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concomitant absence of transcript and proteinoccurs in small patches of crypt cells in unaffectedmucosa from sporadic colorectal carcinoma. DiagnMol Pathol 2006, 15:17-23.64. Ide T, Kitajima Y, Ohtaka K, Mitsuno M, Nakafusa Y,Miyazaki K: Expression of the hMLH1 gene is apossible predictor for the clinical response to 5-fluorouracil after a surgical resection in colorectalcancer. Oncol Rep 2008, 19:1571-1576.65. Hitchins MP, Lin VA, Buckle A, Cheong K, Halani N, KuS, Kwok CT, Packham D, Suter CM, Meagher A et al.:Epigenetic inactivation of a cluster of genesflanking MLH1 in microsatellite-unstable colorectalcancer. Cancer Res 2007, 67:9107-9116.66. Leung WK, To KF, Man EP, Chan MW, Bai AH, Hui AJ,Chan FK, Sung JJ: Quantitative detection ofpromoter hypermethylation in multiple genes in theserum of patients with colorectal cancer. Am JGastroenterol 2005, 100:2274-2279.67. Xiong Z, Wu AH, Bender CM, Tsao JL, Blake C,Shibata D, Jones PA, Yu MC, Ross RK, Laird PW:Mismatch repair deficiency and CpG islandhypermethylation in sporadic colonadenocarcinomas. Cancer Epidemiol Biomarkers Prev2001, 10:799-803.68. Muller HM, Oberwalder M, Fiegl H, Morandell M,Goebel G, Zitt M, Muhlthaler M, Ofner D, Margreiter R,Widschwendter M: Methylation changes in faecalDNA: a marker for colorectal cancer screening?Lancet 2004, 363:1283-1285.69. Chen WD, Han ZJ, Skoletsky J, Olson J, Sah J, MyeroffL, Platzer P, Lu S, Dawson D, Willis J et al.: Detectionin fecal DNA of colon cancer-specific methylationof the nonexpressed vimentin gene. J Natl CancerInst 2005, 97:1124-1132.70. Giovannucci E, Ogino S: DNA methylation, fieldeffects, and colorectal cancer. J Natl Cancer Inst2005, 97:1317-1319.71. Feinberg AP, Ohlsson R, Henikoff S: The epigeneticprogenitor origin of human cancer. Nat Rev Genet2006, 7:21-33.Additional materialAdditional file 1:File format: DOCTitle: Supplementary informationDescription: Methodological details which are not crucial forthe understanding of the work, as well as Additional figurelegends.Additional file 2:File format: JPGTitle: Titration of methylated DNA template illustrates thescoring thresholds for the methylation-specific polymerasechain reaction.Description: Determination of scoring thresholds is visualizedby a titration series of the RUNX3 gene.Additional file 3:File format: XLSTitle: PCR primers used for methylation-specific PCR andmicrosatellite instability analyses.Description: Information on primers and PCR detailsAdditional file 4:File format: XLSTitle: Genetic and epigenetic raw data.Description: Raw data from all analyses are listed for eachtumor included.Additional file 5:File format: XLSTitle: Summarized methylation raw data.Description: Methylation frequencies are presented for eachof the eleven analyzed genes in the 4 different sample typesaccording to what methylation level they exhibited (strong,weak or no methylation).Additional file 6:File format: JPGTitle: Comparison between MSP and quantitative MSP innormal mucosa samples.Description: Hypermethylation of was analyzed with bothnon-quantitative- and quantitative MSP. Here the results fromeach method are presented.Additional file 7:File format: XLSTitle: Correlation between methylated genes.Description: A correlation table including all analyzed forpromoter hypermethylation shown that genes commonlymethylated in MSI tumors are highly correlated.Additional file 8:File format: JPGTitle: Widespread methylation among normal colorectalsamples, adenomas, and carcinomas.Description: A histogram showing the total number ofmethylated genes per sample in non-cancerous normalmucosa, normal mucosa taken in distance from a primarytumor, adenomas, and carcinomas stratified according toMSI status.10
Paper IIITerje Ahlquist, Irene Bottillo, Stine A Danielsen, Gunn IMeling, Torleiv O Rognum, Guro E Lind, Bruno Dallapiccolaand Ragnhild A Lothe.RAS signaling in colorectal carcinomas through alterationsof RAS, RAF, NF1 and/or RASSF1A.Neoplasia. 2008. Jul;10(7):680-6
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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
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 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 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
Page 163 and 164: Critical Reviews TM in Oncogenesis,
Page 165 and 166: TARGET GENES OF MSI COLORECTAL CANC
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TARGET GENES OF MSI COLORECTAL CANC
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