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Cervical Dysplasia, Ploidy, and Human Papillomavirus Status Correlate with Loss of Fhit Expression¹

Department of Microbiology and Immunology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania 19107 [A. V., N. Z., C. M. C., R. M.]; Department of Experimental Medicine and Pathology, University "La Sapienza," Rome, Italy [A. V.]; Centro Ricerche "Ospedale S. Pietro" [D. F., A. V., R. M.] and II University "La Sapienza" [T. P., A. V.], Rome, Italy; and Regina Elena National Cancer Institute, Rome, Italy 00161 [G. T., P. V., C. B.]

Purpose: The tumor suppressor gene, FHIT, has been cloned and mapped at chromosome region 3p14.2, one of the regions most frequently deleted in cervical carcinoma. In this report, we show that the expression of the Fhit protein in relation to human papillomavirus (HPV) subtype, the type of the intraepithelial lesion, HIV-induced immunodeficiency, and the DNA content (ploidy) correlates with the biological behavior of the lesions.

Experimental Design: To investigate involvement of the FHIT gene in squamous intraepithelial lesions of low and high grade (LGSILs and HGSILs, respectively) of the uterine cervix, we examined the Fhit protein expression by immunocytochemistry in 131 cervical smears of 96 HIV-seropositive patients (42 with LGSILs and 10 with HGSILs) and 35 HIV-seronegative (5 with LGSILs) persons.

Results: Fhit protein was detected in normal cells, whereas dysplastic cells (independently of HPV infection and HPV subtypes) showed reduced expression of Fhit (P = 0.00001). Lesions from 52 HIV-seropositive patients, 42 LGSILs and 10 HGSILs, showed diploid DNA content in 63.5%, aneuploid in 32.7%, and polyploid in 3.8%, but 90% of the HGSILs showed an aneuploid DNA content, and all were infected by HPV 16/18 subtypes. 23.8% of LGSIL cases were associated with HPV 16.

Conclusions: These data clearly suggest that loss of Fhit expression occurs in the early stages of cervical carcinogenesis. Pap test represents one of the most convenient and rapid procedures available in identification of cellular changes; hence, Fhit staining might be used as an useful tool in larger population screening to detect early alteration in cellular behaviors.

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