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FGF5 methylation is a sensitivity marker of esophageal squamous cell carcinoma to definitive chemoradiotherapy.

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.

SUBMITTER: Iwabu J

PROVIDER: S-EPMC6746740 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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FGF5 methylation is a sensitivity marker of esophageal squamous cell carcinoma to definitive chemoradiotherapy.

Iwabu Jun J Yamashita Satoshi S Takeshima Hideyuki H Kishino Takayoshi T Takahashi Takamasa T Oda Ichiro I Koyanagi Kazuo K Igaki Hiroyasu H Tachimori Yuji Y Daiko Hiroyuki H Nakazato Hidetsugu H Nishiyama Kazuhiro K Lee Yi-Chia YC Hanazaki Kazuhiro K Ushijima Toshikazu T

Scientific reports 20190916 1

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 = ...[more]

PMID: 31527639

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Project description:BackgroundThe objective of this study was to investigate the relationship between clinical characteristics, as well as dosimetric parameters, and the risk of treatment-related lymphopenia in esophageal squamous cell carcinoma (ESCC) treated with definitive chemoradiotherapy (CRT).Materials and methodsClinical characteristics and dosimetric parameters were collected from 436 patients with ESCC who received definitive CRT from 2010 through 2017. Absolute lymphocyte counts (ALCs) were obtained before, during, and 1 month after CRT. Grade 4 (G4) lymphopenia was defined as ALC <0.2 × 109 /L during CRT. Logistic regression analysis was used to evaluate the effect of each factor on predicting G4 lymphopenia. The relationship between lymphopenia and overall survival (OS) was examined, and a nomogram was developed to predict OS.ResultsG4 lymphopenia was observed in 103 patients (23.6%) during CRT. Multivariate analysis indicated that planning target volume (PTV), lung V10 , heart V10 , performance status, and pretreatment lymphopenia were significant risk factors for G4 lymphopenia. Patients with G4 lymphopenia had significantly worse survival than those without. Based on multivariate analysis, clinical TNM stage, radiotherapy modality, pretreatment ALC, and G4 lymphopenia were predictive of OS and were incorporated into the nomogram, yielding a concordance index of 0.71.ConclusionsG4 lymphopenia during definitive CRT was associated with larger PTVs, higher lung V10 and heart V10 , and worse survival.Implications for practiceThe purpose of this study was to investigate the relationship between clinical characteristics, as well as dosimetric parameters, and the risk of treatment-related lymphopenia in 436 patients with esophageal squamous cell carcinoma who received definitive chemoradiotherapy. Grade 4 (G4) lymphopenia was observed in 23.6% of patients during radiotherapy. G4 lymphopenia was associated with larger planning target volumes, higher lung V10 and heart V10 , and worse survival. Then, a nomogram was built based on multivariate analysis, yielding excellent performance to predict overall survival. Prospective studies are needed to investigate potential approaches for mitigating severe lymphopenia, which may ultimately convert into survival benefits.

Dataset Information

FGF5 methylation is a sensitivity marker of esophageal squamous cell carcinoma to definitive chemoradiotherapy.

Publications

FGF5 methylation is a sensitivity marker of esophageal squamous cell carcinoma to definitive chemoradiotherapy.

Similar Datasets

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