The overall goal of this project is to understand the role of genetics in the etiology and prevention of upper gastrointestinal cancers (esophagus, gastric cardia, gastric body). The objective of current studies is to identify susceptibility genes for these cancers, beginning with cancer of the esophagus. BACKGROUND: Esophageal cancer is the 7th most common cause of cancer death worldwide. Several lines of evidence (family history, familial aggregation, segregation, cytogenetics) suggest that genetic factors may play an important role in the etiology of this malignancy. Identification of susceptibility genes may allow screening of populations to identify persons at particularly high risk who could then be targeted for prevention strategies (e.g., chemoprevention or early detection). METHODS: Several studies are in progress to study these cancers in persons from Shanxi Province, China, where rates are among the highest in the world, including collection of DNA for (1) a tumor/nontumor study of over 500 cases, (2) a high-risk/low-risk population study of 300 subjects, (3) a case-control study of 1,500 cases and 1,500 controls, and (4) a linkage study in 150 families with multiple cases. PROGRESS: (1) a genomewide scan found 5 chromosomal regions with very high (>75%) LOH in esophageal squamous cell carcinoma [ESCC] (Hu et al, Genes Chromosomes Cancer 2000); (2) fine mapping of the region with the highest LOH (chromosome13q) identified 2 deletion regions (Li et al, Genes Chromosomes Cancer 2001); (3) mutational analysis of the TP53 gene showed mutations in 77% of tumors with evidence for biallelic inactivation in 59% (Hu et al, Clin Cancer Res 2000); (4) proteomic analyses from matched normal-tumor samples identified a number of proteins observed only in the normal epithelium that point to potential tumor suppressor genes in ESCC, such as annexin 1 (Emmert-Buck et al, Mol Carcinogen 2000), and further showed that annexin 1 expression was reduced in premalignant lesions as well (Pawelitz et al, Cancer Res 2000); (5) other research in molecular progression showed that 4 (of 12) markers tested with high LOH from our genomewide scan in tumors also showed LOH in low grade dysplasia, making them candidate early detection markers (Roth et al, Cancer Res 2001).
Showing the most recent 10 out of 14 publications
