Molecular Alterations In Cancer

The molecular alterations occurring in cancer typically reflect mutations and can be categorized into two major groups: (1) chromosomal abnormalities and (2) nucleotide sequence abnormalities. There has been some debate in the literature as to which forms of mutation (chromosomal or nucleotide sequence) are more prevalent in cancer cells and/or constitute the foundations of the molecular mechanism of neoplastic transformation (44). However, there is abundant evidence that representations of both of these major categories of genetic abnormalities exist in most tumor cells and that both significantly contribute to neoplastic transformation.

4.1. CHROMOSOMAL ABNORMALITIES Chromosomal alterations in cancer include the gain or loss of one or more chromosomes (aneuploidy), chromosomal rearrangements resulting from DNA strand breakage (translocations, inversions, and other rearrangements), and gain or loss of portions of chromosomes (amplification, large-scale deletion). The direct result of chromosomal translocation is the movement of some segment of DNA from its natural location into a new location within the genome, which can result in altered expression of the genes that are contained within the translocated region. If the chromosomal breakpoints utilized in a translocation are located within structural genes, then hybrid (chimeric) genes can be generated. The major consequence of chromosomal deletion (involving a whole chromosome or a large chromosomal region) is the loss of specific genes that are localized to the deleted chromosomal segment, resulting in changes in the copy number of the affected genes. Likewise, gain of chromosome number or amplification of chromosomal regions results in an increase in the copy numbers of genes found in these chromosomal locations.

4.2. NUCLEOTIDE SEQUENCE ABNORMALITIES Nucleotide sequence alterations in cancer include changes in individual genes involving single-nucleotide changes (missense and nonsense) and small insertions or deletions (some of which result in frameshift mutations). Single-nucleotide alterations that involve a change in the normal coding sequence of the gene (point mutations) can give rise to an alteration in the amino acid sequence of the encoded protein. Missense mutations alter the translation of the affected codon, whereas nonsense mutations alter codons that encode amino acids to produce stop codons. This results in premature termination of translation and the synthesis of a truncated protein product. Small deletions and insertions are typically classified as frameshift mutations, because deletion or insertion of a single nucleotide (for instance) will alter the reading frame of the gene on the 3' side of the affected site. This alteration can result in the synthesis of a protein that bears very little resemblance to the normal gene product or in the production of a abnormal/truncated protein resulting from the presence of a stop codon in the altered reading frame. In addition, deletion or insertion of one or more groups of three nucleotides will not alter the reading frame of the gene, but it will alter the resulting polypeptide product, which will exhibit either loss of specific amino acids or the presence of additional amino acids within its primary structure.

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