Chromosome analysis of esophageal squamous cell carcinoma cell line KYSE 410-4 by repetitive multicolor fluorescence in situ hybridization. J Genet Genomics 35:11-16.
27. Oikawa M, Kuniba H, Kondoh T, Kinoshita A, Nagayasu T, et al. (2010) Familial brain arteriovenous malformation maps to 5p13-q14,15q11-q13 or 18p11:linkage analysis with clipped fingernail DNA on high-density SNP array. Eur J Med Genet 53:244-249.
28. Tuefferd M, de Bondt A, Van den Wyngaert I, Talloen W, Gohlmann H (2011) Microarray profiling of DNA extracted from FFPE tissues using SNP 6.0 Affymetrix platform. Methods Mol Biol 724:147-160.
29. Serizawa M, Takahashi T, Yamamoto N, Koh Y (2013) Genomic aberrations associated with erlotinib resistance in non-small cell lung cancer cells. Anticancer Res 33:5223-5233.
30. Monroy-Jaramillo N, Guerrero-Camacho JL, Rodriguez-Violante M, Boll-Woehrlen MC, Yescas-Gomez P, et al. (2014) Genetic mutations in early-onset Parkinson's disease Mexican patients:Molecular testing implications. Am J Med Genet B Neuropsychiatr Genet.
31. Wang R, Pan Y, Li C, Hu H, Zhang Y, et al. (2012) The use of quantitative real-time reverse transcriptase PCR for 5'and 3'portions of ALK transcripts to detect ALK rearrangements in lung cancers. Clin Cancer Res 18:4725-4732.
32. Hu N, Wang C, Ng D, Clifford R, Yang HH, et al. (2009) Genomic characterization of esophageal squamous cell carcinoma from a high-risk population in China. Cancer Res 69:5908-5917.
33. Lin X, Finkelstein SD, Zhu B, Ujevich BJ, Silverman JF (2009) Loss of heterozygosities in Barrett esophagus, dysplasia, and adenocarcinoma detected by esophageal brushing cytology and gastroesophageal biopsy. Cancer 117:57-66.
34. Howarth KD, Blood KA, Ng BL, Beavis JC, Chua Y, et al. (2008) Array painting reveals a high frequency of balanced translocations in breast cancer cell lines that break in cancer-relevant genes. Oncogene 27:3345-3359.
35. Saracoglu K, Brown J, Kearney L, Uhrig S, Azofeifa J, et al. (2001) New concepts to improve resolution and sensitivity of molecular cytogenetic diagnostics by multicolor fluorescence in situ hybridization. Cytometry 44:7-15.
36. Ying J, Shan L, Li J, Zhong L, Xue L, et al. (2012) Genome-wide screening for genetic alterations in esophageal cancer by aCGH identifies 11q13 amplification oncogenes associated with nodal metastasis. PLoS One 7:e39797.
37. Ruan Y, Ooi HS, Choo SW, Chiu KP, Zhao XD, et al. (2007) Fusion transcripts and transcribed retrotransposed loci discovered through comprehensive transcriptome analysis using Paired-End diTags (PETs). Genome Res 17:828-838.
38. Iacobucci I, Storlazzi CT, Cilloni D, Lonetti A, Ottaviani E, et al. (2009) Identification and molecular characterization of recurrent genomic deletions on 7p12 in the IKZF1 gene in a large cohort of BCR-ABL1-positive acute lymphoblastic leukemia patients:on behalf of Gruppo Italiano Malattie Ematologiche dell'Adulto Acute Leukemia Working Party (GIMEMA AL WP). Blood 114:2159-2167.
39. Lai Y, Zhao H (2005) A statistical method to detect chromosomal regions with DNA copy number alterations using SNP-array-based CGH data. Comput Biol Chem 29:47-54.
40. Pani AM, Hobart HH, Morris CA, Mervis CB, Bray-Ward P, et al. (2010) Genome rearrangements detected by SNP microarrays in individuals with intellectual disability referred with possible Williams syndrome. PLoS One 5:e12349.
41. Pei J, Feder MM, Al-Saleem T, Liu Z, Liu A, et al. (2010) Combined classical cytogenetics and microarray-based genomic copy number analysis reveal frequent 3;5 rearrangements in clear cell renal cell carcinoma. Genes Chromosomes Cancer 49:610-619.
42. Shinozuka H, Cogan NO, Smith KF, Spangenberg GC, Forster JW (2010) Fine-scale comparative genetic and physical mapping supports map-based cloning strategies for the self-incompatibility loci of perennial ryegrass (Lolium perenne L.). Plant Mol Biol 72:343-355.
43. Howard TP,3rd, Hayward AP, Tordillos A, Fragoso C, Moreno MA, et al. (2014) Identification of the maize gravitropism gene lazy plant 1 by a transposon-tagging genome resequencing strategy. PLoS One 9:e87053.
44. Chen W, Song LJ, Zeng YQ, Yang Y, Wang H (2013) Analysis on differential expressed genes of ovarian tissue between high-and low-yield laying hen. Anim Biotechnol 24:278-287.
45. Argimon S, Konganti K, Chen H, Alekseyenko AV, Brown S, et al. (2014) Comparative genomics of oral isolates of Streptococcus mutans by in silico genome subtraction does not reveal accessory DNA associated with severe early childhood caries. Infect Genet Evol 21:269-278.
46. Frohman MA, Downs TR, Chomczynski P, Frohman LA (1989) Cloning and characterization of mouse growth hormone-releasing hormone (GRH) complementary DNA:increased GRH messenger RNA levels in the growth hormone-deficient lit/lit mouse. Mol Endocrinol 3:1529-1536.
47. Bespalova IN, Adkins S, Burmeister M (1998) 3'RACE:skewed ratio of specific to general PCR primers improves yield and specificity. Biotechniques 24:575-577.
48. Mosquera JM, Sboner A, Zhang L, Kitabayashi N, Chen CL, et al. (2013) Recurrent NCOA2 gene rearrangements in congenital/infantile spindle cell rhabdomyosarcoma. Genes Chromosomes Cancer 52:538-550.
49. Kralik JM, Kranewitter W, Boesmueller H, Marschon R, Tschurtschenthaler G, et al. (2011) Characterization of a newly identified ETV6-NTRK3 fusion transcript in acute myeloid leukemia. Diagn Pathol 6:19.
50. Antonescu CR, Zhang L, Shao SY, Mosquera JM, Weinreb I, et al. (2013) Frequent PLAG1 gene rearrangements in skin and soft tissue myoepithelioma with ductal differentiation. Genes Chromosomes Cancer 52:675-682.
51. Burrow AA, Williams LE, Pierce LC, Wang YH (2009) Over half of breakpoints in gene pairs involved in cancer-specific recurrent translocations are mapped to human chromosomal fragile sites. BMC Genomics 10:59.
52. Glover TW, Arlt MF, Casper AM, Durkin SG (2005) Mechanisms of common fragile site instability. Hum Mol Genet 14 Spec No.2:R197-205.
53. Boldog FL, Waggoner B, Glover TW, Chumakov I, Le Paslier D, et al. (1994) Integrated YAC contig containing the 3pl4.2 hereditary renal carcinoma 3;8 translocation breakpoint and the fragile site FRA3B. Genes Chromosomes Cancer 11:216-221.
54. Ritchie RJ, Chakrabarti L, Knight SJ, Harding RM, Davies KE (1997) Population genetics of the FRAXE and FRAXF GCC repeats, and a novel CGG repeat, in Xq28. Am J Med Genet 73:463-469.
55. Casper AM, Nghiem P, Arlt MF, Glover TW (2002) ATR regulates fragile site stability. Cell 111:779-789.
56. Bartkova J, Horejsi Z, Koed K, Kramer A, Tort F, et al. (2005) DNA damage response as a candidate anti-cancer barrier in early human tumorigenesis. Nature 434:864-870.
57. Gorgoulis VG, Vassiliou LV, Karakaidos P, Zacharatos P, Kotsinas A, et al. (2005) Activation of the DNA damage checkpoint and genomic instability in human precancerous lesions. Nature 434:907-913.
58. Debacker K, Kooy RF (2007) Fragile sites and human disease. Hum Mol Genet 16 Spec No.2:R150-158.
59. Coquelle A, Pipiras E, Toledo F, Buttin G, Debatisse M (1997) Expression of fragile sites triggers intrachromosomal mammalian gene amplification and sets boundaries to early amplicons. Cell 89:215-225.
60. Durkin SG, Glover TW (2007) Chromosome fragile sites. Annu Rev Genet 41: 169-192.
61. Aguilera A, Gomez-Gonzalez B (2008) Genome instability:a mechanistic view of its causes and consequences. Nat Rev Genet 9:204-217.
62. Weerkamp F, Dekking E, Ng YY, van der Velden VH, Wai H, et al. (2009) Flow cytometric immunobead assay for the detection of BCR-ABL fusion proteins in leukemia patients. Leukemia 23:1106-1117.
63. Hao JJ, Gong T, Zhang Y, Shi ZZ, Xu X, et al. (2013) Characterization of gene rearrangements resulted from genomic structural aberrations in human esophageal squamous cell carcinoma KYSE150 cells. Gene 513:196-201.
64. Kirovski G, Stevens AP, Czech B, Dettmer K, Weiss TS, et al. (2011) Down-regulation of methylthioadenosine phosphorylase (MTAP) induces progression of hepatocellular carcinoma via accumulation of 5'-deoxy-5'-methylthioadenosine (MTA). Am J Pathol 178:1145-1152.
65. Horvath A, Pakala SB, Mudvari P, Reddy SD, Ohshiro K, et al. (2013) Novel insights into breast cancer genetic variance through RNA sequencing. Sci Rep 3: 2256.
66. Dou JX, Zhang WD, Li WT, Li HL, Cai XS, et al. (2009) [Expression of methylthioadenosine phosphorylase (MTAP) gene and demethylation of its promoter in human colorectal cancer]. Ai Zheng 28:390-394.
67. Hellerbrand C, Muhlbauer M, Wallner S, Schuierer M, Behrmann I, et al. (2006) Promoter-hypermethylation is causing functional relevant downregulation of methylthioadenosine phosphorylase (MTAP) expression in hepatocellular carcinoma. Carcinogenesis 27:64-72.
68. Matsuyama H, Ikemoto K, Eguchi S, Oga A, Kawauchi S, et al. (2013) Copy number aberrations using multicolour fluorescence in situ hybridization (FISH) for prognostication in non-muscle-invasive bladder cancer (NIMBC). BJU Int.
69. Girgis AH, Iakovlev VV, Beheshti B, Bayani J, Squire JA, et al. (2012) Multilevel whole-genome analysis reveals candidate biomarkers in clear cell renal cell carcinoma. Cancer Res 72:5273-5284.
70. Shi ZZ, Shang L, Jiang YY, Hao JJ, Zhang Y, et al. (2013) Consistent and differential genetic aberrations between esophageal dysplasia and squamous cell carcinoma detected by array comparative genomic hybridization. Clin Cancer Res 19:5867-5878.
71. Caunt M, Mak J, Liang WC, Stawicki S, Pan Q, et al. (2008) Blocking neuropilin-2 function inhibits tumor cell metastasis. Cancer Cell 13:331-342.
72. Handa A, Tokunaga T, Tsuchida T, Lee YH, Kijima H, et al. (2000) Neuropilin-2 expression affects the increased vascularization and is a prognostic factor in osteosarcoma. Int J Oncol 17:291-295.
73. Yasuoka H, Kodama R, Hirokawa M, Takamura Y, Miyauchi A, et al. (2011) Neuropilin-2 expression in papillary thyroid carcinoma:correlation with VEGF-D expression, lymph node metastasis, and VEGF-D-induced aggressive cancer cell phenotype. J Clin Endocrinol Metab 96:E1857-1861.
74. Goel HL, Pursell B, Chang C, Shaw LM, Mao J, et al. (2013) GLI1 regulates a novel neuropilin-2/alpha6betal integrin based autocrine pathway that contributes to breast cancer initiation. EMBO Mol Med 5:488-508.
75. Druliner BR, Fincher JA, Sexton BS, Vera DL, Roche M, et al. (2013) Chromatin patterns associated with lung adenocarcinoma progression. Cell Cycle 12: 1536-1543.
76. Yang C, Lu W, Lin T, You P, Ye M, et al. (2013) Activation of Liver FGF21 in hepatocarcinogenesis and during hepatic stress. BMC Gastroenterol 13:67.
77. Hu X, Sui X, Li L, Huang X, Rong R, et al. (2013) Protocadherin 17 acts as a tumour suppressor inducing tumour cell apoptosis and autophagy, and is frequently methylated in gastric and colorectal cancers. J Pathol 229:62-73.
78. Cao W, Chen X, Dai H, Wang H, Shen B, et al. (2004) Mutational spectra of p53 in geographically localized esophageal squamous cell carcinoma groups in China. Cancer 101:834-844.
79. Dar NA, Islami F, Bhat GA, Shah IA, Makhdoomi MA, et al. (2013) Poor oral hygiene and risk of esophageal squamous cell carcinoma in Kashmir. Br J Cancer 109:1367-1372.
80. Hao JJ, Shi ZZ, Zhao ZX, Zhang Y, Gong T, et al. (2012) Characterization of gene rearrangements in esophageal squamous carcinoma cell lines by a combination of M-FISH and array-CGH:further confirmation of some split genomic regions in primary tumors. BMC Cancer 12:367.
81. Das RK, Anura A, Pal M, Bag S, Majumdar S, et al. (2013) Epithelio-mesenchymal transitional attributes in oral sub-mucous fibrosis. Exp Mol Pathol 95:259-269.
82. Mallini P, Lennard T, Kirby J, Meeson A (2013) Epithelial-to-mesenchymal transition:What is the impact on breast cancer stem cells and drug resistance. Cancer Treat Rev.
83. Yamada S, Fuchs BC, Fujii T, Shimoyama Y, Sugimoto H, et al. (2013) Epithelial-to-mesenchymal transition predicts prognosis of pancreatic cancer. Surgery 154:946-954.
84. Yan YR, Xie Q, Li F, Zhang Y, Ma JW, et al. (2013) Epithelial-to-mesenchymal transition is involved in BCNU resistance in human glioma cells. Neuropathology.
85. Zhu XL, Wang YL, Chen JP, Duan LL, Cong PF, et al. (2013) Alternol inhibits migration and invasion of human hepatocellular carcinoma cells by targeting epithelial-to-mesenchymal transition. Tumour Biol.
86. Hwang-Verslues WW, Chang PH, Jeng YM, Kuo WH, Chiang PH, et al. (2013) Loss of corepressor PER2 under hypoxia up-regulates OCT1-mediated EMT gene expression and enhances tumor malignancy. Proc Natl Acad Sci U S A 110: 12331-12336.
87. Hugo H, Ackland ML, Blick T, Lawrence MG, Clements JA, et al. (2007) Epithelial-mesenchymal and mesenchymal-epithelial transitions in carcinoma progression. J Cell Physiol 213:374-383.
88. Radisky DC, Levy DD, Littlepage LE, Liu H, Nelson CM, et al. (2005) Raclb and reactive oxygen species mediate MMP-3-induced EMT and genomic instability. Nature 436:123-127.
89. Illman SA, Lehti K, Keski-Oja J, Lohi J (2006) Epilysin (MMP-28) induces TGF-beta mediated epithelial to mesenchymal transition in lung carcinoma cells. J Cell Sci 119:3856-3865.
90. Chaffer CL, Brennan JP, Slavin JL, Blick T, Thompson EW, et al. (2006) Mesenchymal-to-epithelial transition facilitates bladder cancer metastasis:role of fibroblast growth factor receptor-2. Cancer Res 66:11271-11278.
91. Lee TK, Poon RT, Yuen AP, Ling MT, Kwok WK, et al. (2006) Twist overexpression correlates with hepatocellular carcinoma metastasis through induction of epithelial-mesenchymal transition. Clin Cancer Res 12:5369-5376.
92. Alonso SR, Tracey L, Ortiz P, Perez-Gomez B, Palacios J, et al. (2007) A high-throughput study in melanoma identifies epithelial-mesenchymal transition as a major determinant of metastasis. Cancer Res 67:3450-3460.
1. Burrow AA, Williams LE, Pierce LC, Wang YH (2009) Over half of breakpoints in gene pairs involved in cancer-specific recurrent translocations are mapped to human chromosomal fragile sites. BMC Genomics 10:59.
2. Fehr A, Roser K, Heidorn K, Hallas C, Loning T, et al. (2008) A new type of MAML2 fusion in mucoepidermoid carcinoma. Genes Chromosomes Cancer 47: 203-206.
3. Tonon G, Modi S, Wu L, Kubo A, Coxon AB, et al. (2003) t(11;19)(q21;p13) translocation in mucoepidermoid carcinoma creates a novel fusion product that disrupts a Notch signaling pathway. Nat Genet 33:208-213.
4. Alberti L, Carniti C, Miranda C, Roccato E, Pierotti MA (2003) RET and NTRK1 proto-oncogenes in human diseases. J Cell Physiol 195:168-186.
5. Ciampi R, Knauf JA, Kerler R, Gandhi M, Zhu Z, et al. (2005) Oncogenic AKAP9-BRAF fusion is a novel mechanism of MAPK pathway activation in thyroid cancer. J Clin Invest 115:94-101.
6. Lee JH, Lee ES, Kim YS, Won NH, Chae YS (2006) BRAF mutation and AKAP9 expression in sporadic papillary thyroid carcinomas. Pathology 38:201-204.
7. Petrini P, French CA, Rajan A, Cameron MJ, Jaffe ES, et al. (2012) NUT rearrangement is uncommon in human thymic epithelial tumors. J Thorac Oncol 7: 744-750.
8. Soda M, Choi YL, Enomoto M, Takada S, Yamashita Y, et al. (2007) Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer. Nature 448:561-566.
9. Rikova K, Guo A, Zeng Q, Possemato A, Yu J, et al. (2007) Global survey of phosphotyrosine signaling identifies oncogenic kinases in lung cancer. Cell 131: 1190-1203.
10. Takeuchi K, Choi YL, Togashi Y, Soda M, Hatano S, et al. (2009) KIF5B-ALK, a novel fusion oncokinase identified by an immunohistochemistry-based diagnostic system for ALK-positive lung cancer. Clin Cancer Res 15:3143-3149.
11. Wong DW, Leung EL, Wong SK, Tin VP, Sihoe AD, et al. (2011) A novel KIF5B-ALK variant in nonsmall cell lung cancer. Cancer 117:2709-2718.
12. Du XL, Hu H, Lin DC, Xia SH, Shen XM, et al. (2007) Proteomic profiling of proteins dysregulted in Chinese esophageal squamous cell carcinoma. J Mol Med (Berl) 85:863-875.
13. Teixeira MR (2006) Recurrent fusion oncogenes in carcinomas. Crit Rev Oncog 12: 257-271.
14. Tao J, Deng NT, Ramnarayanan K, Huang B, Oh HK, et al. (2011) CD44-SLC1A2 gene fusions in gastric cancer. Sci Transl Med 3:77ra30.
15. Bass AJ, Lawrence MS, Brace LE, Ramos AH, Drier Y, et al. (2011) Genomic sequencing of colorectal adenocarcinomas identifies a recurrent VTI1A-TCF7L2 fusion. Nat Genet 43:964-968.
16. Tognon C, Knezevich SR, Huntsman D, Roskelley CD, Melnyk N, et al. (2002) Expression of the ETV6-NTRK3 gene fusion as a primary event in human secretory breast carcinoma. Cancer Cell 2:367-376.
17. Lae M, Freneaux P, Sastre-Garau X, Chouchane O, Sigal-Zafrani B, et al. (2009) Secretory breast carcinomas with ETV6-NTRK3 fusion gene belong to the basal-like carcinoma spectrum. Mod Pathol 22:291-298.
18. Stephens PJ, McBride DJ, Lin ML, Varela I, Pleasance ED, et al. (2009) Complex landscapes of somatic rearrangement in human breast cancer genomes. Nature 462: 1005-1010.
19. Ha KC, Lalonde E, Li L, Cavallone L, Natrajan R, et al. (2011) Identification of gene fusion transcripts by transcriptome sequencing in BRCA1-mutated breast cancers and cell lines. BMC Med Genomics 4:75.
20. Chua YL, Ito Y, Pole JC, Newman S, Chin SF, et al. (2009) The NRG1 gene is frequently silenced by methylation in breast cancers and is a strong candidate for the 8p tumour suppressor gene. Oncogene 28:4041-4052.
21. Prentice LM, Shadeo A, Lestou VS, Miller MA, deLeeuw RJ, et al. (2005) NRG1 gene rearrangements in clinical breast cancer:identification of an adjacent novel amplicon associated with poor prognosis. Oncogene 24:7281-7289.
22. Salzman J, Marinelli RJ, Wang PL, Green AE, Nielsen JS, et al. (2011) ESRRA-C11orf20 is a recurrent gene fusion in serous ovarian carcinoma. PLoS Bio19:e1001156.
23. Skalsky YM, Ajuh PM, Parker C, Lamond AI, Goodwin G, et al. (2001) PRCC, the commonest TFE3 fusion partner in papillary renal carcinoma is associated with pre-mRNA splicing factors. Oncogene 20:178-187.
24. Martignoni G, Pea M, Gobbo S, Brunelli M, Bonetti F, et al. (2009) Cathepsin-K immunoreactivity distinguishes MiTF/TFE family renal translocation carcinomas from other renal carcinomas. Mod Pathol 22:1016-1022.
25. Debelenko LV, Raimondi SC, Daw N, Shivakumar BR, Huang D, et al. (2011) Renal cell carcinoma with novel VCL-ALK fusion:new representative of ALK-associated tumor spectrum. Mod Pathol 24:430-442.
26. Marino-Enriquez A, Ou WB, Weldon CB, Fletcher JA, Perez-Atayde AR (2011) ALK rearrangement in sickle cell trait-associated renal medullary carcinoma. Genes Chromosomes Cancer 50:146-153.
27. Tomlins SA, Rhodes DR, Perner S, Dhanasekaran SM, Mehra R, et al. (2005) Recurrent fusion of TMPRSS2 and ETS transcription factor genes in prostate cancer. Science 310:644-648.
28. Shah RB, Chinnaiyan AM (2009) The discovery of common recurrent transmembrane protease serine 2 (TMPRSS2)-erythroblastosis virus E26 transforming sequence (ETS) gene fusions in prostate cancer:significance and clinical implications. Adv Anat Pathol 16:145-153.
29. Morris DS, Tomlins SA, Montie JE, Chinnaiyan AM (2008) The discovery and application of gene fusions in prostate cancer. BJU Int 102:276-282.
30. Han B, Mehra R, Dhanasekaran SM, Yu J, Menon A, et al. (2008) A fluorescence in situ hybridization screen for E26 transformation-specific aberrations:identification of DDX5-ETV4 fusion protein in prostate cancer. Cancer Res 68:7629-7637.
31. French CA, Ramirez CL, Kolmakova J, Hickman TT, Cameron MJ, et al. (2008) BRD-NUT oncoproteins:a family of closely related nuclear proteins that block epithelial differentiation and maintain the growth of carcinoma cells. Oncogene 27: 2237-2242.
32. Greenman CD, Bignell G, Butler A, Edkins S, Hinton J, et al. (2010) PICNIC:an algorithm to predict absolute allelic copy number variation with microarray cancer data. Biostatistics 11:164-175.
33. Sonoki T, Willis TG, Oscier DG, Karran EL, Siebert R, et al. (2004) Rapid amplification of immunoglobulin heavy chain switch (IGHS) translocation breakpoints using long-distance inverse PCR. Leukemia 18:2026-2031.
34. Campbell PJ, Stephens PJ, Pleasance ED, O'Meara S, Li H, et al. (2008) Identification of somatically acquired rearrangements in cancer using genome-wide massively parallel paired-end sequencing. Nat Genet 40:722-729.
35. Hampton OA, Den Hollander P, Miller CA, Delgado DA, Li J, et al. (2009) A sequence-level map of chromosomal breakpoints in the MCF-7 breast cancer cell line yields insights into the evolution of a cancer genome. Genome Res 19:167-177.
36. Volik S, Zhao S, Chin K, Brebner JH, Herndon DR, et al. (2003) End-sequence profiling:sequence-based analysis of aberrant genomes. Proc Natl Acad Sci U S A 100:7696-7701.
37. Vinatzer U, Gollinger M, Mullauer L, Raderer M, Chott A, et al. (2008) Mucosa-associated lymphoid tissue lymphoma:novel translocations including rearrangements of ODZ2, JMJD2C, and CNN3. Clin Cancer Res 14:6426-6431.
38. Adeyinka A, Kytola S, Mertens F, Pandis N, Larsson C (2000) Spectral karyotyping and chromosome banding studies of primary breast carcinomas and their lymph node metastases. Int J Mol Med 5:235-240.
39. Macville M, Schrock E, Padilla-Nash H, Keck C, Ghadimi BM, et al. (1999) Comprehensive and definitive molecular cytogenetic characterization of HeLa cells by spectral karyotyping. Cancer Res 59:141-150.
40. Konig JJ, van Dongen JW, Schroder FH (1993) Preferential loss of abnormal prostate carcinoma cells by collagenase treatment. Cytometry 14:805-810.