The role of p53 inactivation in human cervical cell carcinoma development

Abstract

Smnumry We investigated the association between human papillomavirus (HPV) infection and p53 gene mutation in 47 primary uterine cervical cancers. HPV DNA sequences were present in 43 cancers (91.5%), and one of these cancers contained a p53 gene mutation. In addition, one of the remaining four HPV-negative cancers also contained a p53 gene mutation. As a result, p53 inactivation corresponded to the development of 44 of the primary uterine cervical cancers studied (93.6%). We obtained both primary and recurrent tumours from four cases. In two of these cases, the HPV genomes that were present in an episomal state in the primary tumours were observed to have disappeared in the recurrent tumours. One of these recurrent tumours also contained a p53 gene mutation, which suggested the possibility that p53 inactivation was September 1994 mutations could exist in other genes that interact with p53 or downstream of p53 and thus result in an identical physiological defect within the cell. Third, mutations in other genes, which are totally unrelated to p53, could occur in some cancers, resulting in a transformation process that is qualititatively different from HPV-mediated carcinogenesis. Thus, the present study was undertaken to define the molecular mechanism associated with HPV-negative cancer development.The polymerase chain reaction (PCR) and subsequent restriction enzyme typing are sufficiently sensitive to detect a subgroup of HPVs associated with cervical cancer. Both a sense primer, pU-lM, that is homologous to a region in the E6 open reading frame (ORF) and an antisense primer, pU-2R, that is homologous to a region in the E7 ORF were used for amplification. This method is also useful in identifying potentially new HPV types (Fujinaga et al., 1991). Southern blot hybridisation in conjunction with polymerase chain reaction (PCR) was able to detect lo-5 to 106 copies of the HPV genome per cell, which was sufficient to determine the presence of HPVs (Roman and Fife, 1989). We thus studied the frequency of HPV infection in 51 cervical cancers that involved both primary and recurrent tumours, and found four primary and two recurrent tumours that were HPV negative. The p53 gene mutation was recognised in 1 of the 45 HPV-positive tumours and in two of six HPV-negative tumours. The HPV genomes that were present as episomes in two primary cancers were observed to have disappeared in the recurrent tumours, and thus suggested the possible route of HPV-negative cancer development.The disappearance of the HPV genome was followed by the appearance of a new p53 mutation in one of these two recurrent tumours. These findings might thus imply both p53 inactivation in the initiation of cervical cell carcinogenesis and the maintenance of transformed properties even if the frequency of p53 mutation was low in HPV-negative cancers.The closest analogue to the interaction between E6 and p53 in cervical cancers is provided by the murine double minute 2 (MDM2) genes and p53 in sarcomas. An MDM2 gene product which binds to p53 has been sh...

Elderly Japanese women with cervical carcinoma show higher proportions of both intermediate-risk human papillomavirus types and p53 mutations

“…The p53 mutation frequency in primary cervical carcinomas has been reported to be 0Ð6% (Fujita et al, 1992;Choo and Chong, 1993;Helland et al, 1993;Paquette et al, 1993;Miwa et al, 1995). The p53 mutation rate in this study was relatively higher compared with the previously reported data.…”

“…The p53 protein in cervical carcinoma is thought to be inactivated presumably due to complex formation with HPV E6 oncoprotein. Although Crook et al initially postulated that p53 mutations were confined to the HPVnegative cervical carcinomas (Crook et al, 1991;Crook and Vousden, 1992), several recent studies implicated that p53 mutation was a very rare event and the occurrence was not strictly correlated with HPV status in primary cervical carcinomas (Fujita et al, 1992;Choo and Chong, 1993;Helland et al, 1993;Paquette et al, 1993;Miwa et al, 1995). It has been also shown that p53 mutants identified in the HPV-positive anogenital cancers exhibit increased resistance to HPV E6-directed degradation, suggesting that mutation of p53 may play a role in the progression of the HPV-positive cervical cancer (Crook and Vousden, 1992).…”

“…In this way, once p53 is mutated, DNA damage is fixed and subsequent genetic rearrangement progress which may be putative mechanisms to initiate cancer. Thus far, exceptionally low prevalence (0Ð6%) of the p53 mutations have been documented in cervical carcinomas (Fujita et al, 1992;Choo and Chong, 1993;Helland et al, 1993;Paquette et al, 1993;Miwa et al, 1995). The p53 protein in cervical carcinoma is thought to be inactivated presumably due to complex formation with HPV E6 oncoprotein.…”

Mutations in the TP53 gene and protein expression of p53, MDM 2 and p21/WAF-1 in primary cervical carcinomas with no or low human papillomavirus load

“…data supporting the hypothesis that specific types of human papillomavirus (HPV) play a central role in the pathogenesis of cervical dysplasia and invasive cancer of the cervix have emerged (Bosch et al 1995). The viral E6 and E7 genes of the high-risk HPV are regularly expressed in HPV-positive tumours (Durst et al 1992 : Jiko et al 1994: Ikenberg et al 1995: MildeLangosch et al 1995: Miwa et al 1995. Hence.…”

“…Recent studies have shown that MDM2 amplification is rare in primary cervical carcinoma (Ikenberg. 1995: Miwa, 1995).…”