PCDH10 promoter hypermethylation is frequent in most histologic subtypes of mature lymphoid malignancies and occurs early in lymphomagenesis.
PCDH10 is epigenetically inactivated in multiple tumor types; however, studies in mature lymphoid malignancies are limited. Here, we have investigated the presence of promoter hypermethylation of the PCDH10 gene in a large cohort of well-characterized subsets of lymphomas. PCDH10 promoter hypermethylation was identified by methylation-specific PCR in 57 to 100% of both primary B- and T-cell lymphoma specimens and cell lines. These findings were further validated by Sequenom Mass-array analysis. Promoter hypermethylation was also identified in 28.6% cases of reactive follicular hyperplasia, more commonly occurring in states of immune deregulation and associated with rare presence of clonal karyotypic aberrations, suggesting that PCDH10 methylation occurs early in lymphomagenesis. PCDH10 expression was down regulated via promoter hypermethylation in T- and B-cell lymphoma cell lines. The transcriptional down-regulation resulting from PCDH10 methylation could be restored by pharmacologic inhibition of DNA methyltransferases in cell lines. Both T- and B-cell lymphoma cell lines harboring methylation-mediated inactivation of PCDH10 were resistant to doxorubicin treatment, suggesting that hypermethylation of this gene might contribute to chemotherapy response.
Department of Pathology and Cell Biology, Columbia University Medical Center, New York Presbyterian Hospital, New York, NY.
Gopeshwar
G
Narayan
Dongxu
D
Xie
Allen J
AJ
Freddy
Ganchimeg
G
Ishdorj
Catherine
C
Do
Prakash
P
Satwani
Hema
H
Liyanage
Lorraine
L
Clark
Sergey
S
Kisselev
Subhadra V
SV
Nandula
Luigi
L
Scotto
Bachir
B
Alobeid
David
D
Savage
Benjamin
B
Tycko
Owen A
OA
O'Connor
Govind
G
Bhagat
Vundavalli V
VV
Murty
D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D015820:Cadherins / Q000235:genetics*; D063646:Carcinogenesis / Q000235:genetics; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D019175:DNA Methylation; D015254:DNA Modification Methylases / Q000037:antagonists & inhibitors; D015536:Down-Regulation / Q000187:drug effects; D004317:Doxorubicin / Q000494:pharmacology*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D059785:Karyotype; D008228:Lymphoma, Non-Hodgkin / Q000235:genetics* / Q000473:pathology; D009101:Multiple Myeloma / Q000235:genetics* / Q000473:pathology; D011401:Promoter Regions, Genetic; D000091363:Protocadherins; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
D000903:Antibiotics, Antineoplastic; D015820:Cadherins; C438603:PCDH10 protein, human; D000091363:Protocadherins; D004317:Doxorubicin; D015254:DNA Modification Methylases