Aberrant methylation of protocadherin 17 and its prognostic value in pediatric acute lymphoblastic leukemia

Abstract

Background The outcome of approximately 20% of patients with acute lymphoblastic leukemia (ALL) remains poor because of disease recurrence. We examined whether DNA methylation of cadherin superfamily genes is a useful biomarker for ALL relapse. Procedure We used Infinium Methylation 450K Arrays to assess genome‐wide DNA methylation status. The methylation status of each individual gene was then determined by a combination of bisulfite restriction analysis and genome bisulfite sequencing. mRNA expression was evaluated by reverse‐transcriptase PCR (RT‐PCR) and quantitative real‐time PCR. Results Cadherin superfamily genes including cadherin (CDH) 1, protocadherin (PCDH) 8, and PCDH17 were selected for analysis of methylation status. In 40 patient samples with B‐cell precursor (BCP) ALL at diagnosis, the methylation frequencies of CDH1, PCDH8, and PCDH17 were 62.5, 55, and 30%, respectively. CDH1 and PCDH8 methylation was also detected in 80 and 20% of control bone marrow (BM) samples, respectively. On the contrary, PCDH17 was unmethylated in all control BM samples. There was a significant correlation between the methylation status of PCDH17 (but not CDH1 and PCDH8) and event‐free survival or overall survival. Univariate and multivariate analyses showed that only PCDH17 methylation was associated with an increased risk for relapse and mortality in patients with BCP ALL. Conclusion PCDH17 methylation at diagnosis was closely related to poor prognosis and thus could be used as a new biomarker to predict relapse in patients with BCP ALL.

Protocadherins at the Crossroad of Signaling Pathways

“…Moreover, a vast array of studies has identified individual PCDH downregulation due to promoter hypermethylation or somatic aberrations (see Table 2). The most frequently reported phenotypes resulting from loss of PCDH expression are increased proliferation and Costa et al, 2011;Lin et al, 2014a; Blood PH c GA12, GB7 Shi et al, 2007;Taylor et al, 2007nc 8, 10, 17 Ying et al, 2007Leshchenko et al, 2010;Narayan et al, 2011;Li et al, 2012b;Uyen et al, 2017 Brain PH c A8, A13, GC4, GA11 Waha et al, 2005;Abe et al, 2008; The clustered (c) and non-clustered (nc) PCDHs are grouped.…”

Aberrant promoter methylation of PCDH10 as a potential diagnostic and prognostic biomarker for patients with breast cancer

“…In addition, promoter methylation has been indicated to trigger inactivation of PCDH-17/20 in various types of cancer. Therefore, aberrant promoter methylation may be a competent diagnostic and prognostic biomarker for cancer ( 55 – 57 ).…”

Frequent promoter methylation of HOXD10 in endometrial carcinoma and its pathological significance

“…Hypermethylation of promoters of a number of TSGs, such as EGF-containing fibulin extracellular matrix protein 1, glutathione S-transferase P1, suppressor of cytokine signaling 3, 3OST2, basic helix-loop-helix family member E22/cysteine deoxygenase 1/CUGBP Elva-like family member 4, SHP1 and transmembrane protein with EGF-like and two follistatin-like domains 2, have been studied in certain EC tissues and cell lines (such as Ishikawa and KLE) and the methylation frequency is high (26)(27)(28)(29)(30)(31). The present study investigated five TSGs (HOXD10, SHH, ZNF545, PCDH17 and MEIS1) whose promoters are reported to be hypermethylated in other malignancies but have not been evaluated for methylation in EC (32)(33)(34)(35)(36)(37)(38)(39)(40). For example, HOXD10 is hypermethylated and lowly expressed in colon adenocarcinoma cells, which downregulates the RHOC/AKT/MAPK pathway to enhance apoptosis and restrict the proliferation, migration and invasion of colon adenocarcinoma (32,33).…”

“…ZNF545 functions as a tumor suppressor in colorectal cancer and is frequently inactivated by promoter methylation (36,37). Hypermethylation of PCDH17 is correlated to poor prognosis in acute lymphoblastic leukemia (38,39). MEIS1 genes are frequently hypermethylated in different types of leukemia (40).…”