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Expression of Fhit Protein and Its Correlation with Human Papillomavirus Infection in Cervical Lesions

Author: WuLiJie
Tutor: YaoJiaZuo
School: China Medical University
Course: Obstetrics and Gynaecology
Keywords: Fhit cervical carcinoma cervical intraepithelial neoplasia (CIN) human papillomavirus ( HPV)
CLC: R711.7
Type: Master's thesis
Year: 2005
Downloads: 91
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Abstract

PrefaceCervical cancer is one of the most common cancer in women. Pap smear screening programs has proven to be a very effective means with which to reduce mortality from cervical cancer, but the ratio of mortality to incidence is 51%. Hence, cervical cancer remains a significant public health concern. However, it is estimated that 12 -50% of high -grade preinvasive cervical lesions will progress to invasive carcinoma if left untreated, and morphological examination a-lone does not allow distinction of those lesions likely to progress from those that will regress or simply persist . Hence, molecular markers to aid in this distinction and to enhance diagnosis of early cervical lesions would have great clinical utility.Although it is well accepted that high - risk human papillomavirus ( HPV) are associated with cervical cancer, several lines of evidence suggest that HPV infection alone is insufficient for the malignant transformation of HPV - infected cells. Hence, other genetic events, such as oncogene activation or tumor suppressor gene inactivation, are likely to be required in addition to infection with HPVs for the development of cervical cancer . The fragile histidine triad ( FHIT) gene is a candidate tumor suppressor gene that has been implicated in the development of cervical carcinoma. Correlation between Fhit protein expression and HPV infection was not clear. The purpose of this study was to evaluate Fhit protein expression in the preinvasive cervical epithelial lesions and invasive cervical carcinomas by immunohistochemistry in order to determine whether loss of Fhitprotein expression might be associated with tumor progression; of particular interest to this study was the comparison of Fhit protein expression in high - grade cervical intraepithelial neoplasia ( CIN) with associated invasive carcinoma versus high - grade CIN without invasive carcinoma, in an attempt to evaluate whether the loss of Fhit protein might be a clinically useful marker of lesions more likely to progress to invasive disease; examined high - risk HPV in cervical carcinoma to evaluate whether HPV correlated with aberrant Fhit protein expression.Materials and MethodsClinical materials; A total of 90 formalin - fixed, paraffin - embedded tissue specimens that had been diagnosed at the First Hospital of China Medical U-niversity were selected for this study, including 20 invasive squamous cell cervical carcinomas, 15 high -grade CIN associated with invasive carcinoma, 20 high — grade CIN, 20 CIN I and 15 normal cervix specimens.Methods: S - P immunohistochemistry methods were used to examine Fhit expression in invasive cervical carcinomas , high - grade CIN associated with concurrent invasive carcinoma , high - grade CIN , CIN I , and normal cervix samples. The brown precipitate located in the cytoplasm indicates the presence of Fhit. Immunostained samples were scored for both intensity ( absent or weak, 1; moderate, 2; strong, 3) and extent (percentage of positive cells: < 10% , 1 ; 10 ~50% , 2; >50% , 3) , The intensity and extent scores were multiplied to give a composite score of 1 ~ 9 for each specimen. Composite scores of 1 ~ 3 were defined as having negative Fhit protein expression, and scores of 4 ~ 9 were considered to be positive for Fhit protein expression. HC - II was used to examine high - risk HPV in cervical carcinomas.Statistics; SPSS version 10. 0 software was employed to analyze all data. Comparisons between groups were tested using correlation analysis, Fishers exact test,and t test.ResultsAll normal cervical epithelium and CIN I exhibited diffuse cytoplasmic im-munostaining of moderate to strong intensity. Fhit protein expression was positive in 35.0% invasive carcinomas, 40.0% high -grade CIN associated with invasive carcinomas, and 75. 0% high - grade CIN . The average score of nomal cervical epithelium, CIN I , high - grade CIN, high - grade CIN associated with invasive carcinomas, invasive carcinomas are 8. 00 ±1. 16,7.65 ±1.53,6.00 ± 2. 83 ,3. 87 ±2. 67 and 3. 20 ±2. 40 respectively. The results confirm that Fhit protein expression is reduced or absent in the majority of cervical carcinomas; absent or reduced Fhit protein is observed at a significantly higher frequency in high - grade CIN associated with invasive carcinoma than in high - grade CIN ; from nomal cervical epithelia through CIN I , high - grade CIN to invasive carcinomas, Fhit protein expression decreases gradually , linear regression analysis proves that between Fhit protein expression and the development of cervical lesion is negative correlation( r = -0. 617,P <0.01). 16 cases of cervical carcinomas were exmanied by HC -11,14 cases (87. 5% ) were high -risk HPV infection. Negative Fhit expression was found in 57. 1% (8/14) of HPV positive cases, contrasted with 0/2 without HPV cases had a significant increase tendency ,but without statistical significance( P =0. 23 ).Conclusions1. Fhit protein expression positive rate is observed at a significantly lower frequency in high - grade CIN and invasive carcinomas than in CIN I and normal cervix;2. Fhit protein expression decreases gradually with the development of cervical lesions;3. Fhit protein expression positive rate is observed at a significantly lower frequency in high - grade CIN associated with invasive carcinoma than in high -grade CIN , Fhit protein abnormalities maybe raise the possibility of a mechanis-

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