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Previous studies have shown that RCC2 (also known as TD-60) is associated with thesegregation of chromosomes in metaphase.[34] Indeed, RCC2 is critical for the integrationof kinetochores into the mitotic spindle, and may be required for overall spindleassembly.[35] siRNA suppression shows that RCC2 is absolutely required for progressionfrom prometaphase to metaphase and that its suppression activates the spindle assemblycheckpoint, hence creating an effective G2/M arrest, indefinitely blocking cells fromcompleting mitosis.[35] The same study also suggested that the presence of RCC2 is criticalfor the recruitment of other proteins involved in cell division to inner centromeres inmitosis, supported by a novel study which show that RCC2 is important for AURORA B (aprotein involved in the chromosomal passenger complex) localization, but not activity, andthat RCC2-depleted extracts were impaired in their ability to align chromosomes to themetaphase plate.[36]These findings support the assumption that mutation in RCC2 can be associated withimproved survival as cells with this mutation will be arrested before cell division if themutation causes transcriptional inactivation. The (A)10 repeat in RCC2 is located in exon 1which is in the 5’ untranslated region (UTR) of the gene, 76 bases upstream of the startcodon. UTRs are known to affect mRNA nuclear export, cytoplasmic localization andtranslational efficiency and stability.[37] The majority of translational control occurs at thelevel of initiation, thus implicating the 5’ UTR as a major site of translationalregulation.[38;39] It has also been shown that mononucleotide repeats in UTRs areconserved due to possible selective pressure relating to a functional role, and that theseconserved repeats are frequently altered in MSI-cancers, and so are speculated to be involvedin regulating gene expression.[40] Whether or not the indels seen in RCC2 arrest the cells22
entering M-phase remains to be seen, but the aforementioned studies combined with thepositive survival data seen here indicates that this might be the case.To summarize, by use of two independent tumor series we have showed that indels in RCC2divide the MSI subgroup into those with good and poor prognosis, and that this holds evenafter stratifying the tumors according to tumor stage.23
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Novel genetic and epigenetic altera
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TABLE OF CONTENTSACKNOWLEDGEMENTS .
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ACKNOWLEDGEMENTSThe present work ha
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Prefacetechnology[3]. This new tech
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SummaryThe subgroup of carcinomas w
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Introduction“Epigenetic inheritan
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Introductionamino acid change it is
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Introductionmethylation during embr
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IntroductionDNA is most of the time
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IntroductionFigure 5. DNA methylati
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IntroductionFigure 6. Incidence rat
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IntroductionFigure 8. Tumor staging
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Introductioninasmuch as 80% of colo
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IntroductionInstabilities involved
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Introductionthere seems to be a fid
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Introductionsevere alterations are
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Introductionpopulation-wide screeni
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IntroductionFigure 12. Present and
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RESULTS IN BRIEFPaper Ia. “DNA hy
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Results in Briefinstability, and se
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Results in BriefUnivariate survival
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Discussionseveral factors, and full
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Discussionlow threshold, we increas
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DiscussionIt may seem like unnecess
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Discussionthan 96% DHPLC do not sta
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DiscussionFigure 13. Mutation detec
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DiscussionClinical impact of molecu
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Discussionmarkers with a very high
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Discussionchromosomes in metaphase[
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DiscussionThese examples underline
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Discussiongenes. One is based on mu
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CONCLUSIONSWe have identified novel
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Future PerspectivesMolecular risk a
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REFERENCES1. Breasted J (1930) The
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References29. Deng G, Chen A, Pong
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References57. Al-Sukhni W, Aronson
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References84. Kunkel TA (1993) Nucl
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ReferencesLeggett B, Levine J, Kim
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References133. Lind GE, Thorstensen
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References156. Meling GI, Lothe RA,
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ReferencesT, Song X, Day RH, Sledzi
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References196. Honda S, Haruta M, S
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ORIGINAL ARTICLESAPPENDIXAppendix I
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GASTROENTEROLOGY 2007;132:1631-1639
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Paper IbGuro E Lind, Terje Ahlquist
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Journal of Translational Medicine 2
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Page 102 and 103: Journal of Translational Medicine 2
Page 105: Paper IITerje Ahlquist, Guro E Lind
Page 108 and 109: BackgroundMost cases of colorectal
Page 110 and 111: ADAMTS1 CDKN2A CRABP1 HOXA9 MAL MGM
Page 112 and 113: pseudogene, leading to a high rate
Page 114 and 115: strands. Proc Natl Acad Sci U S A 1
Page 116 and 117: concomitant absence of transcript a
Page 119 and 120: Volume 10 Number 7 July 2008 pp. 68
Page 121 and 122: 682 RAS Signaling in Colorectal Car
Page 127: Table W2. Detailed Somatic Events o
Page 131 and 132: Identification of RCC2 as a prognos
Page 133 and 134: INTRODUCTIONMicrosatellite instabil
Page 135 and 136: unselected series of primary tumors
Page 137 and 138: specificity, i.e. that they only am
Page 139 and 140: On the assumption that DNA repair a
Page 141 and 142: In order to ensure that gene mutati
Page 143 and 144: Figure 2. Mutation frequency differ
Page 145 and 146: and TAF1B (0.50), ACVR2A and ASTE1
Page 147 and 148: Multivariate analysesA multivariate
Page 149 and 150: When comparing our findings of muta
Page 151: The test series included a low numb
Page 155 and 156: 12. Duval A, Reperant M, Hamelin R
Page 157 and 158: 34. Martineau-Thuillier S, Andreass
Page 159: AppendicesAppendix I:List of abbrev
Page 163 and 164: Critical Reviews TM in Oncogenesis,
Page 165 and 166: TARGET GENES OF MSI COLORECTAL CANC
Page 191: TARGET GENES OF MSI COLORECTAL CANC
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