Aberrant methylation of the promoter regions of the SOX7 and p15INK4b genes and Wnt signaling pathway antagonists in patients with acute myeloid leukemias

Kostroma, I.; Грицаев, С. В.; Sidorova, Zh Yu; Свитина, С П; Drizhun, Yu S; Чубукина, Ж В; Martynkevich, Irina; Капустин, С И; Бессмельцев, С. С.

doi:10.17116/terarkh201688731-36

Cited by 2 publications

(2 citation statements)

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“…The mutation and aberrant methylation in the promoter region of tumor suppressor genes, oncogenes, transcription factors and drug response genes could influence the gene expression and play important role in the tumorgenesis, tumor progression and response to treatment [20–22]. However, the AKT1 mutation and the methylation profile in its promoter region and their role in breast cancer are still not clear.…”

Section: Introductionmentioning

confidence: 99%

Integrated analysis of promoter mutation, methylation and expression of AKT1 gene in Chinese breast cancer patients

Heng

Guo

et al. 2017

PLoS ONE

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BackgroundAs downstream mediators of PI3K /PTEN /AKT /mTORC1 pathway, the AKT isoforms play critical roles in tumorgenesis. Although the pleiotropic effects of AKT1 in breast cancer have been reported, the genetic and epigenetic characteristics of AKT1 promoter region in breast cancer remains to be identified. In this study we aimed to investigate the promoter mutation spectrum, methylation and gene expression pattern of AKT1 and their relationship with breast cancer.MethodsBy using PCR target sequence enrichment and next-generation sequencing technology, we sequenced AKT1 promoter region in pairs of breast tumor and normal tissues from 95 unselected Chinese breast cancer patients. The methylation of the promoter region and the expression profile of AKT1 in the same cohort were detected with bisulfite next-generation sequencing and qPCR, respectively.ResultsWe identified 28 somatic mutations in 23 of the 95 (24.2%) breast cancer samples. And 19 of the 28 mutations were located in transcription factor (TF) binding sites. In the 23 patients with somatic mutations, no significant change of methylation or expression was found comparing with other patients. AKT1 promoter region was significantly hypo-methylated in tumor compared with matched normal tissue (P = 0.0014) in the 95 patients. The expression of AKT1 was significantly suppressed in tumor tissue (P = 0.0375). In clinicopathological factor analysis, AKT1 showed significant hypo-methylation (P = 0.0249) and suppressed expression (P = 0.0375) in HER2 negative subtype. And a trend of decrease in expression level (P = 0.0624) of AKT1 in the ER negative subtype was observed, which is significantly decreased in basal-like breast tumor (P = 0.0328).ConclusionsHypo-methylation and suppressed expression of AKT1 was observed to be associated with breast cancer in our cohort. The methylation and expression of AKT1 were both significantly associated with HER2 status. The promoter mutation of AKT1 did not show significant association with its methylation and expression status. These results suggested that the promoter mutation, methylation and gene expression of AKT1 may play distinct roles in tumorgenesis of breast cancer and the integrated analysis of methylation and expression of AKT1 might serve as potential biomarkers for diagnosis and classification of breast cancer.

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Section: Introductionmentioning

confidence: 99%

Integrated analysis of promoter mutation, methylation and expression of AKT1 gene in Chinese breast cancer patients

Heng

Guo

et al. 2017

PLoS ONE

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“…In the past few years, numerous studies have indicated that the pathogenesis of AML involves the abnormal activation of Wnt signaling pathway, which has a key role in extensive cellular processes of hematopoietic progenitor proliferation and differentiation. 12 – 14 Wnt signaling pathway comprises the canonical pathway with β-catenin and the non-canonical pathways involving calcium ions and planar cell polarity. 15 – 17 Growing evidence suggests that the Wnt signaling pathway plays an important role in normal HSCs maintenance, whereas nuclear β-catenin is a key molecule that mediates transcriptional activation of specific gene expression and is thought to have the most significance in cancer development.…”

Section: Introductionmentioning

confidence: 99%

Hypermethylation of secreted frizzled-related proteins predicts poor prognosis in non-M3 acute myeloid leukemia

Guo

Zhang²,

Wen

et al. 2017

OTT

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ObjectiveSecreted frizzled-related proteins (SFRPs) as Wnt signaling antagonists have been found to be dysregulated by promoter hypermethylation in several cancers including acute myeloid leukemia (AML). This study aimed to investigate the methylated status of SFRPs promoter region and its clinical relevance in Chinese non-M3 AML patients.MethodsSFRPs methylation in 139 primary non-M3 AML patients was determined using methylation-specific real-time quantitative polymerase chain reaction.ResultsThe frequency of aberrant methylation was as follows: 30.2% for SFRP1, 27.3% for SFRP2, 5.0% for SFRP4, and 1.4% for SFRP5. Hypermethylation of at least one SFRP gene occurred in 51.8% (72/139) of non-M3 AML patient samples, which was significantly higher compared to normal control (0/21) (P<0.001). Hypermethylation of SFRP1 was potentially associated with N/K-RAS mutations (P=0.043), and the frequency of SFRPs methylation was higher in patients ≥50 years compared to those <50 years, especially for SFRP2 (P<0.05). Furthermore, both whole cohort and cytogenetically normal (CN) patients with high SFRPs-methylated group showed a shorter overall survival (OS) compared to those with low group (P=0.036 and P=0.035, respectively). Moreover, Cox regression multivariate analysis revealed that SFRPs hypermethylation acts as an independent prognostic biomarker among both whole cohort (hazard ratio =1.804, P=0.026) and CN (hazard ratio =2.477, P=0.023) patients. In leukemic cell line HL60 treated with 5-aza-2′-deoxycytidine, the alteration of SFRP1/2 expression inversely correlated with change in SFRP1/2 methylation (r=−0.975, P=0.005 and r=−0.975, P=0.005, respectively). A tendency of negative correlation was observed between SFRP1 expression and its promoter methylation in AML patients (r=−0.334, P=0.038).ConclusionThese findings suggested that hypermethylation of SFRP1/2 was a frequent event and silenced SFRP1/2 expression in AML. Moreover, hypermethylation of SFRPs promoter was an adverse risk factor for OS in Chinese non-M3 AML patients.

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Aberrant methylation of the promoter regions of the SOX7 and p15INK4b genes and Wnt signaling pathway antagonists in patients with acute myeloid leukemias

Cited by 2 publications

References 24 publications

Integrated analysis of promoter mutation, methylation and expression of AKT1 gene in Chinese breast cancer patients

Integrated analysis of promoter mutation, methylation and expression of AKT1 gene in Chinese breast cancer patients

Hypermethylation of secreted frizzled-related proteins predicts poor prognosis in non-M3 acute myeloid leukemia

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