'Drawing' a Molecular Portrait of CIN and Cervical Cancer: a Review of Genome-Wide Molecular Profiling Data

  • Kurmyshkina, Olga V (Institute of High-Tech Biomedicine, Petrozavodsk State University) ;
  • Kovchur, Pavel I (Institute of High-Tech Biomedicine, Petrozavodsk State University) ;
  • Volkova, Tatyana O (Institute of High-Tech Biomedicine, Petrozavodsk State University)
  • Published : 2015.06.26


In this review we summarize the results of studies employing high-throughput methods of profiling of HPV-associated cervical intraepithelial neoplasia (CIN) and squamous cell cervical cancers at key intracellular regulatory levels to demonstrate the unique identity of the landscape of molecular changes underlying this oncopathology, and to show how these changes are related to the 'natural history' of cervical cancer progression and the formation of clinically significant properties of tumors. A step-wise character of cervical cancer progression is a morphologically well-described fact and, as evidenced by genome-wide screenings, it is indeed the consistent change of the molecular profiles of HPV-infected epithelial cells through which they progressively acquire the phenotypic hallmarks of cancerous cells. In this sense, CIN/cervical cancer is a unique model for studying the driving forces and mechanisms of carcinogenesis. Recent research has allowed definition of the whole-genome spectrum of both random and regular molecular alterations, as well as changes either common to processes of carcinogenesis or specific for cervical cancer. Despite the existence of questions that are still to be investigated, these findings are of great value for the future development of approaches for the diagnostics and treatment of cervical neoplasms.


Cervical cancer;CIN;HPV;molecular profile;genome;signature


Supported by : Russian Foundation


  1. Akagi K, Li J, Broutian TR, et al (2014). Genome-wide analysis of HPV integration in human cancers reveals recurrent, focal genomic instability. Genome Res, 24, 185-99.
  2. Bae SM, Lee CH, Cho YL, et al (2005). Two-dimensional gel analysis of protein expression profile in squamous cervical cancer patients. Gynecol Oncol, 99, 26-35.
  3. Bai LX, Wang JT, Ding L, et al (2014). Folate deficiency and FHIT hypermethylation and HPV 16 infection promote cervical cancerization. Asian Pac J Cancer Prev, 15, 9313-7.
  4. Banno K, Iida M, Yanokura M, et al (2014). MicroRNA in cervical cancer: OncomiRs and tumor suppressor miRs in diagnosis and treatment. Scientific World J, 2014, 178075.
  5. Brandsma JL, Harigopal M, Kiviat NB, et al (2014). Methylation of twelve CpGs in human papillomavirus type 16 (HPV16) as an informative biomarker for the triage of women positive for HPV16 infection. Cancer Prev Res (Phila), 7, 526-33.
  6. Chao A, Wang TH, Lai CH (2007). Overview of microarray analysis of gene expression and its applications to cervical cancer investigation. Taiwan J Obstet Gynecol, 46, 363-73.
  7. Chen Y, Miller C, Mosher R, et al (2003). Identification of cervical cancer markers by cDNA and tissue microarrays. Cancer Res, 63, 1927-35.
  8. Chen J, Yao D, Li Y, et al (2013). Serum microRNA expression levels can predict lymph node metastasis in patients with early-stage cervical squamous cell carcinoma. Int J Mol Med, 32, 557-67.
  9. Chen YC, Huang RL, Huang YK, et al (2014). Methylomics analysis identifies epigenetically silenced genes and implies an activation of $\beta$-catenin signaling in cervical cancer. Int J Cancer, 135, 117-27.
  10. Cortes-Gutierrez EI, Hernandez-Garza F, Garcia-Perez JO, et al (2012). Evaluation of DNA single and double strand breaks in women with cervical neoplasia based on alkaline and neutral comet assay techniques. J Biomed Biotechnol, 2012, 385245.
  11. Cunniffe C, Ryan F, Lambkin H, Brankin B (2012). Expression of tight and adherens junction proteins in cervical neoplasia. Br J Biomed Sci, 69, 147-53.
  12. Ding H, Wu YL, Wang YX, Zhu FF (2014). Characterization of the microRNA expression profile of cervical squamous cell carcinoma metastases. Asian Pac J Cancer Prev, 15, 1675-79.
  13. Doorbar J (2006). Molecular biology of human papillomavirus infection and cervical cancer. Clin Sci (Lond), 110, 525-41.
  14. Doorbar J, Quint W, Banks L, et al (2012). The biology and life-cycle of human papillomaviruses. Vaccine, 30, 55-70.
  15. Duenas-Gonzalez A, Lizano M, Candelaria M, et al (2005). Epigenetics of cervical cancer. An overview and therapeutic perspectives. Mol Cancer, 4, 38-61.
  16. Fang J, Zhang H, Jin S (2014). Epigenetics and cervical cancer: from pathogenesis to therapy. Tumour Biol, 35, 5083-93.
  17. Feng D, Wu J, Tian Y, et al (2013). Targeting of histone deacetylases to reactivate tumour suppressor genes and its therapeutic potential in a human cervical cancer xenograft model. PLoS One, 8, 80657.
  18. Gibb EA, Becker-Santos DD, Enfield KS, et al (2012). Aberrant expression of long noncoding RNAs in cervical intraepithelial neoplasia. Int J Gynecol Cancer, 22, 1557-63.
  19. Gius D, Funk MC, Chuang EY, et al (2007). Profiling microdissected epithelium and stroma to model genomic signatures for cervical carcinogenesis accommodating for covariates. Cancer Res, 67, 7113-23.
  20. Gocze K, Gombos K, Juhasz K, et al (2013). Unique microRNA expression profiles in cervical cancer. Anticancer Res, 33, 2561-7.
  21. Gomez-Gomez Y, Organista-Nava J, Gariglio P (2013). Deregulation of the miRNAs expression in cervical cancer: human papillomavirus implications. Biomed Res Int, 2013, 407052.
  22. Gonzalez-Herrera A, Salgado-Bernabe M, Velazquez-Velazquez C, et al (2015). Increased expression of HOXB2 and HOXB13 proteins is associated with HPV infection and cervical cancer progression. Asian Pac J Cancer Prev, 16, 1349-53.
  23. Guo P, Wang D, Wu J, et al (2014). The landscape of alternative splicing in cervical squamous cell carcinoma. Onco Targets Ther, 8, 73-9.
  24. Halim TA, Farooqi AA, Zaman F (2013). Nip the HPV encoded evil in the cancer bud: HPV reshapes TRAILs and signaling landscapes. Cancer Cell Int, 13, 61-78.
  25. Hansel A, Steinbach D, Greinke C, et al (2014). A promising DNA methylation signature for the triage of high-risk human papillomavirus DNA-positive women. PLoS One, 9, 91905.
  26. Higareda-Almaraz JC, Enriquez-Gasca MR, Hernandez-Ortiz M, Resendis-Antonio O, Encarnacion-Guevara S (2011). Proteomic patterns of cervical cancer cell lines, a network perspective. BMC Syst Biol, 5, 96-112.
  27. Higareda-Almaraz JC, Valtierra-Gutierrez IA, Hernandez-Ortiz M, et al (2013). Analysis and prediction of pathways in HeLa cells by integrating biological levels of organization with systems-biology approaches. PLoS One, 8, 65433.
  28. How C, Pintilie M, Bruce JP, et al (2015). Developing a prognostic micro-rna signature for human cervical carcinoma. PLoS One, 10, 123946.
  29. Hu Z, Zhu D, Wang W, et al (2015). Genome-wide profiling of HPV integration in cervical cancer identifies clustered genomic hot spots and a potential microhomology-mediated integration mechanism. Nat Genet, 47, 158-63.
  30. Ibeanu OA (2011). Molecular pathogenesis of cervical cancer. Cancer Biol Ther, 11, 295-306.
  31. Jimenez-Wences H, Peralta-Zaragoza O, Fernandez-Tilapa G (2014). Human papilloma virus, DNA methylation and microRNA expression in cervical cancer (Review). Oncol Rep, 31, 2467-76.
  32. Johannsen E, Lambert PF (2013). Epigenetics of human papillomaviruses. Virol, 445, 205-12.
  33. Kaczkowski B, Morevati M, Rossing M, Cilius F, Norrild B (2012). A Decade of global mRNA and miRNA profiling of HPV-positive cell lines and clinical specimens. Open Virol J, 6, 216-31.
  34. Katargin AN, Pavlova LS, Kisseljov FL, Kisseljova NP (2009). Hypermethylation of genomic 3.3-kb repeats is frequent event in HPV-positive cervical cancer. BMC Med Genomics, 2, 30.
  35. Kim HJ, Kim SC, Ju W, et al (2014). Aberrant sialylation and fucosylation of intracellular proteins in cervical tissue are critical markers of cervical carcinogenesis. Oncol Rep, 31, 1417-22.
  36. Korzeniewski N, Spardy N, Duensing A, Duensing S (2011). Genomic instability and cancer: lessons learned from human papillomaviruses. Cancer Lett, 305, 113-22.
  37. Lando M, Holden M, Bergersen LC, et al (2009). Gene dosage, expression, and ontology analysis identifies driver genes in the carcinogenesis and chemoradioresistance of cervical cancer. PLoS Genet, 5, 1000719.
  38. Lee BH, Roh S, Kim YI, Lee A, Kim SY (2012). Difference of genome-wide copy number alterations between highgrade squamous intraepithelial lesions and squamous cell carcinomas of the uterine cervix. Korean J Pathol, 46, 123-30.
  39. Liang WS, Aldrich J, Nasser S, et al (2014). Simultaneous characterization of somatic events and HPV-18 integration in a metastatic cervical carcinoma patient using DNA and RNA sequencing. Int J Gynecol Cancer, 24, 329-38.
  40. Lomnytska MI, Becker S, Hellman K, et al (2010). Diagnostic protein marker patterns in squamous cervical cancer. Proteomics Clin Appl, 4, 17-31.
  41. Los Santos-Munive V de, Alonso-Avelino JA (2013). Chromosomal instability in carcinogenesis of cervical cancer. Rev Med Inst Mex Seguro Soc, 51, 644-9.
  42. Lou Z, Wang S (2014). E3 ubiquitin ligases and human papillomavirus-induced carcinogenesis. J Int Med Res, 42, 247-60.
  43. Luo Y, Wu Y, Peng Y, et al (2015). Systematic analysis to identify a key role of CDK1 in mediating gene interaction networks in cervical cancer development. Ir J Med Sci, [Epub ahead of print].
  44. Lyng H, Brovig RS, Svendsrud DH, et al (2006). Gene expressions and copy numbers associated with metastatic phenotypes of uterine cervical cancer. BMC Genomics, 7, 268-82.
  45. Mattarocci S, Abbruzzese C, Mileo AM, et al (2014). Identification of pivotal cellular factors involved in HPVinduced dysplastic and neoplastic cervical pathologies. J Cell Physiol, 229, 463-70.
  46. Mazurenko NN, Bliev AIu, Bidzhieva BA, et al (2006). Loss of heterozygosity at chromosome 6 as a marker of early genetic alterations in cervical intraepithelial neoplasias and microinvasive carcinomas. Mol Biol (Mosk), 40, 436-47.
  47. Medina-Martinez I, Barron V, Roman-Bassaure E, et al (2014). Impact of gene dosage on gene expression, biological processes and survival in cervical cancer: a genome-wide follow-up study. PLoS One, 9, 97842.
  48. Min W, Wen-li M, Zhao-hui S, et al (2009). Microarray analysis identifies differentially expressed genes induced by human papillomavirus type 18 E6 silencing RNA. Int J Gynecol Cancer, 19, 547-63.
  49. Mine KL, Shulzhenko N, Yambartsev A, et al (2013). Gene network reconstruction reveals cell cycle and antiviral genes as major drivers of cervical cancer. Nat Commun, 4, 1806.
  50. Mo W, Tong C, Zhang Y, Lu H (2015). MicroRNAs' differential regulations mediate the progress of human papillomavirus (HPV)-induced cervical intraepithelial neoplasia (CIN). BMC Syst Biol, 9, 4.
  51. Narayan G, Bourdon V, Chaganti S, et al (2007). Gene dosage alterations revealed by cDNA microarray analysis in cervical cancer: identification of candidate amplified and overexpressed genes. Genes Chromosomes Cancer, 46, 373-84.
  52. Narayan G, Murty VV (2010). Integrative genomic approaches in cervical cancer: implications for molecular pathogenesis. Future Oncol, 6, 1643-52.
  53. Oh EK, Kim YW, Kim IW, et al (2012). Differential DNA copy number aberrations in the progression of cervical lesions to invasive cervical carcinoma. Int J Oncol, 41, 2038-46.
  54. Ojesina AI, Lichtenstein L, Freeman SS, et al (2014). Landscape of genomic alterations in cervical carcinomas. Nature, 506, 371-5.
  55. Organista-Nava J, Gomez-Gomez Y, Gariglio P (2014). Embryonic stem cell-specific signature in cervical cancer. Tumour Biol, 35, 1727-38.
  56. Paradkar PH, Joshi JV, Mertia PN, Agashe SV, Vaidya RA (2014). Role of cytokines in genesis, progression and prognosis of cervical cancer. Asian Pac J Cancer Prev, 15, 3851-64.
  57. Peng G, Dan W, Jun W, et al (2015). Transcriptome profiling of the cancer and adjacent nontumor tissues from cervical squamous cell carcinoma patients by RNA sequencing. Tumour Biol, [Epub ahead of print].
  58. Petrenko AA, Korolenkova LI, Skvortsov DA, et al (2010). Cervical intraepithelial neoplasia: Telomerase activity and splice pattern of hTERT mRNA. Biochimie, 92, 1827-31.
  59. Qian K, Pietila T, Ronty M, et al (2013). Identification and validation of human papillomavirus encoded microRNAs. PLoS One, 8, 70202.
  60. Rajkumar T, Sabitha K, Vijayalakshmi N, et al (2011). Identification and validation of genes involved in cervical tumourigenesis. BMC Cancer, 11, 80-93.
  61. Rivera-Juarez M de L, Rosas-Murrieta NH, Mendieta-Carmona V, et al (2014). Promoter polymorphisms of ST3GAL4 and ST6GAL1 genes and associations with risk of premalignant and malignant lesions of the cervix. Asian Pac J Cancer Prev, 15, 1181-6.
  62. Rolen U, Kobzeva V, Gasparjan N, et al (2006). Activity profiling of deubiquitinating enzymes in cervical carcinoma biopsies and cell lines. Mol Carcinog, 45, 260-9.
  63. Rosty C, Sheffer M, Tsafrir D, et al (2005). Identification of a proliferation gene cluster associated with HPV E6/E7 expression level and viral DNA load in invasive cervical carcinoma. Oncogene, 24, 7094-104.
  64. Rotondo JC, Bosi S, Bassi C, et al (2015). Gene expression changes in progression of cervical neoplasia revealed by microarray analysis of cervical neoplastic keratinocytes. J Cell Physiol, 230, 806-12.
  65. Saavedra K, Brebi P, Roa JC (2012). Epigenetic alterations in preneoplastic and neoplastic lesions of the cervix. Clin Epigenetics, 4, 13-9.
  66. Senchenko VN, Kisseljova NP, Ivanova TA, et al (2013). Novel tumor suppressor candidates on chromosome 3 revealed by NotI-microarrays in cervical cancer. Epigenetics, 8, 409-20.
  67. Sgarlato GD, Eastman CL, Sussman HH (2005). Panel of genes transcriptionally up-regulated in squamous cell carcinoma of the cervix identified by representational difference analysis, confirmed by macroarray, and validated by realtime quantitative reverse transcription-PCR. Clin Chem, 51, 27-34.
  68. Shin HJ, Joo J, Yoon JH, Yoo CW, Kim JY (2014). Physical status of human papillomavirus integration in cervical cancer is associated with treatment outcome of the patients treated with radiotherapy. PLoS One, 9, 78995.
  69. Shulzhenko N, Lyng H, Sanson GF, Morgun A (2014). Menage a trois: an evolutionary interplay between human papillomavirus, a tumor, and a woman. Trends Microbiol, 22, 345-53.
  70. Solorzano C, Angel Mayoral M, de los Angeles Carlos M, et al (2012). Overexpression of glycosylated proteins in cervical cancer recognized by the Machaerocereus eruca agglutinin. Folia Histochem Cytobiol, 50, 398-406.
  71. Sopov I, Sorensen T, Magbagbeolu M, et al (2004). Detection of cancer-related gene expression profiles in severe cervical neoplasia. Int J Cancer, 112, 33-43.
  72. Srivastava P, Mangal M, Agarwal SM (2014). Understanding the transcriptional regulation of cervix cancer using microarray gene expression data and promoter sequence analysis of a curated gene set. Gene, 535, 233-8.
  73. Steenbergen RD, Snijders PJ, Heideman DA, Meijer CJ (2014). Clinical implications of (epi)genetic changes in HPVinduced cervical precancerous lesions. Nat Rev Cancer, 14, 395-405.
  74. Sveen A, Johannessen B, Teixeira MR, Lothe RA, Skotheim RI (2014). Transcriptome instability as a molecular pan-cancer characteristic of carcinomas. BMC Genomics, 15, 672.
  75. Tang T, Wong HK, Gu W, et al (2013). MicroRNA-182 plays an onco-miRNA role in cervical cancer. Gynecol Oncol, 129, 199-208.
  76. Thomas A, Mahantshetty U, Kannan S, et al (2013). Expression profiling of cervical cancers in Indian women at different stages to identify gene signatures during progression of the disease. Cancer Med, 2, 836-48.
  77. Thomas LK, Bermejo JL, Vinokurova S, et al (2014). Chromosomal gains and losses in human papillomavirusassociated neoplasia of the lower genital tract-a systematic review and meta-analysis. Eur J Cancer, 50, 85-98.
  78. Velazquez-Marquez N, Santos-Lopez G, Jimenez-Aranda L, Reyes-Leyva J, Vallejo-Ruiz V (2012). Sialyl Lewis x expression in cervical scrapes of premalignant lesions. J Biosci, 37, 999-1004.
  79. Vermeulen CF, Jordanova ES, Zomerdijk-Nooijen YA, et al (2005). Frequent HLA class I loss is an early event in cervical carcinogenesis. Hum Immunol, 66, 1167-73.
  80. Vidal AC, Henry NM, Murphy SK, et al (2014). PEG1/MEST and IGF2 DNA methylation in CIN and in cervical cancer. Clin Transl Oncol, 16, 266-72.
  81. Wang L, Wang Q, Li HL, Han LY (2013). Expression of MiR200a, miR93, metastasis-related gene RECK and MMP2/MMP9 in human cervical carcinoma-relationship with prognosis. Asian Pac J Cancer Prev, 14, 2113-8.
  82. Wang W, Jia HL, Huang JM, et al (2014). Identification of biomarkers for lymph node metastasis in early-stage cervical cancer by tissue-based proteomics. Br J Cancer, 110, 1748-58.
  83. Warowicka A, Kwasniewska A, Gozdzicka-Jozefiak A (2013). Alterations in mtDNA: a qualitative and quantitative study associated with cervical cancer development. Gynecol Oncol, 129, 193-8.
  84. Williams VM, Filippova M, Filippov V, Payne KJ, Duerksen- Hughes P (2014). Human papillomavirus type 16 E6* induces oxidative stress and DNA damage. J Virol, 88, 6751-61.
  85. Wilting SM, Steenbergen RD, Tijssen M, et al (2009). Chromosomal signatures of a subset of high-grade premalignant cervical lesions closely resemble invasive carcinomas. Cancer Res, 69, 647-55.
  86. Wilting SM, Snijders PJ, Verlaat W, et al (2013). Altered microRNA expression associated with chromosomal changes contributes to cervical carcinogenesis. Oncogene, 32, 106-16.
  87. Wilting SM, Verlaat W, Jaspers A, et al (2013a). Methylationmediated transcriptional repression of microRNAs during cervical carcinogenesis. Epigenetics, 8, 220-8.
  88. Wong YF, Selvanayagam ZE, Wei N, et al (2003). Expression genomics of cervical cancer: molecular classification and prediction of radiotherapy response by DNA microarray. Clin Cancer Res, 9, 5486-92.
  89. Wright AA, Howitt BE, Myers AP, et al (2013). Oncogenic mutations in cervical cancer: genomic differences between adenocarcinomas and squamous cell carcinomas of the cervix. Cancer, 119, 3776-83.
  90. Xu B, Chotewutmontri S, Wolf S, et al (2013). Multiplex Identification of Human Papillomavirus 16 DNA Integration Sites in Cervical Carcinomas. PLoS One, 8, 66693.
  91. Yu Q, Liu SL, Wang H, et al (2014). miR-126 Suppresses the proliferation of cervical cancer cells and alters cell sensitivity to the chemotherapeutic drug bleomycin. Asian Pac J Cancer Prev, 14, 6569-72.
  92. Zhao S, Yao DS, Chen JY, Ding N (2013). Aberrant expression of miR-20a and miR-203 in cervical cancer. Asian Pac J Cancer Prev, 14, 2289-93.
  93. Zhao XY, Cui Y, Jiang SF, et al (2015). Human telomerase gene and high-risk human papillomavirus infection are related to cervical intraepithelial neoplasia. Asian Pac J Cancer Prev, 16, 693-7.
  94. Zheng ZM, Wang X (2011). Regulation of cellular miRNA expression by human papillomaviruses. Biochim Biophys Acta, 1809, 668-77.
  95. Zheng CH, Quan Y, Li YY, et al (2014). Expression of transcription factor FOXC2 in cervical cancer and effects of silencing on cervical cancer cell proliferation. Asian Pac J Cancer Prev, 15, 1589-95.
  96. Zhou J, Cai J, Huang Z, et al (2013). Proteomic identification of target proteins following Drosha knockdown in cervical cancer. Oncol Rep, 30, 2229-37.

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