A six-CpG panel with DNA methylation biomarkers predicting treatment response of chemoradiation in esophageal squamous cell carcinoma.
BACKGROUND
Prognosis of esophageal squamous cell carcinoma (ESCC) patients remains poor, and the chemoradiotherapy (CRT) applied to ESCC patients often failed. Therefore, development of biomarkers to predict CRT response is immensely important for choosing the best treatment strategy of an individual patient.


METHODS
The methylation array and pyrosequencing methylation assay were performed in pre-treatment endoscopic biopsies to identify probes with differential CpG methylation levels between good and poor CRT responders in a cohort of 12 ESCC patients. Receiver operating characteristic curves and multivariate logistic regressions were conducted to build the risk score equation of selected CpG probes in another cohort of 91 ESCC patients to predict CRT response. Kaplan-Meier analysis was used to estimate progression-free survival or time-to-progression of patients predicted with good and poor CRT responses.


RESULTS
Nine differentially methylated CpG probes were identified to be associated with CRT response. A risk score equation comprising six CpG probes located in IFNGR2, KCNK4, NOTCH4, NPY, PAX6, and SOX17 genes were built. The risk score was derived from the sum of each probe multiplied by its corresponding coefficient. Such a risk score has a good prediction performance in discriminating poor CRT responders from good responders (AUC: 0.930). Moreover, poor CRT responders predicted by risk score significantly had poorer prognosis in terms of shorter progression-free survival and time-to-progression (p = 0.004-0.008).


CONCLUSIONS
We established a proof-of-concept CRT response prediction panel consisting of six-CpG methylation biomarkers in identifying ESCC patients who are at high risk of CRT failure and need intensive care.
Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, 701, Taiwan.
Wei-Lun
WL
Chang
Department of Surgery, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, 701, Taiwan.
Wu-Wei
WW
Lai
Department of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, 701, Taiwan.
I-Ying
IY
Kuo
Department of Pharmacology, College of Medicine, National Cheng Kung University, Tainan, 701, Taiwan.
Chien-Yu
CY
Lin
Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, 701, Taiwan.
Pei-Jung
PJ
Lu
Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, 701, Taiwan. sheubs@mail.ncku.edu.tw.|Department of Internal Medicine, Tainan Hospital, Ministry of Health and Welfare, Tainan, 700, Taiwan. sheubs@mail.ncku.edu.tw.
Bor-Shyang
BS
Sheu
Department of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, 701, Taiwan. ycw5798@mail.ncku.edu.tw.|Department of Pharmacology, College of Medicine, National Cheng Kung University, Tainan, 701, Taiwan. ycw5798@mail.ncku.edu.tw.
Yi-Ching
http://orcid.org/0000-0002-7694-2067
YC
Wang
D014408:Biomarkers, Tumor / Q000235:genetics; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000628:therapy*; D059248:Chemoradiotherapy / Q000379:methods*; D015331:Cohort Studies; D018899:CpG Islands / Q000235:genetics*; D019175:DNA Methylation / Q000235:genetics*; D018572:Disease-Free Survival; D004938:Esophageal Neoplasms / Q000235:genetics / Q000628:therapy*; D000077277:Esophageal Squamous Cell Carcinoma; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D016896:Treatment Outcome
D014408:Biomarkers, Tumor
Chemoradiotherapy; CpG methylation biomarker; Endoscopic ultrasonography; Esophageal squamous cell carcinoma; Prognosis
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