ABSTRACT
BACKGROUND AND AIM: High risk human papillomavirus (HR-HPV) types have been closely associated with cervical carcinoma. However, other genetic events are likely to be required, in addition to HPV infection, for the development of cervical cancer. We investigated 20 human cervical carcinomas and 15 normal cervical tissues for the correlation between aberrant expression of the FHIT, p53 and MMR genes and their prognostic impact. METHODS AND RESULTS: The expression of p53, FHIT and MMR genes (hMSH2, hMLH1,GTBP/hMSH6,hPMS2, hPMS1) was assessed in relation to HPV infection by immunohistochemistry and PCR. HPV-16 and 18 DNA were detected in 95% and 25%, HPV m-RNA in 90% and 10% of cases; respectively. Homozygous deletion (HZD) and reduced FHIT protein was detected in 40% and 65% of cases, respectively; 25% of which showed abnormal gene transcripts. Reduced MMR gene expression was found in 19 cases. hMSH2 and hMLH1 showed the highest frequency (80% and 70%, respectively). p53 overexpression was present in 50% of cases with a single mutation in exon 7. There was a significant relation between FHIT aberrations, HPV-16 RNA, reduced hMLH-1 and hMSH- 2 expression; between reduced expression of hMSH-2 and p53 overexpression, GTPB-6, as well as between GTPB-6 and hMLH-1. Aberrant expression of p53, FHIT, hMLH1and GTPB-6 was significantly associated with recurrence. CONCLUSIONS: Aberrations involving MMR genes, FHIT and p53 are frequent in HPV-associated cervical carcinoma with a significant correlation between them. However, only the FHIT, p53, hMLH1 and GTPB6 aberrations could be used as predictors of tumor recurrences.
Subject(s)
Biomarkers, Tumor/genetics , Carcinoma/virology , Gene Expression , Neoplasm Recurrence, Local/epidemiology , Papillomavirus Infections/genetics , Uterine Cervical Neoplasms/virology , Acid Anhydride Hydrolases/genetics , Carcinoma/genetics , Carcinoma/pathology , DNA Repair Enzymes/genetics , DNA, Viral/analysis , Female , Human papillomavirus 16/isolation & purification , Humans , Middle Aged , Neoplasm Proteins/genetics , Neoplasm Recurrence, Local/genetics , Prognosis , RNA, Messenger/analysis , Tumor Suppressor Protein p53/genetics , Uterine Cervical Neoplasms/genetics , Uterine Cervical Neoplasms/pathologyABSTRACT
PURPOSE: Brachytherapy plays a major role in the treatment of patients with carcinoma of the cervix. However, routine intracavitary brachytherapy may not be feasible or adequate to treat locally advanced disease. The purpose of this retrospective study (spanning a 20-year period) was to determine the outcome of interstitial low-dose-rate brachytherapy in the treatment of bulky or locally advanced cervical cancer. The long-term survival and safety of this technique were evaluated, along with its impact on local and locoregional control, disease-free survival, and complications. METHODS AND MATERIALS: A total of 185 previously untreated patients with cervical cancer were treated between 1977 and 1997. According to the International Federation of Gynecology and Obstetrics classification, 21 patients had Stage IB (barrel), 77 Stage II, 77 Stage III, and 10 Stage IV disease. All patients were treated by a combination of external megavoltage irradiation to the pelvis to a dose of 5040 cGy followed by interstitial-intracavitary implants to a dose of 40-50 Gy to the implanted volume in two applications. RESULTS: Clinical local control was achieved in 152 (82%) of the 185 patients. A 5-year disease-free survival rate of 65%, 67%, 49%, and 17% was achieved for patients with Stage IB, II, III, and IV disease, respectively. Eighteen (10%) of the 185 patients developed Radiation Therapy Oncology Group Grade 3 or 4 late complications. CONCLUSION: Patients with locally advanced cervical cancer, or with distorted anatomy, may be treated adequately with interstitial brachytherapy to achieve excellent locoregional control and a reasonable chance of cure with acceptable morbidity.
