2013 Articles

PCDH10 Promoter Hypermethylation is Frequent in most Histologic Subtypes of Mature Lymphoid Malignancies and Occurs Early in Lymphomagenesis

Narayan, Gopeshwar; Xie, Dongxu; Freddy, Allen J.; Ishdorj, Ganchimeg; Do, Catherine; Satwani, Prakash; Liyanage, Hema; Clark, Lorraine N.; Kisselev, Sergey; Nandula, Subhadra; Scotto, Luigi; Alobeid, Bachir; Savage, David G.; Tycko, Benjamin; O’Connor, Owen Anthony; Bhagat, Govind; Vundavalli, Murty V.

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 hyperpla- sia, 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 regu- lated 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.