Cohypermethylation of p14 in combination with CADM1 or DCC as a recurrence‐related prognostic indicator in stage I esophageal squamous cell carcinoma

• Published in: Cancer Vol. 119; no. 9; pp. 1752 - 1760
• Main Authors: Lee, Eunju, Lee, Bo Bin, Ko, Eunkyung, Kim, Yujin, Han, Jungho, Shim, Young Mog, Park, Joobae, Kim, Duk‐Hwan
• Format: Journal Article
• Language: English
• Published: Hoboken Wiley Subscription Services, Inc., A Wiley Company 01.05.2013; Wiley-Blackwell
• Subjects: Aged; Biological and medical sciences; Carcinoma, Squamous Cell - genetics; Carcinoma, Squamous Cell - pathology; Cell Adhesion Molecule-1; Cell Adhesion Molecules - genetics; DCC; DCC Receptor; DNA Methylation; esophageal cancer; Esophageal Neoplasms - genetics; Esophageal Neoplasms - pathology; Esophagus; Female; Gastroenterology. Liver. Pancreas. Abdomen; Humans; hypermethylation; Immunoglobulins - genetics; Immunohistochemistry; Male; Medical sciences; Middle Aged; Multiple tumors. Solid tumors. Tumors in childhood (general aspects); Neoplasm Recurrence, Local; p14; Polymerase Chain Reaction; Prognosis; Receptors, Cell Surface - genetics; recurrence; Retrospective Studies; Tumor Suppressor Protein p14ARF - genetics; Tumor Suppressor Proteins - genetics; Tumors; Drug combination; Relapse; Prognosis; esophageal cancer; DCC; Esophageal disease; Esophagus squamous cell carcinoma; hypermethylation; Early stage; Malignant tumor; Esophagus cancer; CDKN2 gene; Indicator; recurrence; p14; Cancerology; Digestive diseases; Methylation; Cancer; Tumor suppressor gene
• ISSN: 0008-543X; 1097-0142
• DOI: 10.1002/cncr.27948

BACKGROUND: The objective of this study was to discover molecular biomarkers associated with the recurrence of esophageal squamous cell carcinoma (ESCC). METHODS: The authors retrospectively analyzed the hypermethylation status of 11 genes using methylation‐specific polymerase chain reaction (PCR) and the expression of epidermal growth factor receptor (EGFR), O‐6 methylguanine‐DNA methyltransferase (MGMT), tumor protein 53 (p53), and transforming growth factor β (TGFβ) using immunohistochemistry in 329 formalin‐fixed, paraffin‐embedded ESCCs. RESULTS: Recurrence was identified in 151 of 329 ESCCs (46%) at a median follow‐up of 4.5 years. The recurrence was associated with hypermethylation of the genes cell adhesion molecule 1 (CADM1) (P = .003), deleted in colon carcinoma (DCC) (P = .04), or cyclin‐dependent kinase inhibitor 2A (p14) (P = .02) in patients with stage I ESCC. Thirty‐six of 37 Stage I ESCCs (97%) that had cohypermethylation of at least 2 of the 3 genes had hypermethylation of p14 plus either CADM1 or DCC or both CADM1 and DCC. The 5‐year recurrence‐free survival (RFS) rates were 93% in patients who had stage I disease without hypermethylation of the 3 genes and 56% in those who had cohypermethylation of p14 in combination with CADM1 and/or DCC. Patients who had stage I ESCC with cohypermethylation of p14 in combination with DCC and/or CADM1 had 7.13 times (95% confidence interval, 1.61‐31.64 times; P = .009) poorer RFS compared with those who had no hypermethylation of the 3 genes after adjusting confounding factors. Hypermethylation of the other 8 genes and altered expression of 4 proteins were not associated with recurrence across pathologic stages. CONCLUSIONS: The current results suggested that cohypermethylation of p14 in combination with DCC and/or CADM1 may be an independent prognostic factor for recurrence in patients with stage I ESCC. Cancer 2013. © 2013 American Cancer Society. Despite significant advances in the detection and treatment of esophageal cancer, the prognosis for patients with the disease is very poor, which results in part from the high rate of recurrence. This study indicates that the analysis of methylation statuses of the genes cyclin‐dependent kinase inhibitor 2A (p14), cell adhesion molecule 1 (CADM1), and deleted in colon carcinoma (DCC) in patients with stage I esophageal squamous cell carcinoma will allow the identification of patients who are at high risk of recurrence after esophagectomy.