Novel genetic and epigenetic alterations in ... - Ous-research.no
Novel genetic and epigenetic alterations in ... - Ous-research.no Novel genetic and epigenetic alterations in ... - Ous-research.no
Figure 3.Representativeelectropherogramresults and thesequenceconfirmation. SampleID and mutation statusas determined withfragment analysis areshown in the top leftcorner of each sample.The electro-pherogramsare shown in the toppanel for each of theASTE1, PTHLH andZMYND8. The bottompanel of each geneincludes the sequenceconfirming thefragment analysis. Thecorrect mononucleotiderepeat is (A)11, (A)11and (A)8, respectively.As the sequences areobtained using thereverse primer, thebases are inversed andcomplementary to thereference sequence.Correlation analysesBimodal Pearson’s correlation analyses were performed in order to detect any co-occurrenceof mutations between the different genes. Mutations in ACVR2A and TGFBR2 (correlationcoefficient 0.54), TAF1B and ASTE1 (0.57), TAF1B and ACVR2A (0.55), and MRE11Aand ASTE1 (0.51) correlated significantly in the test series (P = 2.9x10 -7 , 2.5x10 -8 , 1.2x10 -7 ,2.3x10 -6 , respectively).Significant correlation of mutations between TAF1B and ACVR2A (correlation coefficient0.58) and MRE11A and ASTE1 (0.61) (P = 5.5x10 -9 and 4.2x10 -10 , respectively) were verifiedin the validation series. In addition, mutations in MARCKS and ACVR2A (0.57), MRE11A14
and TAF1B (0.50), ACVR2A and ASTE1 (0.54), PCNXL2 and ACVR2A (0.51), andMRE11A and PTHLH (0.59) showed correlation greater than 0.50 (P = 1.7x10 -7 , 1.6x10 -6 ,2.9x10 -9 , 1.1x10 -7 and 2.6x10 -9 , respectively).Genetic and clinico-pathological associationsNo associations were seen between individual mutation status and tumor stage or gender,except for MSH3 and female gender (P = 0.025) in the test series. Nor when comparing themean number of mutated genes per sample to gender or tumor stage any associations wereseen.Several of the genes show a significant difference in mutation frequency when comparingtumor location, as right-sided MSI tumors often show a higher mutation frequency than leftsidedand especially rectal tumors. ACVR2A, ASTE1, CASP5, MARCKS, MBD4,MRE11A, MSH3, TAF1B and TFGBR2 were all significantly more mutated in right-sidedtumors compared to both left-sided and rectal tumors (Table 1). In addition, PRDM2, BAXand E2F4 showed the same tendency, although not reaching a 5% level of significance (P =0.081, 0.094 and 0.077, respectively). When comparing the mean number of mutations, theright-sided tumors carried a significantly higher number compared to the rectal tumors(mean rank 20.4 and 10.6, respectively, P = 0.008). The association between mutationfrequency and site for the five MSI consensus genes, BAX, IGF2R, MSH3, MSH6 andTGFBR2, are included in another study (Teixeira et al., unpublished).15
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- Page 105: Paper IITerje Ahlquist, Guro E Lind
- Page 108 and 109: BackgroundMost cases of colorectal
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- Page 133 and 134: INTRODUCTIONMicrosatellite instabil
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- Page 159: AppendicesAppendix I:List of abbrev
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Figure 3.Representativeelectropherogramresults <strong>and</strong> thesequenceconfirmation. SampleID <strong>and</strong> mutation statusas determ<strong>in</strong>ed withfragment analysis areshown <strong>in</strong> the top leftcorner of each sample.The electro-pherogramsare shown <strong>in</strong> the toppanel for each of theASTE1, PTHLH <strong>and</strong>ZMYND8. The bottompanel of each gene<strong>in</strong>cludes the sequenceconfirm<strong>in</strong>g thefragment analysis. Thecorrect mo<strong>no</strong>nucleotiderepeat is (A)11, (A)11<strong>and</strong> (A)8, respectively.As the sequences areobta<strong>in</strong>ed us<strong>in</strong>g thereverse primer, thebases are <strong>in</strong>versed <strong>and</strong>complementary to thereference sequence.Correlation analysesBimodal Pearson’s correlation analyses were performed <strong>in</strong> order to detect any co-occurrenceof mutations between the different genes. Mutations <strong>in</strong> ACVR2A <strong>and</strong> TGFBR2 (correlationcoefficient 0.54), TAF1B <strong>and</strong> ASTE1 (0.57), TAF1B <strong>and</strong> ACVR2A (0.55), <strong>and</strong> MRE11A<strong>and</strong> ASTE1 (0.51) correlated significantly <strong>in</strong> the test series (P = 2.9x10 -7 , 2.5x10 -8 , 1.2x10 -7 ,2.3x10 -6 , respectively).Significant correlation of mutations between TAF1B <strong>and</strong> ACVR2A (correlation coefficient0.58) <strong>and</strong> MRE11A <strong>and</strong> ASTE1 (0.61) (P = 5.5x10 -9 <strong>and</strong> 4.2x10 -10 , respectively) were verified<strong>in</strong> the validation series. In addition, mutations <strong>in</strong> MARCKS <strong>and</strong> ACVR2A (0.57), MRE11A14
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