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p53 mutation and cancer

p53 MUTATIONS IN CERVIX CANCER

Tommasino, M., Accardi, R., Caldeira, S., Dong, W., Malanchi, I., Smet, A. and Zehbe, I. (2003) The role of TP53 in Cervical carcinogenesis. Hum Mutat, 21, 307-312.-> Download

Cervix cancer

There is evidence associating specific human papillomaviruses with certain human anogenital cancers (Howley 1991; Zur Hausen and Schneider 1987), most notably cervical cancer. Some studies have demonstrated thatmore than 90 % of cervical carcinomas contain DNA from a high risk HPV (mostly HPV16 and 18 and to a lesser extent, HPV 31, 33, 35, 39, 45, 51, 52 and 56). The DNA is usually found to be integrated but there are some cases where it is apparently extrachromosomal.

The finding that the E6 protein from high risk HPV can induce the degradation of p53 either in vitro or in vivo has led to the proposal that such an inactivation pathway could be involved in the neoplastic process leading to a cervical cancer (Crook et al. 1991; Scheffner et al. 1990). This observation prompted some investigators to study the distribution of p53 mutations in human primary cervical carcinoma (or cell lines) with and without HPV infection. In a first report, Crook et al. (Crook et al. 1991) showed that six HPV-positive cervical cell lines expressed wild-type p53, whereas two apparently HPV-negative lines expressed mutant p53. Scheffner et al. (Scheffner et al. 1991) reported that two other HPV-negative cervical cell lines expressed mutant p53. Analysis of tumor samples from 28 women with primary cancer of the cervix showed that 25 were HPV (16 or 18)-positive but sequencing of the entire coding region of the p53 gene failed to reveal any mutation (Crook et al. 1992). By contrast, sequencing revealed point mutations in p53 from the three HPV-negative tumors.

The fact that HPV-negative carcinomas have a worse prognosis than HPV-positive ones reinforces these results. Inactivation of p53 by E6 protein only leads to the loss of functional p53, whereas somatic mutation results in the expression of an altered p53 protein, which interfering with wild-type p53 can elicit positive transforming activity.

DISTRIBUTION OF p53 MUTATIONS IN CERVIX CANCER

MUTATIONAL EVENTS IN CERVIX CANCER

REFERENCES
•  Busby-Earle RMC, Steel CM, Williams ARW, Cohen B and Bird CC (1992) Papillomaviruses, p53, and cervical cancer. Lancet 339: 1350.
• Borresen AL, Helland A, Nesland J, Holm R, Trope C and Kaern J (1992) Papillomaviruses, p53, and cervical cancer. Lancet 339: 1350-1351.
• Crook T, Wrede D, Tidy JA, Mason WP, Evans DJ and Vousden KH (1992) Clonal p53 mutation in primary cervical cancer - association with human-papillomavirus-negative tumours. Lancet 339: 1070-1073.
• Crook T, Wrede D and Vousden KH (1991) p53 point mutation in HPV negative human cervical carcinoma cell lines. Oncogene 6: 873-875.
• Fujita M, Inoue M, Tanizawa O, Iwamoto S and Enomoto T (1992) Alterations of the p53 gene in human primary cervical carcinoma with and without human papillomavirus infection. Cancer Res 52: 5323-5328.
• Howley PM (1991) Role of human papillomaviruses in human cancer. cancer Res. 51: 5019s-5022s.
• Mcgregor JM, Levison DA, Macdonald DM and Yu CC (1992) Papillomaviruses, p53, and cervical cancer. Lancet 339: 1351.
• Scheffner M, Munger K, Byrne JC and Howley PM (1991) The State of the p53 and retinoblastoma genes in human cervical carcinoma cell lines. Proc Natl Acad Sci USA 88: 5523-5527.
• Scheffner M, Werness BA, Huibregtse JM, Levine AJ and Howley PM (1990) The E6 oncoprotein encoded by human papillomavirus type-16 and type-18 promotes the degradation of p53. Cell 63: 1129-1136.
• Zur Hausen H and Schneider A (1987) The role of papillomaviruses in human anogenital cancer. Papovaviridae 2: 245-263.