ABSENCE OR REDUCTION OF FHIT EXPRESSION IN MOST CLEAR-CELL RENAL CARCINOMAS

The FHIT gene at human chromosome region 3p14.2 straddles the common f ragile site, FRA3B, and numerous homozygous deletions in cancer cell l ines and primary tumors,;Also, the 3p14.2 chromosome breakpoint of the familial clear cell kidney carcinoma-associated translocation, t(3;8) (p14.2;q24), disrupts one FRIT allele between exons 3 and 4, fulfillin g one criterion for a familial tumor suppressor gene: that one allele is constitutionally inactivated. Because the FHIT gene sustains bialle lic intragenic deletions rather than mutations, there has not been evi dence that the FHIT gene frequently plays a role in kidney cancer, alt hough replacement of Fhit expression in a Fhit-negative renal carcinom a cell line suppressed tumor growth in nude mice. We have now assessed 11 clear cell renal carcinomas for expression of Fhit by immunohistoc hemistry. Normal renal tubule epithelial cells express Fhit uniformly and strongly, whereas 51% of the tumors are completely negative, 34% o f tumors show a mixture of positive and negative cells, and 14% are un iformly positive, although usually less strongly positive than the nor mal epithelial cells, Most interestingly, there was a correlation betw een complete absence of Fhit and the G1 morphological grade and early clinical stage. ?Morphological grades G2 and G3 exhibited a mixture of positive and negative cells with a tendency for a higher fraction of negative cells in G3, Fhit inactivation is likely to be an early event in G1 tumors and mag be associated with progression in G2 and G3 tumo rs.