Loss of fhit expression in invasive cervical carcinomas and intraepithelial lesions associated with invasive disease

Allelic losses involving chromosome 3p are frequently observed in cervical cancers. Deletion mapping studies of primary cervical carcinomas have local ized common regions of deletion to 3p14.2 and 3p21. The candidate tumor sup pressor gene FHIT has been mapped to 3p14.2, and previous studies have demo nstrated reduced or aberrant FHIT transcripts and reduced or absent Fhit pr otein expression in a large percentage of cervical cancer-derived cell line s and primary cervical carcinomas. To expand these observations to preinvas ive cervical epithelial lesions and to determine whether loss of Fhit prote in expression might be associated with tumor progression, immunohistochemic al methods were used to examine Fhit expression in 95 invasive cervical car cinomas, 33 high-grade squamous intraepithelial lesions (HSILs) associated with concurrent invasive cancer, 38 HSILs unassociated with invasive cancer , 24 low-grade squamous intraepithelial lesions, and 22 normal cervix sampl es. All normal cervical epithelia and low-grade squamous intraepithelial le sions exhibited diffuse cytoplasmic immunostaining of moderate to strong in tensity. Fhit protein expression was markedly reduced or absent in 67 of 95 (71%) invasive cancers, 17 of 33 (52%) HSILs associated with invasive canc er, and 8 of 38 (21%) HSILs without associated invasive cancer. The results confirm that Fhit protein expression is reduced or absent in the majority of cervical carcinomas and suggest that loss of Fhit expression often accom panies cervical tumor progression. Moreover, absent or reduced Fhit protein is observed at a significantly higher frequency in HSILs associated with p rogression to invasive cancer than in HSILs with unknown risk for progressi on (P = 0.012). These findings suggest that loss of Fhit expression in HSIL s could serve as a useful marker of high-grade preinvasive lesions that hav e an increased likelihood of progression to invasive carcinoma.