The gene for TP53 (the term p53 comes from 53-kDa nuclear phosphoprotein) is located at  human chromosome band 17p13.1 . This gene is 20 kb long and has 11 exons. The processed mRNA of this gene is 2.2-2.5 kb long. The first exon (213 bases) is noncoding and is 6-10 kb from the other exons. The product of the TP53 tumour suppressor gene functions as a transcription factor that binds to a specific DNA sequence in the promoter region of TP53-responsive genes (Levine 1993).

The human TP53 protein with its 393 amino acid residues can be divided into several functional domains which is thoroughly reviewed (Ko et al. 1996). In haematological tumour cells, the main function of TP53 protein is in cell-cycle regulation at the G1/S (Bae et al. 1995a) and G2/M (Agarwal et al. 1995) checkpoints, stimulation of apoptosis (Yonish-Rouach et al. 1991) and genetic stability (Wahl et al. 1997). The literature states that alterations of the TP53 gene may play a central role in the carcinogenesis process, prognosis and response to treatment in a variety of tumours, including hematopoietic tumours (Ichikawa 2000).

 

The clinical significance of the TP53 tumour suppressor status has been studied by many authors because it is believed that this knowledge may contribute to the selection of chemotherapy for individual patients (Tolis et al. 2000). However, controversy exists when the relationship between TP53 mutation status and response or survival of patients is considered (Sohn et al. 2003; Akasaka et al. 1996; Chilosi et al. 1996; Kramer et al. 1996; Johnston et al. 1997; Osada et al. 1997; Kasimir-Bauer et al. 1998; Zhou et al. 1998; Lam et al. 1999; Pescarmona et al. 1999; Ahn et al. 2000; Stokke et al. 2000; Pagnano et al. 2001; Liu et al. 2002). Differences in results and conclusions between those studies are due to  the sensitivity of techniques like immunohistochemistry, used to detect mutations in TP53. This was observed by recent studies also (Amini et al. 2002; Jezersek-Novakovic et al. 2002), which suggest that such techniques fail to correlate TP53 mutation with outcome of therapy. Accumulation of TP53 protein is not only due to of the presence of mutation in its gene. DNA damage is one of the major causes for TP53 overexpression. Binding with several cellular or viral factors also was reported to increase the half-life of TP53 protein in the nucleus, hence, leading to accumulation of wt-TP53 (Wynford-Thomas 1992). MDM2 is one of the cellular factors that were found to bind with and inactivate TP53. Interestingly, this regulator of TP53, itself is directly regulated by TP53 on the transcription level after genetic stress (Bae et al. 1995b). On the other hand, TP53 negative staining does not always mean that TP53 is not mutant. Soussi database on TP53 mutations shows several studies that reported point mutations in exon 4 and lead to premature stop-signal at codon 122 giving a short non-functioning polypeptide that may not lack epitopes of N terminus but it is quickly degradable in the cytoplasm since it lacks the nuclear localization domain (Soussi et al. 1994). It is important to note that studies which used direct DNA-sequencing for the detection of TP53 gene mutation did not involve all cases. Only TP53 IHC-positive cases were considered for sequencing.

Therefore, the data from such studies on the relationship of TP53 mutation status to clinicopathological parameters as well as clinical outcomes are questionable.

 

References: A to K / L to Z

 

Why we are slow with predictors?

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ãÑÈÚ äÕ: A predictor is a tumour marker that helps select therapy that is most likely to be effective against a patient’s tumour. It may actually be the target of the therapy, or may be an associated molecule or pathway that modifies the effectiveness of the therapy. Predictive factors can include changes at the genetic level, at the transcriptional level, at the translational or posttranslational level, and/or at the functional level (Hayes 2000). Each of these changes can be assessed by one or more assays, which can be performed using one or more methods with different reagents.

Molecular Oncology

Why we are slow with predictors?

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