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Gene Discovery in Cervical Cancer

Towards Diagnostic and Therapeutic Biomarkers

  • Cancer
  • Published:
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Abstract

Cervical cancer is a potentially preventable disease; however, it remains the second most common malignancy in women worldwide. The human papillomavirus (HPV) is the single most important etiological agent in cervical cancer. HPV contributes to neoplastic progression through the action of two viral oncoproteins E6 and E7, which interfere with critical cell cycle pathways, tumor protein p53, and retinoblastoma protein. However, evidence suggests that HPV infection alone is insufficient to induce malignant changes, and other host genetic variations are important in the development of cervical cancer. Advances in molecular biology and high throughput technologies have heralded a new era in biomarker discovery and identification of molecular targets related to carcinogenesis. These advancements have improved our understanding of carcinogenesis and will facilitate screening, early detection, management, and personalized targeted therapy. A number of these developments and molecular targets associated with cervical cancer will be addressed in this review.

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References

  1. Ferlay J, Bray F, Pisani P, et al. Globocan 2002: cancer incidence, mortality and prevalence worldwide. IARC CancerBase No. 5. Version 2.0. Lyon: IARC Press, 2004

    Google Scholar 

  2. Bray F, Carstensen B, Moller H, et al. Incidence trends of adenocarcinoma of the cervix in 13 European countries. Cancer Epidemiol Biomarkers Prev 2005; Sep; 14(9): 2191–9

    Article  PubMed  Google Scholar 

  3. Schorge JO, Knowles LM, Lea JS. Adenocarcinoma of the cervix. Curr Treat Options Oncol 2004 Apr; 5(2): 119–27

    Article  PubMed  Google Scholar 

  4. Franco EL, Duarte-Franco E, Ferenczy A. Cervical cancer: epidemiology, prevention and the role of human papillomavirus infection. CMAJ 2001; 164(7): 1017–25

    PubMed  CAS  Google Scholar 

  5. Nanda K, McCrory DC, Myers ER, et al. Accuracy of the Papanicolaou test in screening for and follow-up of cervical cytologic abnormalities: a systematic review. Ann Intern Med 2000 May 16; 132(10): 810–9

    PubMed  CAS  Google Scholar 

  6. Walboomers JM, Jacobs MV, Manos MM, et al. Human papillomavirus is a necessary cause of invasive cervical cancer worldwide. J Pathol 1999 Sep; 189(1): 12–9

    Article  PubMed  CAS  Google Scholar 

  7. de Villiers EM, Fauquet C, Broker TR, et al. Classification of papillomaviruses. Virology 2004 Jun 20; 324(1): 17–27

    Article  PubMed  CAS  Google Scholar 

  8. zur Hausen H. Papillomaviruses and cancer: from basic studies to clinical application. Nat Rev Cancer 2002 May; 2(5): 342–50

    Article  PubMed  CAS  Google Scholar 

  9. Doorbar J. Molecular biology of human papillomavirus infection and cervical cancer. Clin sci (Lond) 2006 May; 110(5): 525–41

    Article  CAS  Google Scholar 

  10. Andersson S, Safari H, Mints M, et al. Type distribution, viral load and integration status of high-risk human papillomaviruses in pre-stages of cervical cancer (CIN). Br J Cancer 2005 Jun 20; 92(12): 2195–200

    Article  PubMed  CAS  Google Scholar 

  11. Derchain SF, Rabelo-Santos SH, Sarian LO, et al. Human papillomavirus DNA detection and histological findings in women referred for atypical glandular cells or adenocarcinoma in situ in their Pap smears. Gynecol Oncol 2004 Dec; 95(3): 618–23

    Article  PubMed  CAS  Google Scholar 

  12. Tjalma WA, Van Waes TR, Van den Eeden LE, et al. Role of human papillomavirus in the carcinogenesis of squamous cell carcinoma and adenocarcinoma of the cervix. Best Pract Res Clin Obstet Gynaecol 2005 Aug; 19(4): 469–83

    Article  PubMed  CAS  Google Scholar 

  13. Cuschieri KS, Whitley MJ, Cubie HA. Human papillomavirus type specific DNA and RNA persistence: implications for cervical disease progression and monitoring. J Med Virol 2004 May; 73(1): 65–70

    Article  PubMed  CAS  Google Scholar 

  14. Molden T, Nygard JF, Kraus I, et al. Predicting CIN2+ when detecting HPV mRNA and DNA by PreTect HPV-proofer and consensus PCR: a 2-year follow-up of women with ASCUS or LSIL Pap smear. Int J Cancer 2005 May 10; 114(6): 973–6

    Article  PubMed  CAS  Google Scholar 

  15. The FUTURE II Study Group. Quadrivalent vaccine against human papillomavirus to prevent high-grade cervical lesions. N Engl J Med 2007 May 10; 356: 1915–27

    Article  Google Scholar 

  16. Harper DM, Franco EL, Wheeler CM, et al., and the HPV Vaccine Study group. Sustained efficacy up to 4. 5 years of a bivalent L1 virus-like particle vaccine against human papillomavirus types 16 and 18: follow-up from a randomised control trial. Lancet 2006 Apr 15; 367(9518): 1247–55

    Article  PubMed  CAS  Google Scholar 

  17. Duensing S, Munger K. Mechanisms of genomic instability in human cancer: insights from studies with human papillomavirus oncoproteins. Int J Cancer 2004 Mar 20; 109(2): 157–62

    Article  PubMed  CAS  Google Scholar 

  18. Thorland EC, Myers SL, Gostout BS, et al. Common fragile sites are preferential targets for HPV16 integrations in cervical tumors. Oncogene 2003 Feb 27; 22(8): 1225–37

    Article  PubMed  CAS  Google Scholar 

  19. Yang YC, Shyong WY, Chang MS, et al. Frequent gain of copy number on the long arm of chromosome 3 in human cervical adenocarcinoma. Cancer Genet Cytogenet 2001 Nov; 131(1): 48–53

    Article  PubMed  CAS  Google Scholar 

  20. Huang FY, Kwok YK, Lau ET, et al. Genetic abnormalities and HPV status in cervical and vulvar squamous cell carcinomas. Cancer Genet Cytogenet 2005 Feb; 157(1): 42–8

    Article  PubMed  CAS  Google Scholar 

  21. Wilting SM, Snijders PJ, Meijer GA, et al. Increased gene copy numbers at chromosome 20q are frequent in both squamous cell carcinomas and adenocarcinomas of the cervix. J Pathol 2006 Jun; 209(2): 220–30

    Article  PubMed  CAS  Google Scholar 

  22. Umayahara K, Numa F, Suehiro Y, et al. Comparative genomic hybridization detects genetic alterations during early stages of cervical cancer progression. Genes Chromosomes Cancer 2002 Jan; 33(1): 98–102

    Article  PubMed  CAS  Google Scholar 

  23. Rao PH, Arias-Pulido H, Lu XY, et al. Chromosomal amplifications, 3q gain and deletions of 2q33-q37 are the frequent genetic changes in cervical carcinoma. BMC Cancer 2004 Feb 6; 4: 5

    Article  PubMed  Google Scholar 

  24. Kirchhoff M, Rose H, Petersen BL, et al. Comparative genomic hybridization reveals a recurrent pattern of chromosomal aberrations in severe dysplasia/carcinoma in situ of the cervix and in advanced-stage cervical carcinoma. Genes Chromosomes Cancer 1999 Feb; 24(2): 144–50

    Article  PubMed  CAS  Google Scholar 

  25. Lockwood WW, Chari R, Chi B, et al. Recent advances in array comparative genomic hybridization technologies and their applications in human genetics. Eur J Hum Genet 2006 Feb; 14(2): 139–48

    Article  PubMed  CAS  Google Scholar 

  26. Hidalgo A, Baudis M, Petersen I, et al. Microarray comparative genomic hybridization detection of chromosomal imbalances in uterine cervix carcinoma. BMC Cancer 2005 Jul 9; 5: 77

    Article  PubMed  CAS  Google Scholar 

  27. Kirchhoff M, Rose H, Petersen BL, et al. Comparative genomic hybridization reveals non-random chromosomal aberrations in early preinvasive cervical lesions. Cancer Genet Cytogenet 2001 Aug; 129(1): 47–51

    Article  PubMed  CAS  Google Scholar 

  28. Hidalgo A, Monroy A, Arana RM, et al. Chromosomal imbalances in four new uterine cervix carcinoma derived cell lines. BMC Cancer 2003 Mar 20; 3: 8

    Article  PubMed  Google Scholar 

  29. Arias-Pulido H, Narayan G, Vargas H, et al. Mapping common deleted regions on 5pl5 in cervical carcinoma and their occurrence in precancerous lesions. Mol Cancer 2002 Oct 1; 1: 3

    Article  PubMed  Google Scholar 

  30. Kailash U, Soundararajan CC, Lakshmy R, et al. Telomerase activity as an adjunct to high-risk human papillomavirus types 16 and 18 and cytology screening in cervical cancer. Br J Cancer 2006 Nov 6; 95(9): 1250–7

    Article  PubMed  CAS  Google Scholar 

  31. Branca M, Giorgi C, Ciotti M, et al. Upregulation of telomerase (hTERT) is related to the grade of cervical intraepithelial neoplasia, but is not an independent predictor of high-risk human papillomavirus, virus persistence, or disease outcome in cervical cancer. Diagn Cytopathol 2006 Nov; 34(11): 739–48

    Article  PubMed  CAS  Google Scholar 

  32. Guo Z, Hu X, Afink G, et al. Comparison of chromosome 3p deletions between cervical precancers synchronous with and without invasive cancer. Int J Cancer 2000 May 15; 86(4): 518–23

    Article  PubMed  CAS  Google Scholar 

  33. Huang LW, Chao SL, Chen TJ. Reduced Fhit expression in cervical carcinoma: correlation with tumor progression and poor prognosis. Gynecol Oncol 2003 Aug; 90(2): 331–7

    Article  PubMed  CAS  Google Scholar 

  34. Holschneider CH, Baldwin RL, Tumber K, et al. The fragile histidine triad gene: a molecular link between cigarette smoking and cervical cancer. Clin Cancer Res 2005 Aug 15; 11(16): 5756–63

    Article  PubMed  CAS  Google Scholar 

  35. Grepmeier U, Dietmaier W, Merk J, et al. Deletions at chromosome 2q and 12p are early and frequent molecular alterations in bronchial epithelium and NSCLC of long-term smokers. Int J Oncol 2005 Aug; 27(2): 481–8

    PubMed  CAS  Google Scholar 

  36. Nicolas P, Sun F, Li LM. A model-based approach to selection of tag SNPs. BMC Bioinformatics 2006 Jun 15; 7: 303

    Article  PubMed  Google Scholar 

  37. Steemers FJ, Gunderson KL. Whole genome genotyping technologies on the BeadArray platform. Biotechnol J 2007 Jan; 2(1): 41–9

    Article  PubMed  CAS  Google Scholar 

  38. Emahazion T, Feuk L, Jobs M, et al. SNP association studies in Alzheimer’s disease highlight problems for complex disease analysis. Trends Genet 2001 Jul; 17(7): 407–13

    Article  PubMed  CAS  Google Scholar 

  39. Mitra S, Misra C, Singh RK, et al. Association of specific genotype and haplotype of p53 gene with cervical cancer in India. J Clin Pathol 2005 Jan; 58(1): 26–31

    Article  PubMed  CAS  Google Scholar 

  40. Harris N, Brill E, Shohat O, et al. Molecular basis for heterogeneity of the human p53 protein. Mol Cell Biol 1986 Dec; 6(12): 4650–6

    PubMed  CAS  Google Scholar 

  41. Matlashewski GJ, Tuck S, Pirn D, et al. Primary structure polymorphism at amino acid residue 72 of human p53. Mol Cell Biol 1987 Feb; 7(2): 961–3

    PubMed  CAS  Google Scholar 

  42. Ara S, Lee PS, Hansen MF, et al. Codon 72 polymorphism of the TP53 gene. Nucleic Acids Res 1990 Aug 25; 18(16): 4961

    Article  PubMed  CAS  Google Scholar 

  43. Thomas M, Kalita A, Labrecque S, et al. Two polymorphic variants of wild-type p53 differ biochemically and biologically. Mol Cell Biol 1999 Feb; 19(2): 1092–100

    PubMed  CAS  Google Scholar 

  44. Storey A, Thomas M, Kalita A, et al. Role of a p53 polymorphism in the development of human papillomavirus-associated cancer. Nature 1998 May 21; 393(6682): 229–34

    Article  PubMed  CAS  Google Scholar 

  45. Dokianakis DN, Spandidos DA. P53 codon 72 polymorphism as a risk factor in the development of HPV-associated cervical cancer. Mol Cell Biol Res Commun 2000 Feb; 3(2): 111–4

    Article  PubMed  CAS  Google Scholar 

  46. Agorastos T, Lambropoulos AF, Constantinidis TC, et al. p53 codon 72 polymorphism and risk of intra-epithelial and invasive cervical neoplasia in Greek women. Eur J Cancer Prev 2000 Apr; 9(2): 113–8

    Article  PubMed  CAS  Google Scholar 

  47. Zamai L, Ahmad M, Bennett IM, et al. Natural killer (NK) cell-mediated cytotoxicity: differential use of TRAIL and Fas ligand by immature and mature primary human NK cells. J Exp Med 1998 Dec 21; 188(12): 2375–80

    Article  PubMed  CAS  Google Scholar 

  48. Screpanti V, Wallin RP, Ljunggren HG, et al. A central role for death receptor-mediated apoptosis in the rejection of tumors by NK cells. J Immunol 2001 Aug 15; 167(4): 2068–73

    PubMed  CAS  Google Scholar 

  49. Ando K, Hiroishi K, Kaneko T, et al. Perform, Fas/Fas ligand, and TNF-alpha pathways as specific and bystander killing mechanisms of hepatitis C virus-specific human CTL. J Immunol 1997 Jun 1; 158(11): 5283–91

    PubMed  CAS  Google Scholar 

  50. O’Connell J, Bennett MW, O’Sullivan GC, et al. The Fas counterattack: cancer as a site of immune privilege. Immunol Today 1999 Jan; 20(1): 46–52

    Article  PubMed  Google Scholar 

  51. Huang QR, Morris D, Manolios N. Identification and characterization of polymorphisms in the promoter region of the human Apo-1/Fas (CD95) gene. Mol Immunol 1997; 34: 577–82

    Article  PubMed  CAS  Google Scholar 

  52. Kanemitsu S, Ihara K, Saifddin A, et al. A functional polymorphism in fas (CD95/APO-1) gene promoter associated with systemic lupus erythematosus. J Rheumatol 2002 Jun; 29(6): 1183–8

    PubMed  CAS  Google Scholar 

  53. Sibley K, Rollinson S, Allan JM, et al. Functional FAS promoter polymorphisms are associated with increased risk of acute myeloid leukemia. Cancer Res 2003 Aug 1; 63(15): 4327–30

    PubMed  CAS  Google Scholar 

  54. Ueda M, Hung YC, Terai Y, et al. Fas gene promoter -670 polymorphism (A/G) is associated with cervical carcinogenesis. Gynecol Oncol 2005 Jul; 98(1): 129–33

    Article  PubMed  CAS  Google Scholar 

  55. Lai HC, Sytwu HK, Sun CA, et al. Single nucleotide polymorphism at Fas promoter is associated with cervical carcinogenesis. Int J Cancer 2003 Jan 10; 103(2): 221–5

    Article  PubMed  CAS  Google Scholar 

  56. Lai HC, Lin WY, Lin YW, et al. Genetic polymorphisms of FAS and FASL (CD95/CD95L) genes in cervical carcinogenesis: An analysis of haplotype and gene-gene interaction. Gynecol Oncol 2005 Oct; 99(1): 113–8

    Article  PubMed  CAS  Google Scholar 

  57. Dybikowska A, Sliwinski W, Emerich J, et al. Evaluation of Fas gene promoter polymorphism in cervical cancer patients. Int J Mol Med 2004 Sep; 14(3): 475–8

    PubMed  CAS  Google Scholar 

  58. Zoodsma M, Nolte IM, Schipper M, et al. Interleukin-10 and Fas polymorphisms and susceptibility for (pre)neoplastic cervical disease. Int J Gynecol Cancer 2005 Nov–Dec; 15Suppl. 3: 282–90

    Article  PubMed  Google Scholar 

  59. Sun T, Zhou Y, Li H, et al. FASL -844C polymorphism is associated with increased activation-induced T cell death and risk of cervical cancer. J Exp Med 2005 Oct 3; 202(7): 967–74

    Article  PubMed  CAS  Google Scholar 

  60. Robertson KD. DNA methylation, methyltransferases, and cancer. Oncogene 2001 May 28; 20(24): 3139–55

    Article  PubMed  CAS  Google Scholar 

  61. Herman JG, Graff JR, Myohanen S, et al. Methylation-specific PCR: a novel PCR assay for methylation status of CpG islands. Proc Natl Acad sci U S A 1996 Sep 3; 93(18): 9821–6

    Article  PubMed  CAS  Google Scholar 

  62. Gao L, Cheng L, Zhou JN, et al. DNA microarray: a high throughput approach for methylation detection. Colloids Surf B Biointerfaces 2005 Feb 25; 40(3–4): 127–31

    Article  PubMed  CAS  Google Scholar 

  63. Dong SM, Kim HS, Rha SH, et al. Promoter hypermethylation of multiple genes in carcinoma of the uterine cervix. Clin Cancer Res 2001 Jul; 7(7): 1982–6

    PubMed  CAS  Google Scholar 

  64. Narayan G, Arias-Pulido H, Koul S, et al. Frequent promoter methylation of CDH1, DAPK, RARB, and HIC1 genes in carcinoma of cervix uteri: its relationship to clinical outcome. Mol Cancer 2003 May 13; 2: 24

    Article  PubMed  Google Scholar 

  65. Yang HJ, Liu VW, Wang Y, et al. Differential DNA methylation profiles in gynecological cancers and correlation with clinico-pathological data. BMC Cancer 2006 Aug 23; 6: 212

    Article  PubMed  CAS  Google Scholar 

  66. Jeong DH, Youm MY, Kim YN, et al. Promoter methylation of p16, DAPK, CDH1, and TIMP-3 genes in cervical cancer: correlation with clinicopathologic characteristics. Int J Gynecol Cancer 2006 May–Jun; 16(3): 1234–40

    Article  PubMed  CAS  Google Scholar 

  67. Kang S, Kim J, Kim HB, et al. Methylation of p16INK4a is a non-rare event in cervical intraepithelial neoplasia. Diagn Mol Pathol 2006 Jun; 15(2): 74–82

    Article  PubMed  CAS  Google Scholar 

  68. Virmani AK, Muller C, Rathi A, et al. Aberrant methylation during cervical carcinogenesis. Clin Cancer Res 2001 Mar; 7(3): 584–9

    PubMed  CAS  Google Scholar 

  69. Wisman GB, Nijhuis ER, Hoque MO, et al. Assessment of gene promoter hypermethylation for detection of cervical neoplasia. Int J Cancer 2006 Oct 15; 119(8): 1908–14

    Article  PubMed  CAS  Google Scholar 

  70. Duenas-Gonzalez A, Lizano M, Candelaria M, et al. Epigenetics of cervical cancer: an overview and therapeutic perspectives. Mol Cancer 2005 Oct 25; 4: 38

    Article  PubMed  CAS  Google Scholar 

  71. Lea JS, Coleman R, Kurien A, et al. Aberrant p16 methylation is a biomarker for tobacco exposure in cervical squamous cell carcinogenesis. Am J Obstet Gynecol 2004 Mar; 190(3): 674–9

    Article  PubMed  CAS  Google Scholar 

  72. Lin Z, Gao M, Zhang X, et al. The hypermethylation and protein expression of p16 INK4A and DNA repair gene O6-methylguanine-DNA methyltransferase in various uterine cervical lesions. J Cancer Res Clin Oncol 2005 Jun; 131(6): 364–70

    Article  PubMed  CAS  Google Scholar 

  73. Lin TS, Lee H, Chen RA, et al. An association of DNMT3b protein expression with P16INK4a promoter hypermethylation in non-smoking female lung cancer with human papillomavirus infection. Cancer Lett 2005 Aug 8; 226(1): 77–84

    Article  PubMed  CAS  Google Scholar 

  74. Kang S, Kim JW, Kang GH, et al. Comparison of DNA hypermethylation patterns in different types of uterine cancer: cervical squamous cell carcinoma, cervical adenocarcinoma and endometrial adenocarcinoma. Int J Cancer 2006 May 1; 118(9): 2168–71

    Article  PubMed  CAS  Google Scholar 

  75. Badal V, Chuang LS, Tan EH, et al. CpG methylation of human papillomavirus type 16 DNA in cervical cancer cell lines and in clinical specimens: genomic hypomethylation correlates with carcinogenic progression. J Virol 2003 Jun; 77(11): 6227–34

    Article  PubMed  Google Scholar 

  76. Kim K, Garner-Hamrick PA, Fisher C, et al. Methylation patterns of papillomavirus DNA, its influence on E2 function, and implications in viral infection. J Virol 2003 Dec; 77(23): 12450–9

    Article  PubMed  CAS  Google Scholar 

  77. Lyko F, Brown R. DNA methyltransferase inhibitors and the development of epigenetic cancer therapies. J Natl Cancer Inst 2005 Oct 19; 97(20): 1498–506

    Article  PubMed  CAS  Google Scholar 

  78. Sheils O, Smyth P, Sherlock J, et al. Microarrays and functional genomics. In: Crocker J, Burnett D, editors. The science of laboratory diagnosis. 2nd ed. Chichester: John Wiley & Sons, Ltd, 2005: 515–21

    Google Scholar 

  79. Shim C, Zhang W, Rhee CH, et al. Profiling of differentially expressed genes in human primary cervical cancer by complementary DNA expression array. Clin Cancer Res 1998 Dec; 4(12): 3045–50

    PubMed  CAS  Google Scholar 

  80. Cheng Q, Lau WM, Chew SH, et al. Identification of molecular markers for the early detection of human squamous cell carcinoma of the uterine cervix. Br J Cancer 2002 Jan 21; 86(2): 274–81

    Article  PubMed  CAS  Google Scholar 

  81. Santin AD, Zhan F, Bignotti E, et al. Gene expression profiles of primary HPV16-and HPV18-infected early stage cervical cancers and normal cervical epithelium: identification of novel candidate molecular markers for cervical cancer diagnosis and therapy. Virology 2005 Jan 20; 331(2): 269–91

    Article  PubMed  CAS  Google Scholar 

  82. Chao A, Wang TH, Lee YS, et al. Molecular characterization of adenocarcinoma and squamous carcinoma of the uterine cervix using microarray analysis of gene expression. Int J Cancer 2006 Jul 1; 119(1): 91–8

    Article  PubMed  CAS  Google Scholar 

  83. Contag SA, Gostout BS, Clayton AC, et al. Comparison of gene expression in squamous cell carcinoma and adenocarcinoma of the uterine cervix. Gynecol Oncol 2004 Dec; 95(3): 610–7

    Article  PubMed  CAS  Google Scholar 

  84. Hudelist G, Czerwenka K, Singer C, et al. cDNA array analysis of cytobrush-collected normal and malignant cervical epithelial cells: a feasibility study. Cancer Genet Cytogenet 2005 Apr 1; 158(1): 35–42

    Article  PubMed  CAS  Google Scholar 

  85. Manavi M, Hudelist G, Fink-Retter A, et al. Gene profiling in Pap-cell smears of high-risk human papillomavirus-positive squamous cervical carcinoma. Gynecol Oncol 2007 May; 105(2): 418–26

    Article  PubMed  CAS  Google Scholar 

  86. Bachtiary B, Boutros PC, Pintilie M, et al. Gene expression profiling in cervical cancer: an exploration of intratumor heterogeneity. Clin Cancer Res 2006 Oct 1; 12(19): 5632–40

    Article  PubMed  CAS  Google Scholar 

  87. Murphy N, Ring M, Heffron CC, et al. p16INK4A, CDC6, and MCM5: predictive biomarkers in cervical preinvasive neoplasia and cervical cancer. J Clin Pathol 2005 May; 58(5): 525–34

    Article  PubMed  CAS  Google Scholar 

  88. Bose S, Evans H, Lantzy L, et al. p16 (INK4A) is a surrogate biomarker for a subset of human papilloma virus-associated dysplasias of the uterine cervix as determined on the Pap smear. Diagn Cytopathol 2005 Jan; 32(1): 21–4

    Article  PubMed  Google Scholar 

  89. Martin CM, Astbury K, O’Leary JJ. Molecular profiling of cervical neoplasia. Expert Rev Mol Diagn 2006 Mar; 6(2): 217–29

    Article  PubMed  CAS  Google Scholar 

  90. Davidson B, Goldberg I, Lerner-Geva L, et al. Expression of topoisomerase II and Ki-67 in cervical carcinoma: clinicopathological study using immunohis-tochemistry. APMIS 2000 Mar; 108(3): 209–15

    Article  PubMed  CAS  Google Scholar 

  91. Sopov I, Sorensen T, Magbagbeolu M, et al. Detection of cancer-related gene expression profiles in severe cervical neoplasia. Int J Cancer 2004 Oct 20; 112(1): 33–43

    Article  PubMed  CAS  Google Scholar 

  92. Shi J, Liu H, Wilkerson M, et al. Evaluation of p16, MCM2, DNA topoisomerase IIA and ProExC in cervical squamous intraepithelial lesions. Lab Invest 2007; 87Suppl. 1: 214A

    Google Scholar 

  93. Sullivan ME, Kilner E, Meyer RE, et al. ProExC™: a helpful tool for difficult cervical specimens? Lab Invest 2007; 87Suppl. 1: 215A

    Google Scholar 

  94. Godlewska J, Luniewski W, Zagrodzki B, et al. Biological evaluation of omega-(dialkylamino)alkyl derivatives of 6H-indolo[2,3-b]quinoline—novel cytotoxic DNA topoisomerase II inhibitors. Anticancer Res 2005; Jul–Aug; 25(4): 2857–68

    PubMed  CAS  Google Scholar 

  95. Rose PG, Blessing JA, Buller RE, et al. Prolonged oral etoposide in recurrent or advanced non-squamous cell carcinoma of the cervix: a Gynecologic Oncology Group study. Gynecol Oncol 2003 May; 89(2): 267–70

    Article  PubMed  CAS  Google Scholar 

  96. Altieri DC. Validating survivin as a cancer therapeutic target. Nat Rev Cancer 2003 Jan; 3(1): 46–54

    Article  PubMed  CAS  Google Scholar 

  97. Kim HS, Shiraki K, Park SH. Expression of survivin in CIN and invasive squamous cell carcinoma of uterine cervix. Anticancer Res 2002 Mar–Apr; 22(2A): 805–8

    PubMed  CAS  Google Scholar 

  98. Branca M, Giorgi C, Santini D, et al. and the HPV-Pathogen ISS Study Group. Survivin as a marker of cervical intraepithelial neoplasia and high-risk human papillomavirus and a predictor of virus clearance and prognosis in cervical cancer. Am J Clin Pathol 2005 Jul; 124(1): 113–21

    Article  PubMed  CAS  Google Scholar 

  99. Borbely AA, Murvai M, Konya J, et al. Effects of human papillomavirus type 16 oncoproteins on survivin gene expression. J Gen Virol 2006 Feb; 87 (Pt 2): 287–94

    Article  PubMed  CAS  Google Scholar 

  100. Jimenez LG, Aguilar MC, Monroy OL, et al. Detection of autoantibodies to survivin in cervical mucus from patients with human papillomavirus-associated cervical cancer and precursor lesions. Autoimmunity 2007 Feb; 40(1): 66–72

    Article  PubMed  CAS  Google Scholar 

  101. Li QX, Zhao J, Liu JY, et al. Survivin stable knockdown by siRNA inhibits tumor cell growth and angiogenesis in breast and cervical cancers. Cancer Biol Ther 2006 Jul; 5(7): 860–6

    Article  PubMed  CAS  Google Scholar 

  102. Altieri DC. Targeted therapy by disabling crossroad signaling networks: the survivin paradigm. Mol Cancer Ther 2006 Mar; 5(3): 478–82

    Article  PubMed  CAS  Google Scholar 

  103. Fukada K, Takahashi-Yanaga F, Sakoguchi-Okada N, et al. Celecoxib induces apoptosis by inhibiting the expression of survivin in HeLa cells. Biochem Biophys Res Commun 2007 Jun 15; 357(4): 1166–71

    Article  PubMed  CAS  Google Scholar 

  104. Ishimi Y, Okayasu I, Kato C. Enhanced expression of Mcm proteins in cancer cells derived from uterine cervix. Eur J Biochem 2003 Mar; 270(6): 1089–101

    Article  PubMed  CAS  Google Scholar 

  105. Ha SA, Shin SM, Namkoong H, et al. Cancer-associated expression of minichromosome maintenance 3 gene in several human cancers and its involvement in tumorigenesis. Clin Cancer Res 2004 Dec 15; 10(24): 8386–95

    Article  PubMed  CAS  Google Scholar 

  106. Murphy N, Ring M, Heffron CC, et al. Quantitation of CDC6 and MCM5 mRNA in cervical intraepithelial neoplasia and invasive squamous cell carcinoma of the cervix. Mod Pathol 2005 Jun; 18(6): 844–9

    Article  PubMed  CAS  Google Scholar 

  107. Wohlschlegel JA, Kutok JL, Weng AP, et al. Expression of geminin as a marker of cell proliferation in normal tissues and malignancies. Am J Pathol 2002 Jul; 161(1): 267–73

    Article  PubMed  CAS  Google Scholar 

  108. Dai Y, Zhang X, Peng Y, et al. The expression of cyclooxygenase-2, VEGF and PGs in CIN and cervical carcinoma. Gynecol Oncol 2005 Apr; 97(1): 96–103

    Article  PubMed  CAS  Google Scholar 

  109. Kanda K, Ueda M, Futakuchi H, et al. Transcriptional expression of the genes implicated in angiogenesis and tumor invasion in cervical carcinomas. Gynecol Oncol 2005 Sep; 98(3): 453–61

    Article  PubMed  CAS  Google Scholar 

  110. Chen Y, Miller C, Mosher R, et al. Identification of cervical cancer markers by cDNA and tissue microarrays. Cancer Res 2003 Apr 15; 63(8): 1927–35

    PubMed  CAS  Google Scholar 

  111. Bell SP, Dutta A. DNA replication in eukaryotic cells. Annu Rev Biochem 2002; 71: 333–74

    Article  PubMed  CAS  Google Scholar 

  112. Lei M, Tye BK. Initiating DNA synthesis: from recruiting to activating the MCM complex. J Cell Sci 2001 Apr; 114 (Pt 8): 1447–54

    PubMed  CAS  Google Scholar 

  113. Saxena S, Dutta A. Geminin-Cdt1 balance is critical for genetic stability. Mutat Res 2005 Jan 6; 569(1–2): 111–21

    PubMed  CAS  Google Scholar 

  114. Harima Y, Togashi A, Horikoshi K, et al. Prediction of outcome of advanced cervical cancer to thermoradiotherapy according to expression profiles of 35 genes selected by cDNA microarray analysis. Int J Radiat Oncol Biol Phys 2004 Sep 1; 60(1): 237–48

    Article  PubMed  CAS  Google Scholar 

  115. Cullen BR. Derivation and function of small interfering RNAs and microRNAs. Virus Res 2004 Jun 1; 102(1): 3–9

    Article  PubMed  CAS  Google Scholar 

  116. Lu J, Getz G, Miska EA, et al. MicroRNA expression profiles classify human cancers. Nature 2005 Jun 9; 435(7043): 834–8

    Article  PubMed  CAS  Google Scholar 

  117. Caldas C, Brenton JD. Sizing up miRNAs as cancer genes. Nat Med 2005 Jul; 11(7): 712–4

    Article  PubMed  CAS  Google Scholar 

  118. McManus MT. MicroRNAs and cancer. Semin Cancer Biol 2003 Aug; 13(4): 253–8

    Article  PubMed  CAS  Google Scholar 

  119. Michael MZ, O’Connor SM, van Holst Pellekaan NG, et al. Reduced accumulation of specific microRNAs in colorectal neoplasia. Mol Cancer Res 2003 Oct; 1(12): 882–91

    PubMed  CAS  Google Scholar 

  120. O’Donnell KA, Wentzel EA, Zeller KI, et al. c-Myc-regulated microRNAs modulate E2F1 expression. Nature 2005 Jun 9; 435(7043): 839–43

    Article  PubMed  CAS  Google Scholar 

  121. Martin CM, Astbury K, Becker C, et al. miRNA expression signatures in cervical cancer. Mod Pathol 2006; 19Suppl. 1: 189A

    Google Scholar 

  122. Porkka KP, Pfeiffer MJ, Waltering KK, et al. MicroRNA expression profiling in prostate cancer, Cancer Res 2007 Jul 1; 67(13): 6130–5

    Article  PubMed  CAS  Google Scholar 

  123. Lui WO, Pourmand N, Patterson BK, et al. Patterns of known and novel small RNAs in human cervical cancer. Cancer Res 2007 Jul 1; 67(13): 6031–43

    Article  PubMed  CAS  Google Scholar 

  124. Petricoin EF, Liotta LA. SELDI-TOF-based serum proteomic pattern diagnostics for early detection of cancer. Curr Opin Biotechnol 2004 Feb; 15(1): 24–30

    Article  PubMed  CAS  Google Scholar 

  125. Xiao Z, Prieto D, Conrads TP, et al. Proteomic patterns: their potential for disease diagnosis. Mol Cell Endocrinol 2005 Jan 31; 230(1–2): 95–106

    Article  PubMed  CAS  Google Scholar 

  126. Wong YF, Cheung TH, Lo KW, et al. Protein profiling of cervical cancer by protein-biochips: proteomic scoring to discriminate cervical cancer from normal cervix. Cancer Lett 2004 Aug 10; 211(2): 227–34

    Article  PubMed  CAS  Google Scholar 

  127. Yim EK, Lee SB, Lee KH, et al. Analysis of the in vitro synergistic effect of 5-fluorouracil and cisplatin on cervical carcinoma cells. Int J Gynecol Cancer 2006 May–Jun; 16(3): 1321–9

    Article  PubMed  Google Scholar 

  128. Yim EK, Lee KH, Kim CJ, et al. Analysis of differential protein expression by cisplatin treatment in cervical carcinoma cells. Int J Gynecol Cancer 2006 Mar–Apr; 16(2): 690–7

    Article  PubMed  Google Scholar 

  129. Yim EK, Park JS. Role of proteomics in translational research in cervical cancer. Expert Rev Proteomics 2006 Feb; 3(1): 21–36

    Article  PubMed  CAS  Google Scholar 

  130. Lee KH, Yim EK, Kim CJ, et al. Proteomic analysis of anti-cancer effects by paclitaxel treatment in cervical cancer cells. Gynecol Oncol 2005 Jul; 98(1): 45–53

    Article  PubMed  CAS  Google Scholar 

  131. Lin YW, Lai HC, Lin CY, et al. Plasma proteomic profiling for detecting and differentiating in situ and invasive carcinomas of the uterine cervix. Int J Gynecol Cancer 2006 May–Jun; 16(3): 1216–24

    Article  PubMed  Google Scholar 

  132. Dykxhoorn DM, Novina CD, Sharp PA. Killing the messenger: short RNAs that silence gene expression. Nat Rev Mol Cell Biol 2003; 4(6): 457–67

    Article  PubMed  CAS  Google Scholar 

  133. Elbashir SM, Lendeckel W, Tuschl T. RNA interference is mediated by 21- and 22-nucleotide RNAs. Genes Dev 2001 Jan 15; 15(2): 188–200

    Article  PubMed  CAS  Google Scholar 

  134. Martinez LA, Naguibneva I, Lehrmann H, et al. Synthetic small inhibiting RNAs: efficient tools to inactivate oncogenic mutations and restore p53 pathways. Proc Natl Acad sci U S A 2002 Nov 12; 99(23): 14849–54

    Article  PubMed  CAS  Google Scholar 

  135. Yu JY, DeRuiter SL, Turner DL. RNA interference by expression of short-interfering RNAs and hairpin RNAs in mammalian cells. Proc Natl Acad Sci U S A 2002 Apr 30; 99(9): 6047–52

    Article  PubMed  CAS  Google Scholar 

  136. Miyagishi M, Taira K. U6 promoter-driven siRNAs with four uridine 3′ overhangs efficiently suppress targeted gene expression in mammalian cells. Nat Biotechnol 2002 May; 20(5): 497–500

    Article  PubMed  CAS  Google Scholar 

  137. Paul CP, Good PD, Winer I, et al. Effective expression of small interfering RNA in human cells. Nat Biotechnol 2002 May; 20(5): 505–8

    Article  PubMed  CAS  Google Scholar 

  138. Ling X, Li F. Silencing of antiapoptotic survivin gene by multiple approaches of RNA interference technology. Biotechniques 2004 Mar; 36(3): 450–4, 456-60

    PubMed  CAS  Google Scholar 

  139. Fu GF, Lin XH, Han QW, et al. RNA interference remarkably suppresses bcl-2 gene expression in cancer cells in vitro and in vivo. Cancer Biol Ther 2005 Aug; 4(8): 822–9

    Article  PubMed  CAS  Google Scholar 

  140. Sumimoto H, Miyagishi M, Miyoshi H, et al. Inhibition of growth and invasive ability of melanoma by inactivation of mutated BRAF with lentivirus-mediated RNA interference. Oncogene 2004 Aug 12; 23(36): 6031–9

    Article  PubMed  CAS  Google Scholar 

  141. Pichler A, Zelcer N, Prior JL, et al. In vivo RNA interference-mediated ablation of MDR1 P-glycoprotein. Clin Cancer Res 2005 Jun 15; 11(12): 4487–94

    Article  PubMed  CAS  Google Scholar 

  142. Jiang M, Milner J. Selective silencing of viral gene expression in HPV-positive human cervical carcinoma cells treated with siRNA, a primer of RNA interference. Oncogene 2002 Sep 5; 21(39): 6041–8

    Article  PubMed  CAS  Google Scholar 

  143. Butz K, Ristriani T, Hengstermann A, et al. siRNA targeting of the viral E6 oncogene efficiently kills human papillomavirus-positive cancer cells. Oncogene 2003 Sep 4; 22(38): 5938–45

    Article  PubMed  CAS  Google Scholar 

  144. Koivusalo R, Krausz E, Helenius H, et al. Chemotherapy compounds in cervical cancer cells primed by reconstitution of p53 function after short interfering RNA-mediated degradation of human papillomavirus 18 E6 mRNA: opposite effect of siRNA in combination with different drugs. Mol Pharmacol 2005 Aug; 68(2): 372–82

    PubMed  CAS  Google Scholar 

  145. Kim SH, Song SH, Kim KS, et al. Celecoxib induces apoptosis in cervical cancer cells independent of cyclooxygenase using NF-kappaB as a possible target. J Cancer Res Clin Oncol 2004 Sep; 130(9): 551–60

    Article  PubMed  CAS  Google Scholar 

  146. Karl T, Seibert N, Stohr M, et al. Sulindac induces specific degradation of the HPV oncoprotein E7 and causes growth arrest and apoptosis in cervical carcinoma cells. Cancer Lett 2007 Jan 8; 245(1–2): 103–11

    Article  PubMed  CAS  Google Scholar 

  147. Woodworth CD, Michael E, Marker D, et al. Inhibition of the epidermal growth factor receptor increases expression of genes that stimulate inflammation, apoptosis, and cell attachment. Mol Cancer Ther 2005 Apr; 4(4): 650–8

    Article  PubMed  CAS  Google Scholar 

  148. Li Y, Li H, Yao G, et al. Inhibition of telomerase RNA (hTR) in cervical cancer by adenovirus-delivered siRNA. Cancer Gene Ther 2007 Aug; 14(8): 748–55

    Article  PubMed  CAS  Google Scholar 

  149. Nasu S, Ang KK, Fan Z, et al. C225 antiepidermal growth factor receptor antibody enhances tumor radiocurability. Int J Radiat Oncol Biol Phys 2001 Oct 1; 51(2): 474–7

    Article  PubMed  CAS  Google Scholar 

  150. Guo JM, Xiao BX, Kang GZ, et al. Suppression of telomerase activity and arrest at G1 phase in human cervical cancer HeLa cells by all-trans retinoic acid. Int J Gynecol Cancer 2006 Jan–Feb; 16(1): 341–6

    Article  PubMed  CAS  Google Scholar 

  151. Xi L, Chen G, Zhou J, et al. Inhibition of telomerase enhances apoptosis induced by sodium butyrate via mitochondrial pathway. Apoptosis 2006 May; 11(5): 789–98

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

The authors wish to thank the other members of the Cervical Cancer Research Group at the Coombe Women’s Hospital and Trinity College, Dublin and Cerviva (the Irish Cervical Screening Research Consortium). These groups are funded by the Health Research Board, Cancer Research Ireland, the Royal City of Dublin Trust, The Meath Foundation, Science Foundation Ireland, and the European Union.

The authors have no conflicts of interest that are directly relevant to the content of this review.

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Authors and Affiliations

  1. Department of Pathology, Molecular Pathology Research Group, Coombe Women’s Hospital and Trinity College, Dublin, 8, Ireland

    Cara M. Martin, Louise Kehoe, Cathy O. Spillane & John J. O’Leary

  2. Department of Histopathology, Trinity College, Dublin, Ireland

    Cara M. Martin, Louise Kehoe, Cathy O. Spillane & John J. O’Leary

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  1. Cara M. Martin
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  2. Louise Kehoe
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  3. Cathy O. Spillane
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  4. John J. O’Leary
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Correspondence to Cara M. Martin.

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Martin, C.M., Kehoe, L., Spillane, C.O. et al. Gene Discovery in Cervical Cancer. Mol Diag Ther 11, 277–290 (2007). https://doi.org/10.1007/BF03256249

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