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IntroductionDNA is most of the time wrapped around an octamer of histones, which together make upthe nucleosome (see Figure 4 for DNA packing strategies). The octamer is comprised of twoof each of the histones H2A, H2B, H3 and H4. Methylation of DNA is accompanied bypost-translational modifications of histones which modulate DNA function, regulatechromatin structure and determine the transcriptional state of the DNA wrapped aroundit[31]. The sum of post-translational modifications of amino-terminal tails of histonesconstitutes the histone code[35], and include acetylation, methylation, phosphorylation andubiquitinylation[36]. Certain modifications such as methylation of Lys4 of H3 (H3-K4) isassociated with active gene expression, while others, like methylation of Lys9 of H3 (H3-K9)is associated with transcriptional silencing[8]. There is a whole range of differentmodifications, and much effort is aiming at fully deciphering the histone code.Figure 4.Packaging of DNA.147 bases of thedouble helix iswrapped twicearound the octamerof histones(nucleosome), with ashort stretch of linkerDNA connecting thenucleosomes,resembling beads ona string. The histonetails are available forpost-translationalmodifications at thisstep, and dependingon the modificationthe DNA can bemore or lessaccessible fortranscription factors.The nucleosomes arefurther packed intofibresofnucleosomes which isfurther condenseduntil the ultimatecondensation, thevisible chromosomeduring mitosis.Figure taken from[36].18
IntroductionEven though this study focuses on the role of DNA methylation in cancer, its role in normallife and development must also be addressed. During mammalian embryogenesis both thepaternal and the maternal DNA in the zygote undergo extensive erasure and reprogrammingof DNA methylation[8], resetting close to all methylation marks. The reason for this remethylationprocess is unclear, but it has been suggested that it will lead to decondensationof chromatin and activation of transcription of genes which are important in earlydevelopment[8].Both X-chromosome inactivation and genomic imprinting are closely regulated bymethylation. In contrast to most of the human genes which are expressed in a diploidmanner, imprinted genes and the X-chromosome are only present in one parental copy,while the other is epigenetically silenced. The majority of imprinted genes identified so farare involved in growth, and imprinting might be a strategy to balance the maternal andpaternal demands on the rate of fetal growth[37;38]. IGF2 is an example of an imprintedgene, and while hypermethylation of gene promoters are associated with lost geneexpression, studies have shown that hypermethylation of repressor elements within andupstream of the insulin-like growth factor 2 (Igf2) gene in mice increases the expression asproteins involved in the Igf2 repression are now unable to bind to the sequence.[39;40].DNA methylation is also involved in silencing of repetitive and viral sequences present inour genome[41]. At least 35% of our genome is constituted by tranposons, viral DNA andother parasitic sequences[42], and the human cell protects itself from this by methylationinducedinactivation. While most of the CpG islands remain unmethylated under normalcircumstances, the majority CpG-sites outside the CpG islands are methylated[25], and muchof this methylation can be explained by this protective silencing strategy. Figure 5summarizes the difference in methylation features between a normal and a cancer setting.19
Page 1 and 2: Novel genetic and epigenetic altera
Page 3 and 4: TABLE OF CONTENTSACKNOWLEDGEMENTS .
Page 5 and 6: ACKNOWLEDGEMENTSThe present work ha
Page 7 and 8: Prefacetechnology[3]. This new tech
Page 10 and 11: SummaryThe subgroup of carcinomas w
Page 12 and 13: Introduction“Epigenetic inheritan
Page 14 and 15: Introductionamino acid change it is
Page 16 and 17: Introductionmethylation during embr
Page 20 and 21: IntroductionFigure 5. DNA methylati
Page 22 and 23: IntroductionFigure 6. Incidence rat
Page 24 and 25: IntroductionFigure 8. Tumor staging
Page 26 and 27: Introductioninasmuch as 80% of colo
Page 28 and 29: IntroductionInstabilities involved
Page 30 and 31: Introductionthere seems to be a fid
Page 32 and 33: Introductionsevere alterations are
Page 34 and 35: Introductionpopulation-wide screeni
Page 36 and 37: IntroductionFigure 12. Present and
Page 38 and 39: RESULTS IN BRIEFPaper Ia. “DNA hy
Page 40 and 41: Results in Briefinstability, and se
Page 42 and 43: Results in BriefUnivariate survival
Page 44 and 45: Discussionseveral factors, and full
Page 46 and 47: Discussionlow threshold, we increas
Page 48 and 49: DiscussionIt may seem like unnecess
Page 50 and 51: Discussionthan 96% DHPLC do not sta
Page 52 and 53: DiscussionFigure 13. Mutation detec
Page 54 and 55: DiscussionClinical impact of molecu
Page 56 and 57: Discussionmarkers with a very high
Page 58 and 59: Discussionchromosomes in metaphase[
Page 60 and 61: DiscussionThese examples underline
Page 62 and 63: Discussiongenes. One is based on mu
Page 64 and 65: CONCLUSIONSWe have identified novel
Page 66 and 67: 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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Paper IITerje Ahlquist, Guro E Lind
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BackgroundMost cases of colorectal
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ADAMTS1 CDKN2A CRABP1 HOXA9 MAL MGM
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pseudogene, leading to a high rate
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strands. Proc Natl Acad Sci U S A 1
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concomitant absence of transcript a
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Volume 10 Number 7 July 2008 pp. 68
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682 RAS Signaling in Colorectal Car
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Table W2. Detailed Somatic Events o
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Identification of RCC2 as a prognos
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INTRODUCTIONMicrosatellite instabil
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unselected series of primary tumors
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specificity, i.e. that they only am
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On the assumption that DNA repair a
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In order to ensure that gene mutati
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Figure 2. Mutation frequency differ
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and TAF1B (0.50), ACVR2A and ASTE1
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Multivariate analysesA multivariate
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When comparing our findings of muta
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The test series included a low numb
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entering M-phase remains to be seen
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12. Duval A, Reperant M, Hamelin R
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34. Martineau-Thuillier S, Andreass
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AppendicesAppendix I:List of abbrev
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Critical Reviews TM in Oncogenesis,
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TARGET GENES OF MSI COLORECTAL CANC
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