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Aberrant methylation of tumor suppressor genes and allelic imbalance in cervical intraepithelial neoplasia

  • Genomics. Transcriptomics. Proteomics
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Abstract

The methylation status of genes p16, MLH1, HIC1, MGMT, N33, and RB1 was determined in cervical smears of women without gynecological pathology, in biopsies from patients with high-grade cervical intraepithelial neoplasia (CIN3), and in samples of nondysplastic cervical tissue adjacent to CIn3. The level of methylation of these genes in normal smears was insignificant. In CIN3, methylation frequencies were as follows: 58% for p16, 51% for MLH1, 84% for HIC1, and 27% for N33. However, dysplastic tissues did not differ significantly from the control with respect to the methylation frequencies of the MGMT and RB1 genes (8 and 15%, respectively). The methylation frequency of the suppressor genes in nondysplastic, morphologically normal adjacent tissues was also high. We found that 21% of samples (9/42) had microsatellite instability at chromosomes 5q11.2–q14.3 (3/42) and 13q14–q14.3 (6/42). Loss of heterozygosity (LOH) at region 13q14 was detected in 7% of samples (3/42).

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References

  1. Heilmann V., Kreienberg R. 2002. Molecular biology of cervical cancer and its precursors. Curr. Womens Health Rep. 2, 27–33.

    PubMed  Google Scholar 

  2. House M., Guo M., Iacobuzio-Donahue C., Herman J. 2003. Molecular progression of promoter methylation in intraductal papillary mucinous neoplasms of the pancreas. Carcinogenesis. 24, 193–198.

    Article  PubMed  CAS  Google Scholar 

  3. Maruyama R., Toyooka S., Toyooka K., et al. 2002. Aberrant promoter methylation profile of prostate cancers and its relationship to clinicopathological features. Clin. Cancer Res. 8, 514–519.

    PubMed  CAS  Google Scholar 

  4. Muller H., Fiegl H., Widschwendter A., Widschwendter M. 2004. Prognostic DNA methylation marker in serum of cancer patients. Ann. N.Y. Acad. Sci. 1022, 44–49.

    Article  PubMed  CAS  Google Scholar 

  5. Zaletaev D., Nemtsova M., Strel’nikov V., et al. 2004. Diagnostics of epigenetic alterations in heredirtary and oncological disorders. Mol. Biol. 38, 213–223.

    Article  CAS  Google Scholar 

  6. Sutter C., Gebert J., Bischoff P., et al. 1999 Molecular screening of potential HNPCC patients using multiplex microsatellite PCR system. Mol. Cell. Probes. 13, 157–165.

    Article  PubMed  CAS  Google Scholar 

  7. Chen X., Stroun M., Magnenat J., et al. 1996. Microsatellite alterations in plasma DNA of small-cell lung cancer patients. Nature Med. 2, 1033–1035.

    PubMed  CAS  Google Scholar 

  8. Gurin C., Federichi M., Kang L., Boyd J. 1999. Causes and consequences of MSI in endometrial carcinoma. Cancer Res. 59, 462–466.

    PubMed  CAS  Google Scholar 

  9. Knobloch R., Konrad L., Barth P., et al. 2004. Genetic pathways and new progression markers for prostate cancer suggested by microsatellite allelotyping. Clin. Cancer Res. 10, 1064–1073.

    Google Scholar 

  10. Gorgoulis V., Mariatos G., Manolis E., et al. 2000. Allelic imbalance at the 5q14 locus associated with decreased apoptotic rate in NSCLCs. Possible synergistic effect with p53 gene alterations on apoptosis. Lung Cancer. 28, 211–224.

    Article  PubMed  CAS  Google Scholar 

  11. Girard L., Zochbauer-Muller S., Virmani A., et al. 2000. Genome-wide allelotyping of lung cancer identifies new regions of allelic loss, differences between SCLC and NSCLC, and loci clustering. Cancer Res. 60, 4894–4906.

    PubMed  CAS  Google Scholar 

  12. Wong C., Lee J., Lau T., et al. 2002. Clinicopathological significance of loss of heterozygosity on chromosome 13q in hepatocellular carcinoma. Clin. Cancer Res. 8, 2266–2272.

    PubMed  CAS  Google Scholar 

  13. Zemlyakova V., Zhevlova A., Zborovskaya I., et al., 2003. Methylation profile of several tumor suppressor genes in non-small-cell lung cancer. Mol. Biol. 37, 983–988.

    Google Scholar 

  14. Zemlyakova, V., Zhevlova, A., Strel’nikov, V., et al. 2003. Abnormal methylation of several tumor suppressor genes in sporadic breast cancer. Mol. Biol. 37, 696–703.

    Google Scholar 

  15. Ballestar E., Esteller M. 2002. The impact of chromatin in human cancer linking DNA methylation to gene silencing. Carcinogenesis. 23, 1103–1109.

    Article  PubMed  CAS  Google Scholar 

  16. Malyukova A., Loginov V., Khodyrev D., et al. 2004. Methylation of the putative tumor suppressor gene RASSF1A in primary cervical tumors. Mol. Biol. 38, 1005–1013.

    Article  Google Scholar 

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

    PubMed  Google Scholar 

  18. Virmani A., Muller C., Rathi A., et al. 2001. Aberrant methylation during cervical carcinogenesis. Clin. Cancer Res. 7, 584–589.

    PubMed  CAS  Google Scholar 

  19. Dong S., Kim H., Rha S., Sidransky D. 2001. Promoter hypermethylation of multiple genes in carcinoma of the uterine cervix. Clin. Cancer Res. 7, 1982–1986.

    PubMed  CAS  Google Scholar 

  20. Widschwendter A., Muller H., Fiegl H., et al. 2004. DNA methylation in serum and tumors of cervical cancer patients. Clin. Cancer Res. 10, 565–571.

    PubMed  CAS  Google Scholar 

  21. Reesink-Peters N., Wisman G., Jeronimo C., et al. 2004. Detecting cervical cancer by quantitative promoter hypermethylation assay on cervical scrapings: A feasibility study. Mol. Cancer Res. 2, 289–295.

    PubMed  CAS  Google Scholar 

  22. Waki T., Tamara G., Makoto S., Motoyama T. 2003. Age-related methylation of tumor-supressor and tumorrelated genes: An analysis of autopsy samples. Oncogene. 22, 4128–4133.

    Article  PubMed  CAS  Google Scholar 

  23. Feng Q., Balasubramanian A., Hawes S., et al. 2005. Detection of hypermethylated genes in women with and without cervical neoplasia. J. Natl. Cancer Inst. 97, 273–282.

    PubMed  CAS  Google Scholar 

  24. Herman J., Merlo A., Mao L., et al. 1995 Inactivation of the CDKN2/p16/MTS1 gene is frequently associated with abberant DNA methylation in all common human cancers. Cancer Res. 55, 4525–4530.

    PubMed  CAS  Google Scholar 

  25. Kondo Y., Shen L., Issa J. 2003. Critical role of histone methylation in tumor suppressor gene silencing in colorectal cancer. Mol. Cell Biol. 23, 206–215.

    Article  PubMed  CAS  Google Scholar 

  26. Uehara E., Takeuchi S., Tasaka T., et al. 2003. Aberrant methylation in CpG islands of multiple genes in therapyrelated leukemia. Int. J. Oncol. 23, 693–696.

    PubMed  CAS  Google Scholar 

  27. Leung J., Yuen S., Chung L., et al. 1999. hMLH1 promoter methylation and lack of hMLH1 expression in sporadic gastric carcinomas with high-frequency microsatellite instability. Cancer Res. 59, 159–164.

    PubMed  CAS  Google Scholar 

  28. Baylin S., Herman J., Graff J., et al. 1998. Alterations in DNA methylation: A fundamental aspect of neoplasia. Adv. Cancer Res. 72, 141–196.

    PubMed  CAS  Google Scholar 

  29. Lee S., Lee H., Kim J., et al. 2003. Aberrant CpG island hypermethylation along multistep hepatocarcinogenesis. Am. J. Pathol. 163, 1371–1378.

    PubMed  CAS  Google Scholar 

  30. Zochbauer-Muller S., Fong K., Virmani A., et al. 2001. Aberrant promoter methylation of multiple genes in non-small-cell lung cancers. Cancer Res. 61, 249–255.

    PubMed  CAS  Google Scholar 

  31. Bhowmick N., Neilson E., Moses H. 2004. Stromal fibroblasts in cancer initiation and progression. Nature. 432, 332–337.

    Article  PubMed  CAS  Google Scholar 

  32. Heselmeyer K., Schrock E., Manoir S., et al. 1996. Gain of chromosome 3q defines the transition from severe dysplasia to invasive carcinoma of the uterine cervix. Proc. Natl. Acad. Sci. USA 93, 479–484.

    Article  PubMed  CAS  Google Scholar 

  33. Chung T., Cheung T., Lo W., et al. 2000. Loss of heterozygosity at the short arm of chromosome 3 in micro-dissected cervical intraepitelial neoplasia. Cancer Lett. 154, 189–194.

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Institute of Molecular Medicine, Sechenov Medical Academy, Ministry of Health and Social Development of the Russian Federation, Moscow, 119992, Russia

    T. V. Kekeeva, D. V. Zaletaev & M. V. Nemtsova

  2. Research Center for Medical Genetics, Russian Academy of Medical Sciences, Moscow, 115478, Russia

    T. V. Kekeeva, A. I. Zhevlova, D. V. Zaletaev & M. V. Nemtsova

  3. Blockhin Cancer Research Center, Russian Academy of Medical Sciences, Moscow, 115478, Russia

    Yu. I. Podistov

  4. Clinical Hospital no. 70, Moscow, 111396, Russia

    Yu. V. Solov’eva

Authors
  1. T. V. Kekeeva
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  2. A. I. Zhevlova
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  3. Yu. I. Podistov
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  4. Yu. V. Solov’eva
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  5. D. V. Zaletaev
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  6. M. V. Nemtsova
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Original Russian Text © T.V. Kekeeva, A.I. Zhevlova, Yu.I. Podistov, Yu.V. Solov’eva, D.V. Zaletaev, M.V. Nemtsova, 2006, published in Molekulyarnaya Biologiya, 2006, Vol. 40, No. 2, pp. 224–230.

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Kekeeva, T.V., Zhevlova, A.I., Podistov, Y.I. et al. Aberrant methylation of tumor suppressor genes and allelic imbalance in cervical intraepithelial neoplasia. Mol Biol 40, 194–199 (2006). https://doi.org/10.1134/S0026893306020038

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  • DOI: https://doi.org/10.1134/S0026893306020038

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