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| Entity | Various cancers |
| Note | The gene codes for the putative tumor suppressor BLU is primarily expressed in the lung and testis, as tissue-specific isoforms, but the level is low in other tissues. The expression is varied in lung cancer cells, but a non-small lung cancer line, A549 has high level of BLU. A majority of nasopharyngeal carcinoma-derived cell lines, however, has downregulated expression of BLU. Mutation of the gene is relatively rare. Hypermethylation on BLU promoter has been detected ranging from 19% of primary non-small cell lung cancer to 66-74% of nasopharyngeal carcinoma (NPC). |
| Disease | Mutated BLU/ZMYND10 protein with several amino acid residues substitution has been shown to associate with LRRC6, and plays a role in the pathogenesis of primary ciliary dyskinesia. Hypermethylation and downregulation has been described as a frequent event in primary tumours such as glioma (80%), cervical squamous cell carcinomas (77%), NPC (66%), neuroblastoma (41-70%) and NSCLC (19-43%) with lower frequencies observed in gallbladder carcinomas (26%), ependymomas (13.6%) and SCLC (14%). It has been noted that in some tumors like glioma, methylation of BLU is an early detectable event; it was identified in stage II glioma and stage I/II cervical squamous cell carcinomas. |
| Cytogenetics | Unlike t(8;21) translocation frequently seen in acute myelogenous leukemia, involving ZMYND motif containing MTG8, no cytogenetic anomaly affecting BLU has been observed in malignancies. |
| Hybrid/Mutated Gene | No fusion gene(s) involving BLU has been reported. |
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| Entity | Lung cancer |
| Note | BLU is primarily expressed in lung and testis, with different isoforms. The mutation is rare. The expression is absent in a number of lung cancer cell lines, and in 19-43% of non-small lung cancer (NSLC) cases, BLU is silenced due to promoter hypermethylation (Agathanggelou et al., 2003; Marsit et al., 2005). The incidence is higher in adenocarcinoma (AC) than in squamous cell carcinoma (SCC). Frequent methylation for BLU and RASSF1 has been observed but there is no significant association. In lung cancer patients, homozygous deletion of 3p21 region has been association with early age of cigarette smoking initiation. |
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| Entity | Nasopharyngeal carcinoma (NPC) |
| Note | Downregulation of BLU expression was well correlated with the promoter hypermethylation in tumor specimens and cultured cell lines. Methylation on BLU promoter was identified in up to 66% of the tumors, and 6 out 7 passaged cell lines. BLU was observed to inhibit JNK signaling pathway, and cyclin D1 (CCND1) gene promoter activity, arrest cell cycle at G1 phase, and block in vitro and in vivo NPC cell growth. |
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| Entity | Glioma |
| Note | BLU/ZMYND10 hypermethylation and downregulation has been described as a frequent event in up to 80% primary tumours of glioma. BLU/ZMYND10 methylation is an early event detectable in stage II glioma (Hesson et al., 2004). In glioma tumours methylation of BLU/ZMYND10 and/or RASSF1A, located adjacent to BLU/ZMYND10, was detected in more than 95% (52/54) primary tumours. |
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| Entity | Neuroblastoma |
| Note | Methylation leading to downregulation of BLU has been described in up to 70% neuroblastoma (41-70%) (Abe et al., 2005). It was shown that methylation of promoter CGIs of RASSF1A (3p21) and BLU (3p21) was far more frequently observed in neuroblastomas with CpG island methylator phenotype (CIMP). |
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| Entity | Esophageal cancer |
| Note | In esophageal squamous cell carcinoma (ESCC), BLU expression was downregulated in three out of four Asian esophageal carcinoma cell lines, and 4 out of 8 pairs of tumor and normal tissues. Methylation specific-PCR revealed the down-regulation of BLU by epigenetic inactivation. However, exogenous expression of BLU did not functionally suppress tumorigenicity in nude mice. These results suggest that over-expression of BLU alone is not sufficient to inhibit tumorigenicity. (Yi Lo et al., 2006). |
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| Entity | Ovarian carcinoma |
| Note | Epithelial ovarian carcinoma is usually present at the advanced stage, during which the patients generally have poor prognosis. Our study aimed to evaluate the correlation of gene methylation and the clinical outcome of patients with advanced-stage, high-grade ovarian serous carcinoma. The methylation status of eight candidate genes was first evaluated by methylation-specific PCR and capillary electrophoresis to select three potential genes including DAPK, CDH1, and BLU (ZMYND10) from the exercise group of 40 patients. The methylation status of these three genes was further investigated in the validation group consisting of 136 patients. Patients with methylated BLU had significantly shorter progression-free survival (PFS; hazard ratio (HR) 1.48, 95% CI 1.01-2.56, P=0.013) and overall survival (OS; HR 1.83, 95% CI 1.07-3.11, P=0.027) in the multivariate analysis. Methylation of BLU was also an independent risk factor for 58 patients undergoing optimal debulking surgery for PFS (HR 2.37, 95% CI 1.03-5.42, P=0.043) and OS (HR 3.96, 95% CI 1.45-10.81, P=0.007) in the multivariate analysis. A possible mechanism of BLU in chemoresistance was investigated in ovarian cancer cell lines by in vitro apoptotic assays. In vitro studies have shown that BLU could upregulate the expression of BAX and enhance the effect of paclitaxel-induced apoptosis in ovarian cancer cells. Our study suggested that methylation of BLU could be a potential prognostic biomarker for advanced ovarian serous carcinoma. |
| Prognosis | Its correlation with prognosis of serous ovarian carcinoma has been documented. The methylation status of eight candidate genes, including BLU was first evaluated by methylation-specific PCR and capillary electrophoresis from tumor tissues of ovarian carcinoma in a group of patients. Patients with methylated BLU had significantly shorter progression-free survival and overall survival in the multivariate analysis (Chiang et al., 2013). |
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| Entity | Myelodysplastic syndrome (MDS) |
| Note | Hypermethylation in the promoter region and downregulation at mRNA and protein levels of BLU was detected in 34 of 79 (43%) MDS patient samples. There was a statistically significant difference in methylation frequency between different refractory anemia groups. The demethylating agent decitabine could partly reverse hypermethylation and restore the expression of the BLU gene. BLU promoter hypermethylation frequently occurs in higher risk MDS cases. BLU may play a role in the development and etiology of MDS. |
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| Entity | Primary ciliary dyskinesia (PCD) |
| Note | ZMYND10 bound to LRRC6 in HEK293T and in human tracheal epithelial cells. These two proteins localized to both the basal body and the striated rootlet in Xenopus ciliated epithelial cells. The C-terminal MYND domain of ZMYND10 was insufficient for interaction with the CS domain of LRRC6; but a C-terminal fragment expanding 366-440 amino acids extending beyond the MYND domain was necessary for interaction (see the scheme of protein diagram). Similar studies using progressive truncating constructs of LRRC6 confirmed that the C-terminal CS domain of LRRC6 is sufficient for the binding with ZMYND10. The protein-protein interaction is abrogated by truncating mutations in either gene in patients with CILD. |
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