Esophageal Cancer
Copyright ©2005 Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Mar 7, 2005; 11(9): 1267-1272
Published online Mar 7, 2005. doi: 10.3748/wjg.v11.i9.1267
Copy number changes of target genes in chromosome 3q25.3-qter of esophageal squamous cell carcinoma: TP63 is amplified in early carcinogenesis but down-regulated as disease progressed
Chueh-Chuan Yen, Yann-Jang Chen, Chin-Chen Pan, Kai-Hsi Lu, Paul Chih-Hsueh Chen, Jiun-Yi Hsia, Jung-Ta Chen, Yu-Chung Wu, Wen-Hu Hsu, Liang-Shun Wang, Min-Hsiung Huang, Biing-Shiung Huang, Cheng-Po Hu, Po-Min Chen, Chi-Hung Lin
Chueh-Chuan Yen, Po-Min Chen, Division of Medical Oncology, Department of Medicine, Taipei Veterans General Hospital and National Yang-Ming University School of Medicine, Taipei, Taiwan, China
Yann-Jang Chen, Faculty of Life Science, National Yang-Ming University, Taipei, Taiwan, China
Chin-Chen Pan, Paul Chih-Hsueh Chen, Department of Pathology, National Yang-Ming University and Taipei Veterans General Hospital, Taiwan, China
Kai-Hsi Lu, Institute of Microbiology and Immunology, National Yang-Ming University, Taipei, Taiwan, China
Jiun-Yi Hsia, Division of Thoracic Surgery, Department of Surgery, Taichung Veterans General Hospital, Taichung, Taiwan, China
Jung-Ta Chen, Department of Pathology, Taichung Veterans General Hospital, and Department of Pathology, Chung-Shan Medical University, Taichung, Taiwan, China
Yu-Chung Wu, Wen-Hu Hsu, Liang-Shun Wang, Min-Hsiung Huang, Biing-Shiung Huang, Division of Thoracic Surgery, Department of Surgery, Taipei Veterans General Hospital and National Yang-Ming University, Taipei, Taiwan, China
Cheng-Po Hu, Institute of Microbiology and Immunology, National Yang-Ming University, and Department of Medical Research and Education, Taipei Veterans General Hospital, Taipei, Taiwan, China
Chi-Hung Lin, Institute of Microbiology and Immunology, and Institute of Biophotonics, National Yang-Ming University, Taipei, Taiwan, China
Author contributions: All authors contributed equally to the work.
Supported by the National Microarray and Gene Expression Analysis Core Facility of the National Research Program for Genomic Medicine at National Yang-Ming University (http://www.ym.edu.tw/microarray), and annual project Grant From National Science Council (Grant NO. NSC 92-2314-B-075-055), Taiwan, China
Correspondence to: Dr. Chi-Hung Lin, Institute of Microbiology and Immunology, National Yang-Ming University, NO. 155, Li-Non St., Section 2, Taipei 112, Taiwan, China. linch@ym.edu.tw
Telephone: +886-2-28267219 Fax: +886-2-28212880
Received: September 29, 2004
Revised: October 1, 2004
Accepted: October 18, 2004
Published online: March 7, 2005
Abstract

AIM: By using comparative genomic hybridization, gain of 3q was found in 45-86% cases of esophageal squamous cell carcinoma (EC-SCC). Chromosome 3q25.3-qter is the minimal common region with several oncogenes found within this region. However, amplification patterns of these genes in EC-SCC have never been reported. The possible association of copy number changes of these genes with pathologic characteristics is still not clear.

METHODS: Real-time quantitative PCR (Q-PCR) was performed to analyze the copy number changes of 13 candidate genes within this region in 60 primary tumors of EC-SCC, and possible association of copy number changes with pathologic characteristics was analyzed by statistics. Immunohistochemistry (IHC) study was also performed on another set of 111 primary tumors of EC-SCC to verify the association between TP63 expression change and lymph node metastasis status.

RESULTS: The average copy numbers (±SE) per haploid genome of individual genes in 60 samples were (from centromere to telomere): SSR3: 4.19 (±0.69); CCNL1: 5.24 (±0.67); SMC4L1: 2.01 (±0.16); EVI1: 2.02 (±0.12); hTERC: 5.28 (±0.54); SKIL: 2.71 (±0.14); EIF5A2: 1.95 (±0.12); ECT2: 9.18 (±1.68); PIK3CA: 8.13 (±1.17); EIF4G1: 1.07 (±0.05); SST: 3.07 (±0.25); TP63: 2.51 (±0.22); TFRC: 2.42 (±0.19). Four clusters of amplification were found: SSR3 and CCLN1 at 3q25.31; hTERC and SKIL at 3q26.2; ECT2 and PIK3CA at 3q26.31-q26.32; and SST, TP63 and TFRC at 3q27.3-q29. Patients with lymph node metastasis had significantly lower copy number of TP63 in the primary tumor than those without lymph node metastasis. IHC study on tissue arrays also showed that patients with lymph node metastasis have significantly lower TP63 staining score in the primary tumor than those without lymph node metastasis.

CONCLUSION: This study showed that different amplification patterns were seen among different genes within 3q25.3-qter in EC-SCC, and several novel candidate oncogenes (SSR3, SMC4L1, ECT2, and SST) were identified. TP63 is amplified in early stage of EC-SCC carcinogenesis but down-regulated in advanced stage of disease.

Keywords: Chromosomal aberration, Comparative genomic hybridization, Esophageal neoplasm, Immunohistochemistry, Quantitative real-time PCR, Tissue array, Tumor protein 63