P53 mutations

A protein with the innocuous name p53 is one of the most frequently cited biological molecules in the Science Citation Index. The "p" in p53 stands for protein and "53" indicates a molecular mass of 53 kDa. The p53 protein plays a fundamental role in human cell growth and mutations in this protein are frequently associated with the formation of tumors. It is estimated that of the 6.5 million people diagnosed with one or another form of cancer each year about half have p53 mutations in their tumor cells and that the vast majority of these mutations are single point mutations. 

Soini, Y., Welsh, J. A., Fshak, K. G., and Bennet, W. P. (1995). p53 mutations in primary hepatic angiosarcomas not associated with vinyl chloride exposure. Carcinogenesis 16, 2879-2881. 

Frebouig, T. and Friend, S.H. (1992). Cancer risks from germline p53 mutations. J. Clin. Invest. 90, 1637-1641. 

A combination of pulse field gel electrophoresis to separate large DNA restriction fragments, amplification by PCR, and detection with p53 cDNA probes has been useful to study chromosomal deletions and p53 mutations in colorectal cancers (Bl). 

Kuo MY, Huang JS, Hsu HC, Chiang CP, Kok SH, Kuo YS, Hong CY. (1999). Infrequent p53 mutations in patients with areca quid chewing-associated oral squamous cell carcinomas in Taiwan. J Oral Pathol Med. 28(5) 221-25. 

Tannapfel A, Busse C, Weinans L, Benicke M, Katalinic A, Geissler F et al (2001). INK4a ARF alterations and p53 mutations in hepatocellular carcinomas. Oncogene 20 7104 7109. 

Esophagus (squamous carcinoma KYSE-30 cells) DOC Increase in p53 mutations 8... 

Figure 4.2 The spectrum of p53 mutations detected in oesophageal adenocarcinoma tumours. Data were downloaded from the lARC database and based on an analysis of 260 separate mutation profiles.

Akiyama T, Yoshida T, Tsujita T, Shimizu M, Mizukami T, Okabe M, Akinaga S (1997) G1 phase accumulation induced by UCN-01 is associated with dephosphorylation of Rb and CDK2 proteins as well as induction of CDK inhibitor p21/CiplAVAFl/Sdil in p53-mutated human epidermoid carcinoma A431 cells. Cancer Res 57 1495-1501... 

The role ofp53 in flouropyrimidine-radiation interaction remains controversial. Some investigators have suggested that cells which are p53 mutated are more resistant to radiation (48), whereas others have found that p53 status is unrelated to radiation sensitization (49-51). Studies on SW620 cells (which are not sensitized) and HT29 cells... 

Brachman DG, Beckett M, Graves D, et al. p53 mutation does not correlate with radiosensitivity n 24 head and neck cancer cell lines. Cancer Res 1993 53 3667-3669. 

Evidence has also come to light that suggests that cells containing p53 mutations are more sensitive to paclitaxel s cytotoxic effects than those with wild-type copies of the gene (12-14). Wang et al. outline how thep53 status may impact on paclitaxel sensitivity in their review of paclitaxel induced cell death (15). They suggest that ... 

Kandioler-Eckersberger D, Ludwig C, Rudas M, et al. T P53 mutation and p53 overexpression for prediction of response to neoadjuvant treatment in breast cancer patients. Clin Cancer Res 2000 6 50-56. 

Lee JM, Bernstein A. p53 mutations increase resistance to ionizing radiation. Proc Natl Acad Sci USA 1993 90 5742-5746. 

E) Clinical results support that only patients with p53 mutations in their tumors respond to the treatment. 

NT071 Lazarus, P., A. M. Idris, J. Kim, A. Calcagnotto, and D. Hoffmann. p53 mutations in head and neck squamous cell carcinomas from Sudanese snuff (toombak) users. Cancer Detect Prev 1996 20(4) 270-278. 

Kalemi TG, Lambropoulos AF, Gueorguiev M et al (2005) The association of p53 mutations and p53 codon 72, Her 2 codon 655 and MTHFR C677T polymorphisms with breast cancer in Northern Greece. Cancer Lett 222 57-65... 

The large number of known sequences of the p53 gene from tumor patients was particularly valuable for interpretation of the crystal structure since a spectrum could be assembled for p53 mutation in association with tumor formation. The mutation spectrum shown in Fig. 14.9 shows hotspots , positions at which p53 mutations are seen particularly frequently in tumor patients. 

Fig. 14.9. Mutation spectrum of the p53 protein in tumors. The linear strnctnre is shown of p53 and the frequency of mutations found in tumors. The black bars indicate the approximate position and the relative frequency of the p53 mutations. The frequency of mutations in the region of the DNA binding domain is of note. The sites of the most frequent mutations coincide with positions of the p53 protein that are directly involved in interactions with the DNA sequence (see Fig. 14.8). According to Cho et al., (1994), with permission.

Malkin, D. Germline p53 mutations and heritable cancer (1994) Annu. Rev. Gen. 28, 443-465 Marshal, C.J. Tumor suppressor genes (1991) Cell 64, 313-326... 

Mutations in the gene for p53 also cause tumors in more than 90% of human cutaneous squamous cell carcinomas (skin cancers) and about 50% of all other human cancers, p53 is defective. Those very rare individuals who inherit one defective copy of p53 commonly have the Li-Fraumeni cancer syndrome, in which multiple cancers (of the breast, brain, bone, blood, lung, and skin) occur at high frequency and at an early age. The explanation for multiple tumors in this case is the same as that for Rb mutations an individual bom with one defective copy of p53 in every somatic cell is likely to suffer a second p53 mutation in more than one cell in his or her lifetime. 

M. A. Tainsky, and S. H. Friend, Germ line p53 mutations in a familial syndrome of breast cancer, sarcomas, and other neoplasms. Science 250 1233-1238, 1990. 

Zhang Z, Liu Q, Lantry LE, Wang Y, Kelloff GJ, Anderson MW, Wiseman RW, Lubet RA, You M. 2000. A germ-line p53 mutation accelerates pulmonary tumorigenesis p53-independent efficacy of chemopreventive agents green tea or dexamethasone/ myo-inositol and chemotherapeutic agents taxol or adriamycin. Cancer Res 60 901-907. 

Petit, B., Leroy, K., Kanavaros, P., Boulland, M., Druet-Cabanac, M., Haioun, C., Bordessoule, D., and Gaulard, P. 2001. Expression ofp53 protein in T and NK-cell lymphomas is associated with some clinicopathologic entities but rarely related to p53 mutations. Human Pathol. 32 196-204. 

Hollstein M, Sidransky D, Vogelstein B, Harris CC. 1991. p53 mutations in human cancers. Science 253(5015) 49-53. 

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