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Several reports have suggested the importance of p73 polymorphisms in tumor behavior. We investigated the role of a p73 gene polymorphism in the susceptibility to cervical lesions in a southwestern European population. Peripheral blood samples were obtained from Radiotherapy and Gynaecology Departments of Portuguese Institute of Oncology (Porto, Portugal), from 1998 to 2002. We analyzed the p73 cytosine thymine polymorphism in peripheral blood DNA of 176 healthy donors, 38 high-grade squamous intraepithelial lesions (HSIL), and 141 patients with primary untreated invasive cervical cancers (ICC), by polymerase chain reaction-restriction fragment length polymorphism. Our results demonstrate a twofold increased susceptibility to the development of HSIL in women carrying the p73 AT allele (OR=2.39; p=0.022). Further, this association seems to be more evident in women with high parity (OR=12.53; p=0.007). This is in agreement with the possible role of p73 in cervical carcinogenesis, namely, in human papillomavirus-infected transition zone subjected to the action of estrogens and in conjunction with disruption of differentiation program of this squamous epithelium that occurs in HSIL phase before the next step to invasiveness and squamous cervical cancer.

Human papillomavirus (HPV) plays a major role in the etiology of cervical cancer. However, a complex correlation between viral and cellular genes is necessary for cell cycle control deregulation in the progression to invasive cervical cancer (ICC). Cyclin D1 ( CCND1 ) is an important positive regulator of the G1/S phase of the cell cycle. The CCND1 gene is located at 11q13 and is often altered in human cancers. We analyzed the A870G CCND1 polymorphism by polymerase chain reaction/restriction fragment length polymorphism analysis in 246 women including 50 cases with high-grade squamous intraepithelial lesions of the cervix (HSIL), 93 with ICC, and 103 healthy women. The GG genotype was associated with a 4.32-fold higher risk for the development of HSIL [adjusted odds ratio (aOR)=4.32, 95% confidence interval (CI) 1.50–12.46, P =0.0067), and a 3.26-fold increased risk for the development of ICC (aOR=3.26, 95% CI 1.42–7.53, P =0.006). The proportion of cervical cancer cases attributable to the GG CCND1 genotype was 17.26%. This study indicates that the A870G CCND1 polymorphism could act as a cofactor of HPV in the initiation of cervical carcinogenesis, particularly in the transformation zone of HPV-infected women, supporting evidence for a genetic factor in ICC risk.

Infection with human papillomaviruses (HPV) is essential in the carcinogenesis of the uterine cervix. However, a complex interrelation between viral and cellular genes is necessary for cell-cycle control deregulation and development and progression of cervical cancer induction. The TP73 gene is localized in 1p36.3 band, which is often deleted by loss of heterozygosity (LOH) in human cancers. We analyzed the p73 cytosine thymine polymorphism and LOH in this locus by polymerase chain reaction restriction fragment length polymorphism in 134 DNA samples from biopsies of 67 primary untreated invasive cervix tumors and the corresponding peripheral blood. Genotype frequencies of 56.7% for homozygous genotype GC/GC and 43.3% for heterozygous genotype GC/AT were found. The presence of the GC/AT genotype in tumors was associated with lower age at menarche (P=0.039) and high parity (P=0.015). In 20.0% of DNA tumor samples, the AT allele was lost compared with their DNA normal blood pairs. The AT allele was conserved in women with high parity. This was not the case in the group with low parity, with 33.3% of patients showing loss of the AT allele in tumor DNA (P=0.041). These results suggest that TP73 genetic alterations may contribute to the genesis and/or progression of cervical carcinoma in an HPV-infected transformation zone under prolonged exposure to events related to pregnancy.

In a prospective study involving 158 patients with carcinoma of the uterine cervix, DNA content, S-phase fraction (SPF), and Ki-67 proliferative index were evaluated in fresh tissue using flow cytometry and immunocytochemical analysis. Of all tumors, 57.1% were aneuploid. In this subgroup, 25% of tumors had a DNA index between 1.6 and 1.8. SPF values ranged from 0.5 to 57.2% and were significantly higher (P < 0.0001) in tumors with an abnormal DNA content (aneuploid). Ki-67 labeling index ranged from 1.7 to 65.0%. No association was found between any of the above-mentioned parameters and clinical stage or histological type of tumor. When analyzing overall survival, a statistically significant difference was found between stage IIB patients with aneuploid and diploid DNA content. In 39 carcinomas evaluated after 1 week of radiotherapy, irradiation induced a significant decrease in Ki-67 index. In 7 aneuploid tumors where cell cycle analysis was feasible, a significant increase in G2 + M phase fraction was observed (P < 0.02). We suggest these parameters are therefore useful to monitor radiation-induced alterations in cell cycle and proliferation. © 1995 Wiley-Liss, Inc.