"Frequent epigenetic inactivation of the RASSF1A tumor suppressor gene in Hodgkin's lymphoma".

Paul G Murray ¹, Guo-Hua Qiu ² , Li Fu ², Elyse R Waites ¹, Gopesh Srivastava ³, Duncan Heys ¹, Angelo Agathanggelou ⁴, Farida Latif ⁴, Richard G Grundy ⁵, Jillian R Mann ⁵, Jane Starczynski ⁶, John Crocker ⁶, Sheila E Parkes ⁵, Richard F Ambinder ⁷, Lawrence S Young ⁸ and Qian Tao ^{2, 7}

¹ Department of Pathology, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK
² Cancer Epigenetics/Tumor Virology Laboratory, Johns Hopkins Singapore, Singapore
³ Department of Pathology, University of Hong Kong, China
⁴ Section of Medical and Molecular Genetics, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK
⁵ Department of Oncology, The Children's Hospital, Steelhouse Lane, Birmingham B4 6NH, UK
⁶ Department of Cellular Pathology, Birmingham Heartland's Hospital, Bordesley Green East, Birmingham B15   2TT, UK
⁷ Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, MD, USA
⁸ Cancer Research UK Institute for Cancer Studies, Division of Cancer Studies, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK

Correspondence to:

PG Murray,
E-mail:    p.g.murray@bham.ac.uk      or

Q Tao, Cancer Epigenetics/Tumor Virology Laboratory, Johns Hopkins Singapore, CRC (MD11), Level 5, 10 Medical Drive, Singapore 117597, Singapore.
E-mail:    taoqia@jhs.com.sg

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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Further Topics in:  Euchromatin,  active DNA, and  RNA  ribo-regulators:

Reviews and Research:

Links to Euchromatin Activator RNA Reviews:
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Links to Ultrastructural Probes of DNase I-Sensitive Sites:
Links to RNA as a Therapeutic Agent:
Links to Hodgkin Lymphoma Immuno-Pathology:
Links to Activated T-Lymphocyte Immunotherapy:
Links to Medical Systems Biology:

"Ultrastructural Probes of Active DNA Sites, and the RNA Activators of DNA".

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