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

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Cervical Dysplasia, Ploidy, and Human Papillomavirus Status Correlate with Loss of Fhit Expression1 1306 Vol. 7, 1306–1312, May 2001 Clinical Cancer Research Cervical Dysplasia, Ploidy, and Human Papillomavirus Status Correlate with Loss of Fhit Expression1 Andrea Vecchione, Nicola Zanesi, Conclusions: These data clearly suggest that loss of Fhit Giorgio Trombetta, Debora French, Paolo Visca, expression occurs in the early stages of cervical carcinogen- esis. Pap test represents one of the most convenient and Tiziana Pisani, Claudio Botti, Aldo Vecchione, 2 rapid procedures available in identification of cellular Carlo M. Croce, and Rita Mancini changes; hence, Fhit staining might be used as an useful tool Department of Microbiology and Immunology, Kimmel Cancer in larger population screening to detect early alteration in Center, Thomas Jefferson University, Philadelphia, Pennsylvania cellular behaviors. 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.] INTRODUCTION and II University “La Sapienza” [T. P., A. V.], Rome, Italy; and Cervical carcinoma is one of the most deadly neoplasms in Regina Elena National Cancer Institute, Rome, Italy 00161 [G. T., P. V., C. B.] women, particularly in developing countries (1). The relation- ship between HPV3 infection and precancerous cervical lesions, such as LGSILs and HGSILs, has been demonstrated clearly ABSTRACT (2–4). Cytomorphological identification of cellular changes is Purpose: The tumor suppressor gene, FHIT, has been currently the most convenient, rapid, economical, and sensitive cloned and mapped at chromosome region 3p14.2, one of the procedure available for detection of HPV infection in the genital regions most frequently deleted in cervical carcinoma. In tract. this report, we show that the expression of the Fhit protein HPV, a DNA virus, affects both the nucleus and the cyto- in relation to human papillomavirus (HPV) subtype, the plasm of the infected cells with specific changes. HPV DNA type of the intraepithelial lesion, HIV-induced immunodefi- may occur within epithelial cell nuclei as either unintegrated or ciency, and the DNA content (ploidy) correlates with the integrated. Nuclear changes tend to be more pronounced in biological behavior of the lesions. cases with HPV DNA integration into the epithelial cell nuclear Experimental Design: To investigate involvement of the DNA. Such lesions typically appear as dysplastic and atypical. FHIT gene in squamous intraepithelial lesions of low and Chromosome and ploidy alterations, hallmarks of SILs or dys- high grade (LGSILs and HGSILs, respectively) of the uter- plastic change, may occur in these cases. The classic manifes- ine cervix, we examined the Fhit protein expression by tation of HPV infection is the presence of the koilocyte (5). immunocytochemistry in 131 cervical smears of 96 HIV- HIV infection is an important risk factor for HPV infection seropositive patients (42 with LGSILs and 10 with HGSILs) and associated lesions in the anogenital tracts of women (6–9). and 35 HIV-seronegative (5 with LGSILs) persons. Mechanisms by which HIV intensifies the pathogenic effect of Results: Fhit protein was detected in normal cells, HPV in cervical cancer cells are not yet well defined, but whereas dysplastic cells (independently of HPV infection depressed immunological control of HPV replication or inter- action between HPV and HIV may be contributing factors. It has ؍ and HPV subtypes) showed reduced expression of Fhit (P 0.00001). Lesions from 52 HIV-seropositive patients, 42 been demonstrated that HIV has an effect on cervical immune LGSILs and 10 HGSILs, showed diploid DNA content in function, reducing the number of Langerhans cells and their 63.5%, aneuploid in 32.7%, and polyploid in 3.8%, but 90% function (10). These observations suggest a complex influence of the HGSILs showed an aneuploid DNA content, and all of HIV on induced immunosuppression, increased susceptibility were infected by HPV 16/18 subtypes. 23.8% of LGSIL cases to HPV infection, and facilitated evolution of the associated were associated with HPV 16. anogenital lesions. Furthermore, persistent infection of high oncogenic risk HPV types 16/18 associated with HGSIL devel- opment has been observed in HIV-positive women (10, 11). Although HPV infection has an important role in cervico- vaginal carcinogenesis, some authors suggest that it is insuffi- Received 12/14/00; revised 2/8/01; accepted 2/13/01. cient for tumor development (12). Other events, such as tumor The costs of publication of this article were defrayed in part by the suppressor gene inactivation, are probably crucial in cervical payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to carcinoma pathogenesis. Deletions of the short arm of chromo- indicate this fact. some 3 (3p) have been detected by loss of heterozygosity studies 1 Supported by Grant MURST-COFIN 98 from Ministero dell’ Universita`e Ricerca Scientifica e Tecnologica and partially by USPHS Grants CA 77738, CA 51083, and CA 56336 from the National Cancer Institute. 2 To whom requests for reprints should be addressed, at Kimmel Cancer 3 The abbreviations used are: HPV, human papillomavirus; HGSIL, Center, Thomas Jefferson University, Room 1008, 233 South 10th high-grade squamous intraepithelial lesion; LGSIL, low-grade squa- Street, Philadelphia, PA 19107. Phone: (215) 503-4658; Fax: (215) 923- mous intraepithelial lesion; FHIT, fragile histidine triad; APC, adenom- 4498; E-mail: [email protected]. atous polyposis coli. Downloaded from clincancerres.aacrjournals.org on September 27, 2021. © 2001 American Association for Cancer Research. Clinical Cancer Research 1307 Table 1 Cytological diagnoses HPV by PCR. Only HIV-seropositive and -seronegative cases Diagnosis HIVϩa HIVϪb Total with cytological diagnosis of LGSIL and HGSIL (histologically confirmed) were successively evaluated by molecular analysis Within normal limits 12 (40%) 18 (60%) 30 Benign cellular changes 32 (72.7%) 12 (27.3%) 44 for HPV-PCR. LGSIL 42 (89.4%) 5 (10.6%) 47 Immunocytochemistry. All cytological smears with HGSIL 10 (100%) 0 10 LGSILs and HGSILs were stained with rabbit polyclonal anti- Total 96 35 131 Fhit antibody that had been raised against a glutathione S- a HIV seropositive. transferase-Fhit fusion protein, without a preceding antigen re- b HIV seronegative. trieval step. The antibody was used at a 1:2500 dilution for 2 h at room temperature. After this incubation, smears were treated with biotinylated antirabbit antibody and streptavidin-biotin- peroxidase (Immunotech Delta Kit protocol). Diaminobenzidine in cervical cancer (13–15). Regions spanning 3p13–14.3, 3p13– was used as chromogen, and slides were counterstained with 21.3, 3p14.2, and 3p21 have been shown to be deleted, suggest- hematoxylin. As negative controls, we used cell pellets from one ing the presence of tumor suppressor genes responsible for cervical and two lung cancer cell lines that had been shown cervical carcinogenesis in these regions. In addition, cytogenet- previously to be Fhit negative. As positive controls, we used ics studies have suggested a correlation between common chro- similarly processed cell pellets of a Fhit-positive lung cancer mosomal fragile sites and the integration sites of HPV (16). cell line and a cervical cancer cell line. The degree of immu- The tumor suppressor gene, FHIT, has been cloned and nostaining was evaluated by counting diaminobenzidine-stained mapped to chromosome region 3p14.2, one of the regions most cervical cells in a minimum of 500 cells in different microscopic frequently deleted in cervical carcinoma. The FHIT gene en- fields at a magnification of ϫ400 and was expressed as a compasses a region of over 1 Mb, which includes the common percentage. All cell smears were examined independently by FRA3B fragile region, and encodes a protein of Mr 16,800, with two investigators, and complete agreement was found for deter- diadenosine triphosphate hydrolase activity (17). Common con- minations of Fhit protein positivity or negativity. stitutive fragile sites are chromosomal regions that show gaps DNA Ploidy. Ploidy analysis was performed only on 52 and breaks after treatment with chemicals that inhibit DNA HIV-seropositive cases with LGSILs and HGSILs using the replication, usually aphidicolin. These fragile sites, which occur Becton Dickinson CAS 200 apparatus Ploidy Analysis (Program in all individuals, have been shown to be highly recombinogenic 2.3) on a sample stained previously by a modified Feulgen and to participate in deletions and translocations. Accordingly, a method using a commercial kit, Quantitative DNA staining kit papillomavirus integration site, plasmid integration sites, and 102300-01 (Becton Dickinson, Elmhurst, IL). The apparatus cancer-specific translocations have been mapped within the was first calibrated on mouse hepatocytes provided by the same FRA3B fragile site in the FHIT gene (18). manufacturer and then on at least 30 normotypical epithelial In this report, we studied the expression of the Fhit protein elements removed from a healthy area of the lateral fornix and by immunocytochemistry of pap smears in relation to HPV distally smeared on the same slide. Analysis was performed on subtype, the type of the SIL, HIV-induced immunodeficiency, at least 100 morphologically atypical elements. When both and the DNA content (ploidy) to correlate the biological behav- diploid (or polyploid)
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