Clinical prognostic value of DNA methylation in hepatoblastoma: Four novel tumor suppressor candidates

Abstract

Hepatoblastoma (HB) is very rare but the most common malignant neoplasm of the liver occurring in children. Despite improvements in therapy, outcomes for patients with advanced HB that is refractory to standard preoperative chemotherapy remain unsatisfactory. To improve the survival rate among this group, identification of novel prognostic markers and therapeutic targets is needed. We have previously reported that altered DNA methylation patterns are of biological and clinical importance in HB. In the present study, using genome‐wide methylation analysis and bisulfite pyrosequencing with specimens from HB tumors, we detected nine methylated genes. We then focused on four of those genes, GPR180,MST1R,OCIAD2, and PARP6, because they likely encode tumor suppressors and their increase of methylation was associated with a poor prognosis. The methylation status of the four genes was also associated with age at diagnosis, and significant association with the presence of metastatic tumors was seen in three of the four genes. Multivariate analysis revealed that the presence of metastatic tumors and increase of methylation of GPR180 were independent prognostic factors affecting event‐free survival. These findings indicate that the four novel tumor suppressor candidates are potentially useful molecular markers predictive of a poor outcome in HB patients, which may serve as the basis for improved therapeutic strategies when clinical trials are carried out.

High expression of ovarian cancer immunoreactive antigen domain containing 2 (OCIAD2) is associated with poor prognosis in lung adenocarcinoma

“…14,15 On the other hand, two studies have found that low expression of OCIAD2 was correlated with poorer outcome in patients with hepatocellular carcinoma and hepatoblastoma. 16,17 These findings overall suggest that the association between the expression level of OCIAD2 and prognosis might vary among tumors originating from different organs.…”

“…To date, only three reports have indicated that high OCIAD2 expression is associated with poorer prognosis in patients with ovarian mucinous tumor and glioma . On the other hand, two studies have found that low expression of OCIAD2 was correlated with poorer outcome in patients with hepatocellular carcinoma and hepatoblastoma . These findings overall suggest that the association between the expression level of OCIAD2 and prognosis might vary among tumors originating from different organs.…”

Integrated Genomic Characterization of Pancreatic Ductal Adenocarcinoma

“…Notable genes include: ZFP82 , which is epigenetically silenced and suspected to function as a tumor suppressor (Xiao et al, 2014) (Yu et al, 2015) (Fan et al, 2016); PARP6 hypermethylation (Honda et al, 2016) (Qi et al, 2016); DNAJC15, which is hypermethylated in a number of tumor types (Ehrlich et al, 2002; Lindsey et al, 2006), and whose inactivation has been associated with chemotherapeutic drug resistance in breast (Fernandez-Cabezudo et al, 2016) and ovarian cancers (Rein et al, 2011). We also identified genes that were epigenetically silenced at low prevalence through manual examination of the genes known to be important in cancer, including BRCA1 and MGMT (each silenced in one case).…”

Gene expression profiling in hepatoblastoma cases of the Japanese Study Group for Pediatric Liver Tumors-2 (JPLT-2) trial

“…In the comparison between standard-and intermediate-risk tumors, the downregulation of genes involved in the SIBLING signaling pathway indicated that inhibition of tissue differentiation may be associated with local tumor infiltration. As tissue differentiation is regulated by epigenetic modifications, HBL development and progression may also be related to epigenetic regulation [24,25]. The gene expression profiles of the HBL progression or relapse cases showed upregulation of four genes: AFP, SPINK1, PGC, and NQO1.…”