PCDH10 promoter hypermethylation is frequent in most histologic subtypes of mature lymphoid malignancies and occurs early in lymphomagenesis

Abstract

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.

PCDH10, a novel p53 transcriptional target in regulating cell migration

“…The re-expression of PCDH10 could induce cell cycle arrest, apoptosis, and inhibit cell clonogenicity, though with underlying working mechanism undiscovered; however these proposed functions substantiate the tumor suppressive role of PCDH10. 19,20,28,29 The basic transcriptional regulatory mechanism of PCDH10 gene is absent from the previous studies except for the profound epigenetic studies from tumor samples.…”

“…PCDH10 inactivation through genetic deletion or promoter methylation has been presented in multi-kind of human cancers including colon cancer, gastric cancer, prostate cancer and lymphoid malignancies etc. [10][11][12][18][19][20]30 Moreover, that the methylation level of PCDH10 correlates with clinical parameters manifests the significance of PCDH10 in the tumor progression process. 29 For example, methylation status of PCDH10 is associated with poor prognosis in patients with bladder cancer.…”

PCDH10 inhibits cell proliferation of multiple myeloma via the negative regulation of the Wnt/β-catenin/BCL-9 signaling pathway

“…The human PCDH10 gene is located at 4q28.3 and is involved as a tumor-suppressor gene. The promoter methylation and downregulation of PCDH10 gene expression has been demonstrated in various human cancer types including lymphoma, as well as gastric, prostate, bladder, colorectal and cervical cancer (9)(10)(11)(12). In previous studies, we found that PCDH10 is broadly expressed in normal adults, but almost undetectable in ΜΜ tissues and cell lines due to the promoter methylation of PCDH10.…”

der(11)t(1;11)(q11-23;q14-25)

“…The t(9;22)(q34;q11) was found as an accompanying anomaly in one ALL case. A complex karyotype was present in all lymphoma patients, while the 14q32 rearrangement was found as an accompanying anomaly in 4 out of 6 lymphoma patients (Jerkmen et al, 1999;Qian et al, 1999;Le Baccon et al, 2001;Narayan et al, 2013).…”

“…Chronic lymphocytic leukemia was diagnosed in 2 patients (Qian et al, 1999;Travella et al, 2013), one of them transformed to Non hodgkin's lymphoma (Qian et al, 1999). 5 additional cases were diagnosed with lymphoma (Tien et al, 1997;Jerkeman et al, 1999;Le Baccon et al, 2001;Dave et al, 2002;Narayan et al, 2013). The remaining patients were (1 case each) multiple myeloma (Lim et al, 2013), plasma cell leukemia (Avet-Loiseau et al, 2001), Tprolymphocytic leukemia (Yamaguchi et al, 2003) and aggressive natural killer-cell leukemia (Ryder et al, 2007).…”