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

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RØYRVIK ET AL.gene must be validated by functional suppressor studies <strong>in</strong> <strong>in</strong> vivo or <strong>in</strong> vitromodels. These criteria have been criticized as excessively narrow: 160 (1) Inactivationevents are <strong>no</strong>t the only functionally important types of mutation, for example,AXIN2 <strong>and</strong> TCF4 are ack<strong>no</strong>wledged target genes but the mutations to which theyare subject are <strong>no</strong>t expected to be <strong>in</strong>activat<strong>in</strong>g. (2) Biallelic <strong>in</strong>activation need <strong>no</strong>tbe a requirement <strong>in</strong> the case of haplo<strong>in</strong>sufficiency (see below), c.f. the dearth ofbiallelic TAF1B <strong>in</strong>activation. 44 To be truly useful, 3 <strong>and</strong> 4 would have to entailcomplete k<strong>no</strong>wledge both of all possible growth suppressor pathways <strong>and</strong> ofevery gene or pathway <strong>in</strong>volved mismatch repair proficient cancers, <strong>and</strong> 4 <strong>in</strong>cludesthe assumption that the molecular pathway to MSS <strong>and</strong> MSI tumors areessentially equivalent, which is <strong>no</strong>t necessarily the case. Nor do all ack<strong>no</strong>wledgedtarget genes participate <strong>in</strong> growth suppressor pathways, most <strong>no</strong>tablyMSH3/6. 159 Regard<strong>in</strong>g criterion 5, such studies are lack<strong>in</strong>g for most target genes,<strong>and</strong> furthermore, it is unsuitable for several types of potential target genes. Thetransformed phe<strong>no</strong>type, for example, will <strong>no</strong>t be reversed <strong>in</strong> the event of re<strong>in</strong>troductio<strong>no</strong>f a wild-type mutator target gene to a system, 160 <strong>and</strong> a gene with <strong>no</strong>k<strong>no</strong>wn functional significance <strong>in</strong> tumor progression may yet be of prog<strong>no</strong>sticcl<strong>in</strong>ical significance. Among the genes which have been subject to functionalstudies are AXIN2, BAX, E2F4, RIZ, TCF4, <strong>and</strong> TGFRII. 45,68,111,156,161,162Duval <strong>and</strong> Hamel<strong>in</strong> proposed a fourfold, functional classification of affectedgenes <strong>in</strong>to survivor genes, hibernator genes, cooperator genes <strong>and</strong> transformatorgenes. 159Survivor genes encode vital products <strong>and</strong> whose <strong>in</strong>activation should exert anegative selection pressure. Hibernator genes are <strong>no</strong>nvital <strong>and</strong> downregulated,<strong>and</strong> should have a mutation rate <strong>in</strong> the background range. Cooperator genes designatesets of genes with the same term<strong>in</strong>al effect, e.g., promotion of apoptosis,which have a synergistic effect without any one gene requir<strong>in</strong>g a high mutationfrequency. Transformator genes are those which, upon mutation, <strong>in</strong>dependentlyconfer a selection advantage to the cells concerned, <strong>and</strong> therefore should have thehighest mutation frequency. These categories are thought to be mutated <strong>in</strong> a preferentialorder, with the transformator TGFRII be<strong>in</strong>g among the earliest. 49,16352The statistical regression model presented by Woerner et al. takes <strong>in</strong>to considerationthe fact that longer repetitive tracts are more mutable (see below), i.e.the background rate for them is higher, <strong>and</strong> a gene with a mutation frequencyabove the 95% prediction <strong>in</strong>terval for any given repeat length is considered a realtarget gene. TGFRII, BAX, TCF4, MSH3, ACVR2, PTHL3, HT001, <strong>and</strong>SLC23A1 are, by this method, considered genu<strong>in</strong>e positive targets for MSI colorectalcancer, while the authors ack<strong>no</strong>wledge the <strong>in</strong>applicability of the model asregards target pathways, c.f. cooperator genes above.Due to the difficulties of implement<strong>in</strong>g clear-cut qualitative criteria—functional aspects of s<strong>in</strong>gle <strong>genetic</strong> products <strong>and</strong> their <strong>in</strong>teractions are often <strong>in</strong>sufficientlyelucidated, likewise signal<strong>in</strong>g pathways <strong>and</strong> cascades—it has beenmost common to use the unmanipulated mutation frequency as the primary or240

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