Intragenic Mutation Screen


Small intragenic mutations are commonly found in both recessive oncogenes and dominantly acting oncogenes. Therefore the search for and detection of this type of mutation will lead to identification of both classes of oncogene, including those for which no positional mapping information is available. The presence of small intragenic mutations (in particular those that are predicted to encode truncated versions of the protein) is regarded as the strongest structural evidence that a gene is a recessive oncogene. It also is often the only class of structural change found in many dominantly acting oncogenes in human cancers. This project is systematically screening coding exons and flanking splice junctions of all genes in the human genome for somatically acquired small intragenic mutations in human cancer. For this study we are using DNA from primary tumours and normal genomic DNA from the same individuals in addition to cancer cell lines.

Figure 1. Geographical distribution of active and inactive forms of the caspase-12 gene.

Figure 1. Geographical distribution of active and inactive forms of the caspase-12 gene.



We are designing PCR primers to flank the coding exons and splice junctions of genes in the human genome. The first sets of genes include protein kinases and other genes that are potential therapeutic targets. The genes are amplified by the PCR and the products sequenced. The sequences are compared with a control samples to identify novel variants in the tumour samples. When these are found the tumour is resequenced along with it's matched normal DNA to ascertain if the variant is a somatic mutation. The significance of mutated genes is evaluated by screening a larger series of cancers.


The results from this work are collated and stored in COSMIC. In addition, COSMIC contains somatic mutation data that has been published in the scientific literature.

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