Tumors mutation patterns

C. Role of Environment in Shaping Tumor Mutation Patterns... 

Fig. 3A Role of exogenous and endogenous factors in shaping tumor mutation patterns. Mini-hotspots in the p53 coding sequence. Distribution of four mutation types in the coding sequence, GC to AT transitions at CpG (representing 23% of all mutations), GC to TA transversions (15%), GC to CG (8%), and AT to GC (12%). CpG transitions primarily appear as the consequence of an endogenous mutation mechanism and form well-defined mutation hotspots. Because of these major hotspots, the mini-hotspots corresponding to other mutation types are difficult to detect. Only sites that contain more than 1 % of a specific mutation type are shown. Hotspot codons for each mutation type are indicated. Some of the non-CpG hotspots are well-characterized sites of alteration induced by exogenous carcinogens (see Fig. 5).

In human tumors, the pattern of p53 mutations is dominated by base transitions (C to T or G to A) at CpG dinucleotides (23% of all mutations). Although this type of mutation has been observed at 35 different codons, 90% of human CpG transitions are at one of six hotspot codons 175,213,245, 248, 273 and 282 (Fig. 3A) known to be important in maintaining p53 biological activity. CpG dinucleotides are sites of cytosine methylation, and deamination of 5-methylcytosine producing thymine is the most characteristic event generating spontaneous mutations in mammalian cells (Barker et... 

Despite the common features of mutation profiles discussed earlier, the assembly of p53 mutation data provides several contrasting patterns that are statistically significant in a number of well-defined tumor types. Factors that influence the formation of distinctive mutation patterns can be seen as a succession of filters that allow for acquisition and persistence of particular mutations. First, the metabolic capacity of exposed cells and tissues largely determines the initial extent of DNA damage induced by a given mutagen. 

Mass, M.J. and Wang, L. (1997) Arsenic alters cytosine methylation patterns of the promoter of the tumor suppressor gene p53 in human lung cells a model for a mechanism of carcinogenesis. Mutation Research-Reviews in Mutation Research, 386(3), 263-77. 

Trout experimentally exposed to DEN, administered in the diet, also display K-ras mutations82. Seven DEN-induced liver tumors were examined for evidence of K-ras-activating mutations. Of these, a high proportion (6/7) carried a codon 12 GGA to AGA mutation82. The pattern of mutational spectrum for this compound, again,... 

The CTNNBl gene encodes 3-catenin, which is an important intermediary in the Wnt signaling pathway.1 0441 Point mutations of CTNNBl occur in 25% and 66% of poorly differentiated and undifferentiated thyroid carcinomas, respectively. As discussed in a previous section, most tumors with mutations have a nuclear pattern of localization, in contrast to the usual plasma membrane staining pattern of differentiated tumors. 

High-grade neuroendocrine carcinomas in the colon and rectum most commonly occur as a component of poorly differentiated adenocarcinomas more than 50% of the tumor should show neuroendocrine differentiation in order to be called a neuroendocrine carcinoma. Both small cell and non-small cell types exist, and both tend to stain with low-molecular-weight cytokeratin (CAM5.2) in a perinuclear dot pattern, as well as with synaptophysin, chromogranin, and/or NSE (Fig. 14.32). ° ° GDI 17 stains a substantial minority of high-grade neuroendocrine carcinomas however, immunoreactivity has not been linked to c-kit juxta-membrane (exon 11) mutations. 

Wilms tumor Triphasic blastemal, epithelial, and stromal components. Blastemal cells small, round or oval, in nodules or serpentine patterns. Epithelial component primitive rosette-like to tubular or papillary. Mesenchymal component fibrous, myoid, adipose, chondroid, osseous, neural. Blastemal vimentin, desmin. Epithelial cytokeratin. Mesenchymal variable according to differentiation pattern. Various abnormalities including mutations of WT1 at 11 pi 3 and WT2 at 11 pi 5 numeric and structural karyotypic abnormalities of chromosomes 1, 11, 13, 14, 16, 1 7, 19, and 22. 

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