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Methylation of the APAF-1 and DAPK-1 promoter region correlates with progression of renal cell carcinoma in North Indian population

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Tumor Biology

Abstract

Aberrant promoter hypermethylation of cancer associated genes occur frequently during carcinogenesis and may serve as a cancer biomarker. The aim of this study was to investigate the occurrence and relevance of promoter methylation of the tumor suppressor DAPK-1, APAF-1 () and SPARC in relation to different pathological stages and histological grades of tumor progression that might act as possible independent prognostic factor in the susceptibility towards renal cell carcinoma (RCC) in North Indian population. Three tumor suppressor gene promoters namely APAF-1, DAPK-1 and SPARC were assessed by methylation-specific PCR (MS-PCR) in 196 primarily resected renal cell tumors paired with the corresponding normal tissue samples. After genomic DNA isolation and sodium bisulfite modification, methylation levels were determined and correlated with standard clinicopathological parameters, pathological stage and Fuhrman nuclear grade of RCC. Significant differences in methylation frequency among the four subtypes of renal tumors were found for APAF-1 (p < 0.001), DAPK-1 (p < 0.001) and SPARC (p = 0.182), when compared with the corresponding normal tissue. Male subjects showed stronger association of methylation frequency of all the three genes with RCC than the female subjects. Additionally, higher frequency of APAF-1, DAPK-1 and SPARC promoter methylation were directly correlated with higher tumor stage (p trend < 0.001). Higher frequency of promoter methylation of APAF-1 and SPARC were also associated with higher nuclear grade (p < 0.001 and p = 0.036, respectively). This gene panel might contribute to a more optimal diagnostic coverage and information, improving preoperative assessment and therapeutic decision-making in patients harboring suspicious renal masses.

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Abbreviations

RCC:

Renal cell carcinoma

ccRCC:

Clear cell renal cell carcinoma

pRCC:

Papillary renal cell carcinoma

TSG:

Tumor suppressor gene

MS-PCR:

Methylation specific PCR

References

  1. Jemal A, Siegel R, Xu J, Ward E. Cancer statistics, 2010. CA Cancer J Clin. 2010;60:277–300.

    Article  PubMed  Google Scholar 

  2. Ferlay JHRS, Bray F, Forman D, Mathers C, Parkin DM. Globocan 2002. Int J Cancer. 2010;127:2893–917.

    Article  PubMed  CAS  Google Scholar 

  3. Motzer RJ, Bander NH, Nanus DM. Renal-cell carcinoma. New Engl J Med. 1996;335:865.

    Article  PubMed  CAS  Google Scholar 

  4. Jones PA, Vogelzang NJ, Gomez J. Report of the kidney/bladder cancer progress review group. Bethesda: National Cancer Institute; 2002.

    Google Scholar 

  5. Jones PA, Baylin SB. The fundamental role of epigenetic events in cancer. Nat Rev Genet. 2002;3:415–28.

    Article  PubMed  CAS  Google Scholar 

  6. Battagli C, Uzzo RG, Dulaimi E, Ibanez de Caceres I, Krassenstein R, Al-Saleem T, et al. Promoter hypermethylation of tumor suppressor genes in urine from kidney cancer patients. Cancer Res. 2003;63:8695–9.

    PubMed  CAS  Google Scholar 

  7. Norbury CJ, Zhivotovsky B. DNA damage-induced apoptosis. Oncogene. 2004;23:2797–808.

    Article  PubMed  CAS  Google Scholar 

  8. Wolf BB, Schuler M, Li W, Eggers-Sedlet B, Lee W, Tailor P, et al. Defective cytochrome c-dependent caspase activation in ovarian cancer cell lines due to diminished or absent apoptotic protease activating factor-1 activity. J Biol Chem. 2001;276:34244–51.

    Article  PubMed  CAS  Google Scholar 

  9. Raveh T, Droguett G, Horwitz MS, DePinho RA, Kimchi A. Dap kinase activates a p19arf/p53-mediated apoptotic checkpoint to suppress oncogenic transformation. Nat Cell Biol. 2000;3:1–7.

    Google Scholar 

  10. Christoph F, Hinz S, Kempkensteffen C, Schostak M, Schrader M, Miller K. mRNA expression profiles of methylated apaf-1 and dapk-1 tumor suppressor genes uncover clear cell renal cell carcinomas with aggressive phenotype. J Urol. 2007;178:2655–9.

    Article  PubMed  CAS  Google Scholar 

  11. Furukawa Y, Sutheesophon K, Wada T, Nishimura M, Saito Y, Ishii H, et al. Methylation silencing of the apaf-1 gene in acute leukemia. Mol Cancer Res. 2005;3:325–34.

    Article  PubMed  CAS  Google Scholar 

  12. Weikert SHCKS, Miller MSMSK, Christoph F. Ezh2 polycomb transcriptional repressor expression correlates with methylation of the apaf-1 gene in superficial transitional cell carcinoma of the bladder. Tumor Biol. 2007;28:151–7.

    Article  Google Scholar 

  13. Feng Q, Hawes SE, Stern JE, Wiens L, Lu H, Dong ZM, et al. DNA methylation in tumor and matched normal tissues from non-small cell lung cancer patients. Cancer Epidemiol Biomarkers Prev. 2008;17:645–54.

    Article  PubMed  CAS  Google Scholar 

  14. Sage H, Vernon RB, Funk SE, Everitt EA, Angello J. Sparc, a secreted protein associated with cellular proliferation, inhibits cell spreading in vitro and exhibits Ca2+-dependent binding to the extracellular matrix. J Cell Biol. 1989;109:341–6.

    Article  PubMed  CAS  Google Scholar 

  15. Funk SE, Sage EH. The Ca(2+)-binding glycoprotein sparc modulates cell cycle progression in bovine aortic endothelial cells. Proc Natl Acad Sci. 1991;88:2648–52.

    Article  PubMed  CAS  Google Scholar 

  16. Nagaraju GPC, Sharma D. Anti-cancer role of sparc, an inhibitor of adipogenesis. Cancer Treat Rev. 2011, in press.

  17. Greene FL. AJCC cancer staging handbook: From the AJCC cancer staging manual. Springer Verlag, 2002.

  18. Zöchbauer-Müller S, Fong KM, Virmani AK, Geradts J, Gazdar AF, Minna JD. Aberrant promoter methylation of multiple genes in non-small cell lung cancers. Cancer Res. 2001;61:249–55.

    PubMed  Google Scholar 

  19. Sato N, Fukushima N, Maehara N, Matsubayashi H, Koopmann J, Su GH, et al. Sparc/osteonectin is a frequent target for aberrant methylation in pancreatic adenocarcinoma and a mediator of tumor–stromal interactions. Oncogene. 2003;22:5021–30.

    Article  PubMed  CAS  Google Scholar 

  20. Yu J, Ni M, Xu J, Zhang H, Gao B, Gu J, et al. Methylation profiling of 20 promoter-cpg islands of genes which may contribute to hepatocellular carcinogenesis. BMC Cancer. 2002;2:29.

    Article  PubMed  Google Scholar 

  21. Hajra KM, Liu JR. Apoptosome dysfunction in human cancer. Apoptosis. 2004;9:691–704.

    Article  PubMed  CAS  Google Scholar 

  22. Matapurkar A, Lazebnik Y. Requirement of cytochrome c for apoptosis in human cells. Cell Death Differ. 2006;13:2062–7.

    Article  PubMed  CAS  Google Scholar 

  23. Christoph F, Kempkensteffen C, Weikert S, Köllermann J, Krause H, Miller K, et al. Methylation of tumour suppressor genes apaf-1 and dapk-1 and in vitro effects of demethylating agents in bladder and kidney cancer. Br J Cancer. 2006;95:1701–7.

    Article  PubMed  CAS  Google Scholar 

  24. Christoph F, Weikert S, Kempkensteffen C, Krause H, Schostak M, Köllermann J, et al. Promoter hypermethylation profile of kidney cancer with new proapoptotic p53 target genes and clinical implications. Clin Cancer Res. 2006;12:5040–6.

    Article  PubMed  CAS  Google Scholar 

  25. Deiss LP, Feinstein E, Berissi H, Cohen O, Kimchi A. Identification of a novel serine/threonine kinase and a novel 15-kd protein as potential mediators of the gamma interferon-induced cell death. Genes Dev. 1995;9:15–30.

    Article  PubMed  CAS  Google Scholar 

  26. Suzuki M, Hao C, Takahashi T, Shigematsu H, Shivapurkar N, Sathyanarayana UG, et al. Aberrant methylation of sparc in human lung cancers. Br J Cancer. 2005;92:942–48.

    Article  PubMed  CAS  Google Scholar 

  27. Wang Y, Yu Q, Cho AH, Rondeau G, Welsh J, Adamson E, et al. Survey of differentially methylated promoters in prostate cancer cell lines. Neoplasia (New York, NY). 2005;7:748–60.

    Article  CAS  Google Scholar 

  28. Rodriguez-Jimenez FJ, Caldes T, Iniesta P, Vidart JA, Lopez GA. Overexpression of sparc protein contrasts with its transcriptional silencing by aberrant hypermethylation of sparc cpg-rich region in endometrial carcinoma. Oncol Rep. 2007;17:1301–7.

    PubMed  CAS  Google Scholar 

  29. Socha MJ, Said N, Dai Y, Kwong J, Ramalingam P, Trieu V, et al. Aberrant promoter methylation of sparc in ovarian cancer. Neoplasia (New York, NY). 2009;11:126–35.

    CAS  Google Scholar 

  30. Jun G, Jian S, Haojie H, Zhaoshen L, Yiqi D, Jia C, Minghui L, Shunli L, Han L, Yanfang G. Methylation of the sparc gene promoter and its clinical implication in pancreatic cancer. J Exp Clin Cancer Res. 2010;29.

  31. Cheetham S, Tang MJ, Mesak F, Kennecke H, Owen D, Tai IT. Sparc promoter hypermethylation in colorectal cancers can be reversed by 5-aza-2 deoxycytidine to increase sparc expression and improve therapy response. Br J Cancer. 2008;98:1810–9.

    Article  PubMed  CAS  Google Scholar 

  32. Yang E, Kang HJ, Koh KH, Rhee H, Kim NK, Kim H. Frequent inactivation of sparc by promoter hypermethylation in colon cancers. Int J Cancer. 2007;121:567–75.

    Article  PubMed  CAS  Google Scholar 

  33. DiMartino JF, Lacayo NJ, Varadi M, Li L, Saraiya C, Ravindranath Y, et al. Low or absent sparc expression in acute myeloid leukemia with mll rearrangements is associated with sensitivity to growth inhibition by exogenous sparc protein. Leukemia. 2006;20:426–32.

    Article  PubMed  CAS  Google Scholar 

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Acknowledgements

The authors are thankful to the Indian Council of Medical Research (ICMR), New Delhi, India, for providing the funds that allowed us to carry out this research.

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Authors and Affiliations

  1. Section of Molecular Carcinogenesis and Chemoprevention, Department of Medical Elementology and Toxicology, Faculty of Science, Jamia Hamdard, Hamdard University, Hamdard Nagar, New Delhi, 110062, India

    Shiekh Tanveer Ahmad, Wani Arjumand & Sarwat Sultana

  2. Department of Urology, All India Institute of Medical Sciences, Ansari Nagar, New Delhi, 110029, India

    Amlesh Seth & Ashish Kumar Saini

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  1. Shiekh Tanveer Ahmad
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  2. Wani Arjumand
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  3. Amlesh Seth
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  5. Sarwat Sultana
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Correspondence to Sarwat Sultana.

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Ahmad, S.T., Arjumand, W., Seth, A. et al. Methylation of the APAF-1 and DAPK-1 promoter region correlates with progression of renal cell carcinoma in North Indian population. Tumor Biol. 33, 395–402 (2012). https://doi.org/10.1007/s13277-011-0235-9

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  • DOI: https://doi.org/10.1007/s13277-011-0235-9

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