Reduced Fhit expression in cervical carcinoma: correlation with tumor progression and poor prognosis.
OBJECTIVE
The fragile histidine triad (FHIT) gene is located at chromosome 3p14.2 and encompasses the common fragile site, FRA3B, which may contribute to chromosome breakage and rearrangement of cancer cells. Aberrant protein expression and inactivation of the FHIT gene have been identified in a variety of precancerous and cancerous lesions. To identify the potential implications of the FHIT gene in the development of cervical carcinoma and explore the clinical importance of change in gene expression, we assessed the level of Fhit protein in precancerous lesions and carcinomas of the cervix.


METHODS
In our study, 15 low-grade squamous intraepithelial lesions (LSIL), 35 high-grade squamous intraepithelial lesions (HSIL), 12 microinvasive carcinomas, and 103 invasive carcinomas were evaluated. The expression of Fhit was studied by immunohistochemistry using a polyclonal antibody specific for the protein.


RESULTS
All samples of normal epithelium and LSIL exhibited intermediate to strong immunostaining of Fhit. Reduced Fhit protein expression was observed in 30 of 103 (29.1%) invasive carcinomas, 1 of 12 (8.3%) microinvasive carcinomas, and 3 of 35 (8.6%) HISL. Compared with normal epithelium and dysplasia, microinvasive and invasive carcinomas showed significantly lower Fhit expression. Fhit expression was also correlated with clinicopathological status. Reduced Fhit expression was significantly associated with lymph node metastasis (P = 0.005), parametrial invasion (P = 0.023), and vaginal involvement of the tumor (P = 0.016). In univariate analysis, Fhit expression was found to be a significant predictor of survival (relative risk 2.54, P = 0.0091): the patient with reduced Fhit expression had a 154% higher risk of dying from cervical cancer than the patient with opposite values.


CONCLUSIONS
Our results indicate that immunostaining of Fhit expression has potential as a prognostic marker in the management of cervical cancer. The trend of reduced Fhit expression in microinvasive and invasive carcinomas suggests that down-regulation of Fhit is strongly linked to cancer progression. Moreover, loss of Fhit expression was related to lymph node metastasis, parametrial invasion, and vaginal involvement in cervical carcinoma. These results imply that loss of Fhit protein is associated with highly aggressive phenotypes of cervical carcinoma.
Huang
Lee-Wen
LW
Department of Obstetrics and Gynecology, Shin Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan. m002057@ms.skh.org.tw
Chao
Shiouh-Lirng
SL
Chen
Tong-Jong
TJ
D017766:Acid Anhydride Hydrolases; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018450:Disease Progression; D005260:Female; D006801:Humans; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000096:biosynthesis*; D009367:Neoplasm Staging; D011379:Prognosis; D002583:Uterine Cervical Neoplasms / Q000378:metabolism* / Q000473:pathology; D002578:Uterine Cervical Dysplasia / Q000378:metabolism* / Q000473:pathology; D000099170:Bis(5'-adenosyl)triphosphatase
D017766:Acid Anhydride Hydrolases; D009363:Neoplasm Proteins; D000099170:Bis(5'-adenosyl)triphosphatase