Promoter methylation of PARG1, a novel candidate tumor suppressor gene in mantle-cell lymphomas.
OBJECTIVE
Mantle cell lymphoma (MCL), a mature B-cell neoplasm, is genetically characterized by the translocation t(11;14)(q13;q32). However, secondary alterations are required for malignant transformation. The identification of inactivated tumor suppressor genes contributing to the development of MCL may lead to further elucidation of the biology of this disease and help to identify novel targets for therapy.


METHODS
Whole genome microarray-based gene expression profiling on treated versus untreated MCL cell lines was used to identify genes induced by 5-aza-2'-deoxycytidine. The degree of promoter methylation and transcriptional silencing of selected genes was then proven in MCL cell lines and primary cases by methylation-specific polymerase chain reaction (PCR) techniques, real-time PCR and gene expression profiling.


RESULTS
After 5-aza-2'-deoxycytidine treatment, we identified more than 1000 upregulated genes, 16 of which were upregulated > or =3-fold. Most of them were not known to be silenced by methylation in MCL. A low expression of ING1, RUNX3 and BNIP3L was observed in three of the five the MCL cell lines. In addition, the expression of PARG1, which is located in the frequently deleted region 1p22.1, was substantially reduced and displayed at least partial promoter methylation in all investigated MCL cell lines as well as in 31 primary MCL cases.


CONCLUSIONS
In summary, we identified interesting novel candidate genes that probably contribute to the progression of MCL and suggest that PARG1 is a strong candidate tumor suppressor gene in MCL.
Ripperger
Tim
T
Institute of Cell and Molecular Pathology, Hannover Medical School, Hannover, Germany.
von Neuhoff
Nils
N
Kamphues
Kathrin
K
Emura
Makito
M
Lehmann
Ulrich
U
Tauscher
Marcel
M
Schraders
Margit
M
Groenen
Patricia
P
Skawran
Britta
B
Rudolph
Cornelia
C
Callet-Bauchu
Evelyne
E
van Krieken
Johan H J M
JH
Schlegelberger
Brigitte
B
Steinemann
Doris
D
D001374:Azacitidine / Q000031:analogs & derivatives / Q000494:pharmacology; D045744:Cell Line, Tumor / Q000187:drug effects / Q000378:metabolism; D002878:Chromosomes, Human, Pair 1 / Q000235:genetics; D002880:Chromosomes, Human, Pair 11 / Q000648:ultrastructure; D002883:Chromosomes, Human, Pair 14 / Q000648:ultrastructure; D019175:DNA Methylation; D004273:DNA, Neoplasm / Q000737:chemistry* / Q000235:genetics; D000077209:Decitabine; D018450:Disease Progression; D020690:GTPase-Activating Proteins / Q000096:biosynthesis / Q000235:genetics* / Q000502:physiology; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D020868:Gene Silencing / Q000187:drug effects; D016147:Genes, Tumor Suppressor; D006801:Humans; D020522:Lymphoma, Mantle-Cell / Q000235:genetics* / Q000473:pathology; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis; D016133:Polymerase Chain Reaction / Q000379:methods; D011401:Promoter Regions, Genetic / Q000235:genetics*; D014158:Transcription, Genetic / Q000187:drug effects; D014178:Translocation, Genetic
C500429:ARHGAP29 protein, human; D004273:DNA, Neoplasm; D020690:GTPase-Activating Proteins; D009363:Neoplasm Proteins; D000077209:Decitabine; D001374:Azacitidine