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ADAMTS1 CDKN2A CRABP1 HOXA9 MAL MGMT MLH1M U M U M U M U M U M U M USample-typeN1 0 21 0 21 0 21 4 17 1 20 2 19 0 21N2 1 17 2 16 0 18 7 11 2 16 7 10 1 17Adenoma 23 40 10 53 7 53 22 40 45 18 23 39 0 63Carcinomas 36 15 17 35 25 25 12 38 41 9 21 31 11 41MSI statusCarcinomasMSI 19 8 10 17 22 5 7 20 21 6 11 16 11 16MSS 17 7 7 18 3 20 5 18 20 2 10 15 0 25P valueNS NS
An association between hypermethylation and lackof expression has previously been shown for allgenes analyzed in the present study.[8-10,18-21]Although multiple genes are methylated in a cancer,only some are functionally involved intumorigenesis,[22-24] whereas others with unknownfunctional contribution still may serve as goodbiomarkers from a diagnostic perspective.Figure 3. Methylation HeatMap. Hierarchical clusteringreveals that methylation of NR3C1 and RUNX3 are mostclosely related, followed by MLH1 and CRABP1.Methylation of MGMT and HOXA9 are most independentboth from each other and from rest of the set. The genesare presented in columns, while the samples arepresented in rows. Black, unmethylated; red, methylated;and grey, missing values.than the remaining adenomas (mean = 10 mm; P =0.013). In carcinomas, widespread methylation wasseen more frequently in MSI (16/27; 59%) than inMSS (3/25; 12%) samples (P = 0.001). All sixteenMSI samples with widespread methylation showedsimilar molecular profiles when DNA methylationstatus, TP53-, KRAS-, and BRAF-mutation statuswere considered, in line with a CIMP positivephenotype (Figure 4). The three MSS samples withwidespread methylation included one tumor withTP53 mutation, one with both TP53 and KRASmutation and one with BRAF mutation.The distribution of the carcinomas combined withinformation regarding sex, age, MSI-status, andwidespread methylation is illustrated in Figure 5.From the figure we see that widespread methylationis associated with proximal tumors derived fromelderly women.DiscussionWe demonstrate in the present study aberrantpromoter methylation of several genes, at variablefrequencies, in the stepwise development ofcolorectal tumors.Comparing methylation profiles of normalmucosa, adenomas and carcinomas of the largebowelThe identified methylation profiles of normalcolorectal tissues, adenomas, and carcinomasdemonstrated a stepwise increase in CpG islandpromoter methylation towards malignancy,indicating that their inactivation plays a role in theprogression of the tumor. This was evident both forwidespread methylation and at the single gene level(increasing frequencies of methylation from benignto malignant stages) with the exception of HOXA9,MAL, and MGMT. The lack of increase inmethylation frequencies between non-malignantadenomas and carcinomas for these three genesmay suggest that they are more important in theinitiation of cancer, rather than in progression.These genes in addition to ADAMTS1 were alsohypermethylated in comparable frequencies amongMSS and MSI carcinomas. These observations, andthe fact that the separation of the MSI- and MSSpathwayis thought to occur early in colorectaltumorigenesis suggest that alterations of the fourgenes represent early events. ADAMTS1 is believedto be an inhibitor of both angiogenesis andendothelial proliferation,[25] features commonlyactivated in cancer, as a tumor must turn onangiogenesis in order to grow larger than 1-2mm 3 [26]. Members of the HOX gene family areshown to be commonly altered in several cancers,and to the best of our knowledge, this is the firstreport of HOXA9 methylation in colorectalneoplasms. HOXA9 methylation has receivedincreasing interest in recent time as it is included inthe HOXA-cluster which harbors methylation over alarger area than just a single promoter, indicatingthat methylation may mimic genetic micro-deletionsand turn off a cluster of genes rather than just oneat the time, i.e. yet another example of long rangeepigenetic silencing.[27-29]. MAL is involved in T-cell differentiation, especially in the late orintermediate stages.[30] It is also involved inFigure 4. Genetic and epigenetic changes in colorectal carcinomas with known microsatellite statusThe results are visualized according to genetic (top part of the figure) and epigenetic changes (lower part of the figure). Theresults are organized according to MSI, followed by BRAF-, KRAS-, TP53- and methylation-status of the MSI associated genes.5
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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[
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
Page 68 and 69: REFERENCES1. Breasted J (1930) The
Page 70 and 71: References29. Deng G, Chen A, Pong
Page 72 and 73: References57. Al-Sukhni W, Aronson
Page 74 and 75: References84. Kunkel TA (1993) Nucl
Page 76 and 77: ReferencesLeggett B, Levine J, Kim
Page 78 and 79: References133. Lind GE, Thorstensen
Page 80 and 81: References156. Meling GI, Lothe RA,
Page 82 and 83: ReferencesT, Song X, Day RH, Sledzi
Page 84 and 85: References196. Honda S, Haruta M, S
Page 86 and 87: ORIGINAL ARTICLESAPPENDIXAppendix I
Page 89 and 90: GASTROENTEROLOGY 2007;132:1631-1639
Page 91: Paper IbGuro E Lind, Terje Ahlquist
Page 94 and 95: Journal of Translational Medicine 2
Page 105: Paper IITerje Ahlquist, Guro E Lind
Page 108 and 109: BackgroundMost cases of colorectal
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 and 152: The test series included a low numb
Page 153 and 154: entering M-phase remains to be seen
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
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Critical Reviews TM in Oncogenesis,
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TARGET GENES OF MSI COLORECTAL CANC
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