Tumors point 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. 

By examining some of the over one thousand tumor-causing point mutations of p53 in the light of its structure, we can identify features of p53 that are necessary for tumor suppression. The amino acids most frequently changed in cancer cells are at or near the protein-DNA interface residues that are infrequently mutated, if at all, are in general far from the DNA-binding site. 

Alvaro V, Levy L, Dubray C, Roche A, Peillon F, Querat B, Joubert D (1993) Invasive human pituitary tumors express a point-mutated alpha-protein kinase C. J Clin Endocrinol Metab 77 1125-1129... 

The second type of point mutation results in the replacement of one amino acid with another. Such mutations will have more or less of an effect depending on which amino acid is changed. Obviously, if a critical amino acid is replaced by one that is unable to provide the same function, the protein will lose some or all of its activity. Mutations within that Ras and Src genes are two examples in which point mutations lead to disease. In the case of the Ras protein, substitution of a single amino acid, most commonly at either position 12 or 61, is associated with the occurrence of several human tumors. In the case of the Src protein, a point mutation that occurs in a tyrosine residue leads to the constitutive activation of the protein and is associated once again with several types of tumors. 

More than 95% of the alterations in the p53 gene are point mutations that produce the mutant p53 protein, which in most cases has lost its transactivational activity, resulting in loss of tumor suppressor activity. p53 is the most commonly mutated gene in human cancers, and such a gene is involved in the development of at least 50% of clinical tumors (Damton, 1998). 

Chromosomal aberrations alter genomic sequence. Thus they are mutagenic. More importantly, chromosomal aberrations may result in loss of tumor suppressor genes and/or activation of oncogenes. Chromosomal aberrations occur quantitatively at a much smaller scale compared to DNA sequence mutations, their biological consequences, however, are generally more severe than most point mutations. 

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