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Frequent epigenetic inactivation of the RASSF1A tumor suppressor gene in Hodgkin's lymphoma
- Source :
- Oncogene. 23:1326-1331
- Publication Year :
- 2004
- Publisher :
- Springer Science and Business Media LLC, 2004.
-
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.
- Subjects :
- endocrine system
Cancer Research
CD30
Apoptosis
Biology
medicine.disease_cause
BCL9
immune system diseases
hemic and lymphatic diseases
Tumor Cells, Cultured
Genetics
medicine
Humans
Genes, Tumor Suppressor
Gene Silencing
Child
Promoter Regions, Genetic
Molecular Biology
Tumor Suppressor Proteins
MALT lymphoma
DNA Methylation
Hodgkin's lymphoma
medicine.disease
Hodgkin Disease
BCL10
Lymphoma
Gene Expression Regulation, Neoplastic
Immunology
Cancer research
Mantle cell lymphoma
Carcinogenesis
Subjects
Details
- ISSN :
- 14765594 and 09509232
- Volume :
- 23
- Database :
- OpenAIRE
- Journal :
- Oncogene
- Accession number :
- edsair.doi.dedup.....7fc4a71e21a421d3bc0b641e97ac8340