Altered expression of FHIT in carcinoma and precarcinomatous lesions of the esophagus

The FHIT gene, located at chromosome 3p14.2, Is a tumor suppressor gene oft en involved in tumors resulting from exposure to environmental carcinogens. We studied 46 pairs of esophageal primary tumors and corresponding normal squamous mucosa specimens by molecular genetic and immunohistochemical meth ods to investigate the role of the FHIT gene in esophageal carcinoma. In ad dition, we studied several different types of lesions, such as carcinoma in situ or dysplasia by immunohistochemistry. Loss of heterozygosity at or ar ound the FHIT gene was observed in 35 (76%) primary tumors. Immunohistochem ical detection of Fhit protein in the primary tumors demonstrated that 14 ( 30%) were positive and 32 (70%) were negative. We observed concordance betw een loss of Fhit protein and loss of heterozygosity and between loss of Fhi t protein and RNA abnormalities. Because the FHIT/FRA3B locus Is susceptibl e to damage by environmental carcinogens, we investigated the correlation b etween Fhit expression and smoking or alcohol habits. In this relatively sm all study, the patients who were both heavy users of tobacco and alcohol sh owed a significantly higher frequency of loss of Fhit expression than those who were light users. Noncarcinomatous squamous epithelium showed positive Fhit reactivity in most cases; however, five showed negative Fhit reactivi ty, Interestingly, all of these five patients had habits of heavy use of to bacco and alcohol. Eight of 12 carcinomas in situ, 2 of 4 severe dysplasias , 4 of 8 moderate dysplasias, and 3 of 9 mild dysplastic lesions showed neg ative Fhit reactivity, These findings indicated that loss of Fhit expressio n may be an early event in the development of human esophageal carcinoma an d may occur even in normal-appearing squamous epithelium in some patients h eavily exposed to environmental carcinogens.