Loss of Fhit expression as a potential marker of malignant progression in preinvasive squamous cervical cancer

OBJECTIVE: In a previous study using the same cases of squamous cervical neoplasia and microinvasive carcinoma (MICA) we found an association between FHIT gene deletion and infection with high-risk HPV (HR HPV). The purpose of this study was to evaluate Fhit protein expression by immunohistochemistry in order to determine whether FHIT gene deletion or infection with HR HPV correlated with aberrant protein expression and grade of lesion. METHODS: A total of 74 archival LLETZ biopsy cases consisting of 23 cervical intraepithelial neoplasia grade 1 (CIN1), 28 CIN3, and 23 MICA cases were selected for Fhit immunostaining. The results of this study on Fhit immunostaining were analyzed in relation to our previous findings using Epi-Info and SPSS-PC statistical analysis software. RESULTS: Fifty percent (14/28) of CIN3 lesions and 78% (18/23) of MICA lesions had a marked reduction or absence of Fhit protein expression (P = <0.001, strength of association, Cramers' V, 0.632). CIN1 lesions were found to have moderate to strong cytoplasmic expression of Fhit. Seventy percent of cases in this study with reduced/absent Fhit protein expression were also positive for FHIT gene loss of heterozygosity (LOH) (P = 0.04, strength of association, phi, 0.254). A significant statistical relationship was found between Fhit protein expression and HPV 16 infection in combined CIN1, CIN3, and MICA cases (P = <0.001). Eighty-seven percent of cases with reduced/absent Fhit protein expression were positive for HPV 16 (strength of association, phi, 0.552). Ninety percent of HPV 16 and 31 positive cases had reduced/absent Fhit expression. CONCLUSION: Our findings suggest an association between HPV infection and FHIT gene abnormalities raising the possibility of a mechanistic role for the FHIT gene as a cofactor with HPV in triggering the development of cervical cancer.