Alterations of the FHIT gene in breast cancer: Association with tumor progression and patient survival

Our previous results on breast tumors show that LOH (loss of heterozygosity ) at the FHIT locus is associated with reduced Fhit protein expression. We have also shown that LOH at this locus is significantly higher in tumors fr om patients carrying the BRCA2 999del5 mutation than in tumors without this mutation, presumably because of lack of DNA repair. Here. our aim was to d etermine the relationship of FNIT LOH with breast tumor progression. Five m icrosatellite markers located within the FHIT gene were typed in 239 breast tumors and corresponding normal tissue, and the LOH results were compared with clinicopathologic factors and LOH at other chromosome regions. LOH at FHIT is associated with estrogen- and progesterone-negative breast tumors, high S-phase fraction, reduced patient survival, and LOH at chromosome regi ons 6q, 7q, 8p. 9p, 11p, 11q. 13q, 16q, 17p, 17q. 18q, and 20q. A multivari ate analysis shows that LOH at FHIT results in a 60% increased relative ris k of dying. We conclude that the loss of FHIT results in growth advantage o f breast tumor cells, is associated with unstable genome, and may be of pro gnostic value.