Identification and Validation of DNA Methylation Markers to Predict Lymph Node Metastasis of Esophageal Squamous Cell Carcinomas

Gyobu, Ken; Yamashita, Satoshi; Matsuda, Yasunori; Igaki, Hiroyasu; Niwa, Tohru; Oka, Daiji; Kushima, Ryoji; Osugi, Harushi; Lee, Shigeru; Suehiro, Shigefumi

doi:10.1245/s10434-010-1393-5

Cited by 22 publications

(23 citation statements)

References 33 publications

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“…PAX6 was found to influence the fate of some cancer cells, possessing a tumor suppression function [38]. Aberrant DNA methylation of PAX6 is deeply involved in a variety of human carcinomas including ductal breast cancer [11,[24][25][26][27][28][29]. In our work, promoter hypermethylation of PAX6 was detected in 50.0 % of IDCs.…”

Section: Discussionsupporting

confidence: 52%

“…Elongator protein 3 (ELP3) is one candidate TSG whose mRNA level is either low or lost in basal and luminal breast cancers [13], but the real clear functions and molecular interactions of ELP3 gene in breast cancer and its clinical implications have yet to be studied. GATA binding protein 5 (GATA5) and paired box 6 (PAX6), putative TSG, function as transcription factors involved in various developmental processes [16,17], and their aberrant DNA methylation is found in many tumors including breast cancer [11,[18][19][20][21][22][23][24][25][26][27][28][29].…”

Section: Introductionmentioning

confidence: 99%

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Promoter hypermethylation may be an important mechanism of the transcriptional inactivation of ARRDC3, GATA5, and ELP3 in invasive ductal breast carcinoma

Yang

Jin

et al. 2014

Mol Cell Biochem

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Hypermethylation of promoter CpG islands represents an alternative mechanism to inactivate tumor suppressor genes. This study was to detect promoter methylation status and mRNA expression levels of ARRDC3, ELP3, GATA5, and PAX6, and to explore the association between methylation and expression in invasive ductal carcinomas (IDCs) and matched normal tissues (MNTs) from breast cancer patients. Aberrant gene methylation was observed as follows: ARRDC3 in 38.5 %, ELP3 in 73.1 %, GATA5 in 48.1 %, and PAX6 in 50.0 % of IDCs. mRNA expression of ARRDC3, ELP3, and GATA5 in IDCs showed a lower level than that in MNTs (P < 0.001, P = 0.001 and P < 0.001, respectively). For ARRDC3, both methylated and unmethylated IDCs showed significantly lower expression values compared to MNTs (P = 0.001 and P = 0.007, respectively). For ELP3 and GATA5, methylated tumors only showed significantly lower expression values compared to MNTs (P = 0.001 and P < 0.001, respectively). For ARRDC3 and GATA5, methylation was associated with their less fold change in IDCs (P = 0.049 and P = 0.020, respectively). Methylation of ARRDC3 was significantly associated with grades and lymph node status of IDCs (P = 0.036 and P = 0.002, respectively). Methylation frequency of ELP3 was higher in lymph node positive versus lymph node negative tumors (P = 0.020); whereas methylation frequency of PAX6 was lower in tumors with the ER negative samples (P = 0.025). Our data suggested that promoter hypermethylation may be an important mechanism of the transcriptional inactivation of ARRDC3, GATA5, and ELP3 in IDCs.

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Section: Discussionsupporting

confidence: 52%

Section: Introductionmentioning

confidence: 99%

Promoter hypermethylation may be an important mechanism of the transcriptional inactivation of ARRDC3, GATA5, and ELP3 in invasive ductal breast carcinoma

Yang

Jin

et al. 2014

Mol Cell Biochem

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“…In addition, DNA methylation is frequently not restricted to a single CpG island but affects multiple independent loci, which is reflective of a widespread deregulation of DNA methylation pattern in different types of tumors 7,8. However, only a few hypermethylated genes have been identified in ESCC and characterized for their role in ESCC tumorigenesis 9-11 and there is a limited number of studies focusing on prognostic methylation biomarker by genome-wide methylation assay in ESCC 12,13.…”

Section: Introductionmentioning

confidence: 99%

Prognostic CpG Methylation Biomarkers Identified by Methylation Array in Esophageal Squamous Cell Carcinoma Patients

Kuo¹,

Chang²,

Jiang³

et al. 2014

Int. J. Med. Sci.

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Background: Esophageal squamous cell carcinoma (ESCC) is an aggressive cancer with poor prognosis. We aimed to identify a panel of CpG methylation biomarkers for prognosis prediction of ESCC patients.Methods: Illumina's GoldenGate methylation array, supervised principal components, Kaplan-Meier survival analyses and Cox regression model were conducted on dissected tumor tissues from a training cohort of 40 ESCC patients to identify potential CpG methylation biomarkers. Pyrosequencing quantitative methylation assay were performed to validate prognostic CpG methylation biomarkers in 61 ESCC patients. The correlation between DNA methylation and RNA expression of a validated marker, SOX17, was examined in a validation cohort of 61 ESCC patients.Results: We identified a panel of nine CpG methylation probes located at promoter or exon1 region of eight genes including DDIT3, FES, FLT3, NTRK3, SEPT5, SEPT9, SOX1, and SOX17, for prognosis prediction in ESCC patients. Risk score calculated using the eight-gene panel statistically predicted poor outcome for patients with high risk score. These eight-gene also showed a significantly higher methylation level in tumor tissues than their corresponding normal samples in all patients analyzed. In addition, we also detected an inverse correlation between CpG hypermethylation and the mRNA expression level of SOX17 gene in ESCC patients, indicating that DNA hypermethylation was responsible for decreased expression of SOX17.Conclusions: This study established a proof-of-concept CpG methylation biomarker panel for ESCC prognosis that can be further validated by multiple cohort studies. Functional characterization of the eight prognostic methylation genes in our biomarker panel could help to dissect the mechanism of ESCC tumorigenesis.

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“…To isolate genomic regions that were highly likely to be specifically methylated, we selected those with 3 or more flanking probes of consistent values, as previously reported [24,25], and finally isolated 24 genes corresponding to 29 genomic regions. Alternatively, we isolated genomic regions with a higher incidence of methylation but with less chance of validation.…”

Section: Isolation Of Genomic Regions Specifically Methylated In Pancmentioning

confidence: 99%

Pancreatic Cancer Cell Fraction Estimation in a DNA Sample

Ishihara

Yamashita²,

Amano

et al. 2018

Oncology

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Objective: Pancreatic cancers are characterized by dense stroma. To estimate the degree of interference by coexisting noncancer cells in molecular analyses, we aimed to develop a DNA methylation marker that assesses a cancer cell fraction in DNA samples. Methods: The microarray data of 22 pancreatic cancer tissues from the The Cancer Genome Atlas database and 9 noncancer tissues were used for genome-wide screening. Thirty-one surgical tumor samples (10 intraductal papillary mucinous neoplasms [IPMNs] and 21 pancreatic cancers), 4 normal, and 26 nontumor samples were used for validation. Gene-specific methylation analysis was conducted by bisulfite pyrosequencing. Results: Genome-wide screening isolated SIM1, MIR129-2, NR1I2, and HOXB-AS4, as specifically methylated in pancreatic cancer cells. Bisulfite pyrosequencing validated that one or more of three genes (SIM1, MIR129-2, and NR1I2) were methylated in 22 (71.0%) tumor samples (8 IPMNs and 14 cancers), and all showed low levels of methylation in 26 (86.7%) normal and nontumor samples. Therefore, the three genes collectively constituted one marker for a pancreatic cancer cell fraction. The cancer cell fraction estimated by the marker was highly correlated with that estimated using the KRAS mutant allele frequency (R = 0.79). Conclusion: The DNA methylation marker is useful to estimate the pancreatic cancer cell fraction in DNA samples.

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Identification and Validation of DNA Methylation Markers to Predict Lymph Node Metastasis of Esophageal Squamous Cell Carcinomas

Abstract: Methylation statuses of these 2 CGIs were significantly associated with the presence of lymph node metastasis of ESCCs. These CGIs are promising markers to predict the presence of lymph node metastases.

Cited by 22 publications

References 33 publications

Promoter hypermethylation may be an important mechanism of the transcriptional inactivation of ARRDC3, GATA5, and ELP3 in invasive ductal breast carcinoma

Promoter hypermethylation may be an important mechanism of the transcriptional inactivation of ARRDC3, GATA5, and ELP3 in invasive ductal breast carcinoma

Prognostic CpG Methylation Biomarkers Identified by Methylation Array in Esophageal Squamous Cell Carcinoma Patients

Pancreatic Cancer Cell Fraction Estimation in a DNA Sample

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