| RRC ID |
58065
|
| Author |
Iwabu J, Yamashita S, Takeshima H, Kishino T, Takahashi T, Oda I, Koyanagi K, Igaki H, Tachimori Y, Daiko H, Nakazato H, Nishiyama K, Lee YC, Hanazaki K, Ushijima T.
|
| Title |
FGF5 methylation is a sensitivity marker of esophageal squamous cell carcinoma to definitive chemoradiotherapy.
|
| Journal |
Sci Rep
|
| Abstract |
Definitive chemoradiotherapy (dCRT) is the major treatment for esophageal squamous cell carcinoma (ESCC), and prediction of the response to dCRT is important so as not to miss an opportunity to cure an ESCC. Nevertheless, few validated markers are available. Here, we aimed to identify a highly reproducible marker using multi-layer omics analysis. 117 ESCC samples from 67 responders and 50 non-responders were divided into screening, validation, and re-validation sets. In the screening cohort (n = 41), somatic mutations in 114 genes showed no association with dCRT response. Genome-wide DNA methylation analysis using Infinium HumanMethylation450 BeadChip array identified four genic regions significantly associated with dCRT response. Among them, FGF5 methylation was validated to be associated with dCRT response (n = 34; P = 0.001), and further re-validated (n = 42; P = 0.020) by bisulfite-pyrosequencing. The sensitivity and specificity in the combined validation and re-validation sets (n = 76) were 45% and 90%, respectively, by using the cut-off value established in the screening set, and FGF5 methylation had predictive power independent from clinicopathological parameters. In ESCC cell lines, FGF5 promoter methylation repressed its expression. FGF5 expression was induced by cisplatin (CDDP) treatment in three unmethylated cell lines, but not in two methylated cell lines. Exogenous FGF5 overexpression in a cell line with its methylation conferred resistance to CDDP. In non-cancerous esophageal tissues, FGF5 was not expressed, and its methylation was present in a small fraction of cells. These results showed that FGF5 methylation is a validated marker for ESCC sensitivity to dCRT.
|
| Volume |
9(1)
|
| Pages |
13347
|
| Published |
2019-9-16
|
| DOI |
10.1038/s41598-019-50005-6
|
| PII |
10.1038/s41598-019-50005-6
|
| PMID |
31527639
|
| PMC |
PMC6746740
|
| MeSH |
Biomarkers, Tumor / genetics
Cell Line, Tumor
Chemoradiotherapy
DNA Methylation / genetics*
Drug Resistance, Neoplasm / genetics*
Esophageal Mucosa / cytology
Esophageal Neoplasms / genetics*
Esophageal Neoplasms / pathology
Esophageal Neoplasms / therapy
Esophageal Squamous Cell Carcinoma / genetics*
Esophageal Squamous Cell Carcinoma / pathology
Esophageal Squamous Cell Carcinoma / therapy
Female
Fibroblast Growth Factor 5 / genetics*
Humans
Male
Middle Aged
Promoter Regions, Genetic / genetics
Radiation Tolerance / genetics*
Treatment Outcome
|
| IF |
3.998
|
| Times Cited |
0
|
| Resource |
| Human and Animal Cells |
TE-15(RCB1951) |
