Aberrant promoter methylation of multiple genes throughout the clinico-pathologic spectrum of B-cell neoplasia.
OBJECTIVE
Aberrant promoter methylation targets CpG islands causing gene silencing. We explored aberrant promoter methylation of genes potentially involved in B-cell malignancies and encoding proteins implicated in DNA repair (O6-methylguanine-DNA methyltransferase, MGMT), detoxification of environmental xenobiotics (glutathione S-transferase P1, GSTP1), apoptosis regulation (death associated protein kinase, DAP-k and caspase 8, CASP8) and cell cycle control (p73).


METHODS
Three hundred and seventeen B-cell malignancies were investigated by methylation-specific polymerase chain reaction (MSP) of MGMT, GSTP1, DAP-k, CASP8 and p73 genes. In selected cases, MSP results were matched to protein expression studies by immunohistochemistry or Western blotting.


RESULTS
DAP-k promoter methylation occurred at highest frequency in follicular lymphoma (85.0%) and MALT-lymphoma (72.2%). MGMT methylation targeted both precursor B-cell neoplasia (23.8%) and mature B-cell tumors (27.6%). GSTP1 methylation was commonest in hairy cell leukemia (75.0%), follicular lymphoma (55.5%), Burkitt s lymphoma (52.0%), and MALT lymphoma (50.0%). Methylation of p73 and CASP8 was rare or absent. DAP-k and MGMT methylation caused absent protein expression.


CONCLUSIONS
Methylation of MGMT, DAP-k and GSTP1 represents a major pathogenetic event in several B-cell malignancies. In follicular lymphoma and MALT lymphoma, frequent inactivation of the apoptosis extrinsic pathway through DAP-k methylation may reinforce the survival advantage already conferred by deregulation of the intrinsic apoptotic pathway. Inactivation of GSTP1 in gastric MALT lymphoma represents an additional mechanism favoring accumulation of reactive oxygen species and lymphomagenesis. Finally, the frequency of GSTP1 aberrant methylation in diffuse large B-cell lymphoma prompts studies aimed at verifying the prognostic impact of this epigenetic lesion in these lymphomas.
Rossi
Davide
D
Hematology Unit, Dept. of Medical Sciences and IRCAD, Amedeo Avogadro University of Eastern Piedmont, Novara, Italy.
Capello
Daniela
D
Gloghini
Annunziata
A
Franceschetti
Silvia
S
Paulli
Marco
M
Bhatia
Kishor
K
Saglio
Giuseppe
G
Vitolo
Umberto
U
Pileri
Stefano A
SA
Esteller
Manel
M
Carbone
Antonino
A
Gaidano
Gianluca
G
D000217:Acyltransferases / Q000235:genetics; D000782:Aneuploidy; D017209:Apoptosis / Q000235:genetics; D051017:Apoptosis Regulatory Proteins; D001752:Blast Crisis / Q000235:genetics; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000235:genetics; D053181:Caspase 8; D020169:Caspases / Q000235:genetics; D002453:Cell Cycle / Q000235:genetics; D018899:CpG Islands; D019175:DNA Methylation; D004260:DNA Repair / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics; D064550:Death-Associated Protein Kinases; D018450:Disease Progression; D005500:Follow-Up Studies; D020868:Gene Silencing; D016147:Genes, Tumor Suppressor; D006801:Humans; D008658:Inactivation, Metabolic / Q000235:genetics; D015448:Leukemia, B-Cell / Q000145:classification / Q000235:genetics* / Q000473:pathology; D016393:Lymphoma, B-Cell / Q000145:classification / Q000235:genetics* / Q000473:pathology; D009687:Nuclear Proteins / Q000235:genetics; D019853:O(6)-Methylguanine-DNA Methyltransferase / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000235:genetics; D000072160:Tumor Protein p73; D025521:Tumor Suppressor Proteins
D051017:Apoptosis Regulatory Proteins; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; C000606460:TP73 protein, human; D000072160:Tumor Protein p73; D025521:Tumor Suppressor Proteins; D019853:O(6)-Methylguanine-DNA Methyltransferase; D000217:Acyltransferases; D064550:Death-Associated Protein Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; C043403:fatty acyl ethyl ester synthase; C505530:CASP8 protein, human; D053181:Caspase 8; D020169:Caspases