Loss or reduction of Fhit expression in renal neoplasias: correlation with histogenic class

Involvement of the 3p14.2 region of chromosome 3 in kidney cancers was suggested 20 years ago, when a reciprocal constitutional translocation, t(3;8)(p14.2;q24), was shown to segregate with bilateral clear cell renal carcinoma in 3 generations of 1 family. The FHITgene that is interrupted at 3p14.2 by the t(3;8) translocation has been isolated, characterized, and shown to be frequently altered, mainly by internal deletion, in carcinomas or cancer-derived cell lines of the lung, stomach, pancreas, esophagus, cervix, and colon. Although up to 90% of sporadic clear cell renal carcinomas, representing 70% of adult renal carcinomas, exhibit loss of FHIT alleles, FHIT gene alterations have been documented for only a few renal cell carcinoma-derived cell lines. Nevertheless, more than 50% of clear cell carcinomas were recently shown to express little or no Fhit protein, unlike the normal kidney tubule epithelium, which is uniformly strongly positive for Fhit expression. We have extended our immunohistochemical study of expression of Fhit protein to the spectrum of histopathologic subtypes of adult renal tumors. There is an apparent continuum of Fhit expression from the 100% strongly positive oncocytomas through mostly positive papillary and chromophobe to the mostly negative clear cell and sarcomatoid to the negative or predominantly negative collecting duct renal carcinomas. This pattern of diminishing Fhit expression correlates with reported frequency of 3p allele loss in renal carcinomas and may parallel the potential for aggressive behavior of tumors, as suggested by the abundant Fhit expression in the benign oncocytomas and the near absence of Fhit expression in sarcomatoid and collecting duct RCCs.