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  • Oncogenomics
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Frequent epigenetic inactivation of the RASSF1A tumor suppressor gene in Hodgkin's lymphoma

Oncogene volume 23, pages 1326–1331 (2004)Cite this article

Abstract

Epigenetic inactivation of RASSF1A, a putative tumor suppressor with proapoptotic activity, is frequently observed in a number of solid tumors, including a variety of epithelial cancers, but has not been described in hematopoietic tumors. We have analysed the expression and methylation status of RASSF1A in Hodgkin's lymphoma (HL)-derived cell lines, primary HL tumors and serum samples from HL patients. RASSF1A transcription was detectable in only 2/6 HL cell lines. Methylation-specific PCR and bisulfite genomic sequencing revealed that the RASSF1A promoter was hypermethylated in all four RASSF1A-nonexpressing cell lines. 5-aza-2′-deoxycytidine treatment resulted in demethylation of the promoter and RASSF1A expression in these lines. Hypermethylation of RASSF1A was also detected in 34/52 (65%) primary HL tumors and in 2/22 serum samples from these patients. Microdissection of Hodgkin/Reed–Sternberg (HRS) cells from several of these cases confirmed that the RASSF1A hypermethylation we detected in the analysis of whole tumor originated from the tumor cell population. Although hypermethylation of RASSF1A was detected in 5/6 non-Hodgkin's lymphoma (NHL)-derived cell lines, only rare primary NHL (1/10 of Burkitt's lymphoma, 1/12 of post-transplant lymphoma, 1/12 diffuse large B-cell lymphoma, 0/27 of nasal lymphoma, 0/8 follicular center cell lymphoma, 0/4 mantle cell lymphoma, 0/4 anaplastic large cell (Ki-1+) lymphoma, 0/2 MALT lymphoma) showed hypermethylation of the promoter. No methylation was detected in any of the 14 normal PBMC. These results point to an important role for epigenetic silencing of RASSF1A in the pathogenesis of HL. Inactivation of RASSF1A could be one mechanism by which HRS cells escape the apoptosis that should occur following nonproductive immunoglobulin gene rearrangements.

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References

  • Agathanggelou A, Honorio S, Macartney DP, Martinez A, Dallol A, Rader J, Fullwood P, Chauhan A, Walker R, Shaw JA, Hosoe S, Lerman MI, Minna JD, Maher ER and Latif F . (2001). Oncogene, 20, 1509–1518.

  • Astuti D, Agathanggelou A, Honorio S, Dallol A, Martinsson T, Kogner P, Cummins C, Neumann HP, Voutilainen R, Dahia P, Eng C, Maher ER and Latif F . (2001). Oncogene, 20, 7573–7577.

  • Burbee DG, Forgacs E, Zochbauer-Muller S, Shivakumar L, Fong K, Gao B, Randle D, Kondo M, Virmani A, Bader S, Sekido Y, Latif F, Milchgrub S, Toyooka S, Gazdar AF, Lerman MI, Zabarovsky E, White M and Minna JD . (2001). J. Natl. Cancer Inst., 93, 691–699.

  • Dammann R, Li C, Yoon JH, Chin PL, Bates S and Pfeifer GP . (2000). Nat. Genet., 25, 315–319.

  • Dammann R, Yang G and Pfeifer GP . (2001). Cancer Res., 61, 3105–3109.

  • Dreijerink K, Braga E, Kuzmin I, Geil L, Duh FM, Angeloni D, Zbar B, Lerman MI, Stanbridge EJ, Minna JD, Protopopov A, Li J, Kashuba V, Klein G and Zabarovsky ER . (2001). Proc. Natl. Acad. Sci. USA, 98, 7504–7509.

  • Harada K, Toyooka S, Maitra A, Maruyama R, Toyooka KO, Timmons CF, Tomlinson GE, Mastrangelo D, Hay RJ, Minna JD and Gazdar AF . (2002). Oncogene, 21, 4345–4349.

  • Kanzler H, Kuppers R, Hansmann ML and Rajewsky K . (1996). J. Exp. Med., 184, 1495–1505.

  • Khokhlatchev A, Rabizadeh S, Xavier R, Nedwidek M, Chen T, Zhang XF, Seed B and Avruch J . (2002). Curr. Biol., 12, 253–265.

  • Lee MG, Kim HY, Byun DS, Lee SJ, Lee CH and Kim JI et al. (2001). Cancer Res., 61, 6688–6692.

  • Lee TL, Leung WK, Chan MWY, Ng EKW, Tong JHM, Lo KW, Chung SCS, Sung JJY and To KF . (2002). Clin. Cancer Res., 8, 1761–1766.

  • Lo KW, Kwong J, Hui AB, Chan SY, To KF, Chan AS, Chow LS, Teo PM, Johnson PJ and Huang DP . (2001). Cancer Res., 61, 3877–3881.

  • Maruyama R, Toyooka S, Toyooka KO, Harada K, Virmani AK, Zochbauer-Muller S, Farinas AJ, Vakar-Lopez F, Minna JD, Sagalowsky A, Czerniak B and Gazdar AF . (2001). Cancer Res., 61, 8659–8663.

  • Morrissey C, Martinez A, Zatyka M, Agathanggelou A, Honorio S, Astuti D, Morgan NV, Moch H, Richards FM, Kishida T, Yao M, Schraml P, Latif F and Maher ER . (2001). Cancer Res., 61, 7277–7281.

  • Murray PG, Young LS, Rowe M and Crocker J . (1992). J. Pathol., 166, 1–5.

  • Ortiz-Vega S, Khokhlatchev A, Nedwidek M, Zhang XF, Dammann R, Pfeifer GP and Avruch J . (2002). Oncogene, 21, 1381–1390.

  • Ponting CP and Benjamin DR . (1996). Trends Biochem. Sci., 21, 422–425.

  • Shivakumar L, Minna J, Sakamaki T, Pestell R and White MA . (2002). Mol. Cell. Biol., 22, 4309–4318.

  • Tao Q, Huang H, Geiman TM, Lim CY, Fu L, Qiu GH and Robertson KD . (2002). Hum. Mol. Genet., 11, 2091–2102.

  • Tao Q, Swinnen LJ, Yang J, Srivastava G, Robertson KD and Ambinder RF . (1999). Am. J. Pathol., 155, 619–625.

  • Tsai CN, Tsai CL, Tse KP, Chang HY and Chang YS . (2002). Proc. Natl. Acad. Sci. USA, 99, 10084–10089.

  • Vos MD, Ellis CA, Bell A, Birrer MJ and Clark GJ . (2000). J. Biol. Chem., 275, 35669–35672.

  • Zou HZ, Yu BM, Wang ZW, Sun JY, Cang H, Gao F, Li DH, Zhao R, Feng GG and Yi J . (2002). Clin. Cancer Res., 8, 188–191.

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Acknowledgements

We are grateful to Pamela Edwards, Marie Smith and Risa Mann for help in the collection of tissue specimens, and Jianming Ying, Jing Tan and Cynthia Lee for their technical support.

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Authors and Affiliations

  1. Department of Pathology, University of Birmingham, Edgbaston, Birmingham, B15 2TT, UK

    Paul G Murray, Elyse R Waites & Duncan Heys

  2. Cancer Epigenetics/Tumor Virology Laboratory, Johns Hopkins Singapore, Singapore

    Guo-Hua Qiu, Li Fu & Qian Tao

  3. Department of Pathology, University of Hong Kong, China

    Gopesh Srivastava

  4. Section of Medical and Molecular Genetics, University of Birmingham, Edgbaston, Birmingham, B15 2TT, UK

    Angelo Agathanggelou & Farida Latif

  5. Department of Oncology, The Children's Hospital, Steelhouse Lane, Birmingham, B4 6NH, UK

    Richard G Grundy, Jillian R Mann & Sheila E Parkes

  6. Department of Cellular Pathology, Birmingham Heartland's Hospital, Bordesley Green East, Birmingham, B15 2TT, UK

    Jane Starczynski & John Crocker

  7. Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, MD, USA

    Richard F Ambinder & Qian Tao

  8. Division of Cancer Studies, Cancer Research UK Institute for Cancer Studies, University of Birmingham, Edgbaston, Birmingham, B15 2TT, UK

    Lawrence S Young

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Correspondence to Paul G Murray or Qian Tao.

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Murray, P., Qiu, GH., Fu, L. et al. Frequent epigenetic inactivation of the RASSF1A tumor suppressor gene in Hodgkin's lymphoma. Oncogene 23, 1326–1331 (2004). https://doi.org/10.1038/sj.onc.1207313

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