We have previously cloned and identified a novel esophageal cancer related gene 2 (ECRG2; GenBank Accession Number AF268198), which is down-regulated in esophageal squamous cell carcinoma (ESCC) and involved in the induction of the apoptosis in esophageal cancer cell lines. In the present study, we have found a short tandem repeat (STR) polymorphism in the noncoding region of the exon 4 of the ECRG2 gene by using PCR-denaturing high-performance liquid chromatography (DHPLC Esophageal cancer, with a 5-year survival rate Ͻ10%, is one of the most common fetal cancers worldwide and occurs at very high frequencies in certain areas of China, Iran, South Africa, Uruguay, France and Italy. 1 Fifty percent of esophageal cancer cases in the world occur in China. Among high-risk areas of esophageal squamous cell carcinoma (ESCC), Linxian County in Henan Province has the highest age-adjusted mortality rate of this cancer. 2 Epidemiological studies have revealed that the incidence of ESCC is associated with several factors, such as N-nitrosamines, which have been shown to be involved in the etiology of ESCC in Linxian. 3 However, studies in high-risk areas have demonstrated a strong tendency towards familial aggregation or clustering of cases within families, suggesting that genetic susceptibility factors may also play an important role in the etiology of ESCC.Previous studies have shown that several genetic abnormalities including amplification of C-myc, Int-2 and Hst, 4,5 mutation and/or deletion of p53 and Rb 2 and allelic deletion 6 have frequently occurred in human ESCC and esophageal cancer cell lines. However, the genetic events that lead to the development of esophageal cancer are not clear yet. In recent years, many studies of esophageal cancer are focused on the cloning and identification of novel esophageal cancer-related genes, which might play an important role in the carcinogenesis and development of the cancer. [7][8][9] Recently, we have cloned and identified a novel ESCC-related gene, ECRG2 (Genbank Accession Number AF 268198), from human normal esophageal epithelia. Firstly, we obtained an EST fragment by mRNA differential display techniques from 3 normal esophageal epithelia and 2 primary ESCC tissues from high incidence families in Linxian County and named it ECRG2. The RT-PCR detection results demonstrated that the expression of ECRG2 was down-regulated in ESCC as well as colon and brain tumors. 10 Secondly, we obtained the 569 bp full-length cDNA of the ECRG2 gene by SMARTTM RACE technique. We found that the gene contains 4 exons, spans about 3,540 bp on chromosome 5q32-33 and has a 258 bp open reading frame encoding an 85-amino acids polypeptide. 11 Analysis by bioinformatics has shown that 97% of the amino acid sequences of ECRG2 are homologous to a tumor associated KAZAL-type serine protease inhibitor that may play a central role in the protection of esophageal mucosa. 12 Thirdly, we studied the function of the ECRG2 gene by yeast 2-hybrid system and identified that the ECRG2 gene interacts directly ...