Novel genetic and epigenetic alterations in ... - Ous-research.no

TARGET GENES OF MSI COLORECTAL CANCEReven sole criterion for target gene detection, and to treat any involvement of afrequently mutated gene in, e.g., apoptosis or cell cycle control as a bonus. Anotherpotentially complicating factor is that, however detrimental frameshiftsusually are, mutations in the repetitive tracts of target genes do not invariablycause complete inactivation. This appears to be the case for AXIN2, where themutated product is more stable than wild type and may have a dominant negativeeffect, 68 and also for the mutated isoform of TCF4. 162 Both mutated gene productsencourage inappropriate WNT signaling activation, which is cancerpromoting.164The very fact that so many different mutational constellations exist suggeststhat the are few, if any, truly key genes for carcinogenesis among the target genes,TGFRII being the only one to have been accorded such status. 44,55,159 Rather, thecumulative effect of many different and interchangeable mutations may drivetumorigenesis, with very few of the total being decisive in themselves. 159 Nor isit likely that all the relevant microsatellite-containing genes have as yet beentested for mutations in MSI tumors, or even necessarily characterized in anyDNA sequence database. Several studies have used genome-wide sequence databasesearches for genes containing cMNRs as a basis for potential target gene selection.44,53,55,105,119 Such a search * currently yields well over 1000 protein-codinggenes containing the most promising (N)8 repeats, the figure rising more thantenfold when the range is expanded to include (N)6-7. Even allowing for unpublishednegative data, it may be seen from the number of genes in Table I thatfundamental target genes may still lurk in the unplumbed depths of the humangenome.VII. PERSPECTIVESIn addition to the mutational frequency and association studies of small numbersof target genes, future work will hopefully determine the prognostic values ofdistinct combinations of target genes—the prognostic value of any target genemutations is at present unclear. None of the studies examining the matter consistentlycorroborate each other, despite being almost solely concerned with BAXand TGFRII mutations and their inferred effect on patient survival ranges froma poor prognosis through prognostically irrelevant to improved survival.108,154,161,166,167* Scanning for monorepeats in human genes. The 41,030 coding sequences in the transcripts of 20,484 humanprotein-coding genes were downloaded using the BioMart service at www.biomart.org 165 on March 13, 2007. APerl script was written to scan the sequences for repeats. For each gene, only the longest coding sequence wasconsidered. The script identified all mononucleotide repeats of length six and over, and also produced summaryinformation about the repeats in each gene (longest repeat, number of repeats, sum of length of repeats).241